Liver disease in Egypt: Hepatitis C superseded schistosomiasis as a result of iatrogenic and biological factors

Authors

  • G. Thomas Strickland

    Corresponding author
    1. International Health Division, Department of Epidemiology & Preventive Medicine, University of Maryland School of Medicine, Baltimore, MD
    • International Health Division, University of Maryland School of Medicine, Suite 100 Howard Hall, 660 West Redwood Street, Baltimore, MD 21201
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    • fax: 410-706-8013


  • Potential conflict of interest: Nothing to report.

Abstract

In Egypt, schistosomiasis was traditionally the most important public health problem and infection with Schistosoma mansoni the major cause of liver disease. From the 1950s until the 1980s, the Egyptian Ministry of Health (MOH) undertook large control campaigns using intravenous tartar emetic, the standard treatment for schistosomiasis, as community-wide therapy. This commendable effort to control a major health problem unfortunately established a very large reservoir of hepatitis C virus (HCV) in the country. By the mid-1980s, the effective oral drug, praziquantel, replaced tartar emetic as treatment for schistosomiasis in the entire country. This both reduced schistosomal transmission and disease and interrupted the “occult” HCV epidemic. It was evident when diagnostic serology became available in the 1990s that HCV had replaced schistosomiasis as the predominant cause of chronic liver disease. Epidemiological studies reported a high prevalence and incidence of HCV, particularly within families in rural areas endemic for schistosomiasis. Clinical studies showed 70% to 90% of patients with chronic hepatitis, cirrhosis, or hepatocellular carcinoma had HCV infections. Co-infections with schistosomiasis caused more severe liver disease than infection with HCV alone. Schistosomiasis was reported to cause an imbalance in HCV-specific T-cell responses leading to increased viral load, a higher probability of HCV chronicity, and more rapid progression of complications in co-infected persons. As complications of HCV usually occur after 20 years of infection, the peak impact of the Egyptian outbreak has not yet occurred. Efforts have been initiated by the Egyptian MOH to prevent new infections and complications of HCV in the estimated 6 million infected persons. (HEPATOLOGY 2006;43:915–922.)

The Nile River has been an epicenter for schistosomiasis since antiquity. In 1980, an estimated 10% of the 200 million persons infected with Schistosoma were Egyptians.1, 2 Two of the three most important human species of Schistosoma are endemic in Egypt: S. haematobium, which primarily causes disease in the urinary tract, and S. mansoni, which principally causes morbidity in the gut and liver. In 1851, Theodore Bilharz, for whom the clinical disease bilharziasis was named, first described the trematode during autopsy of a patient in Cairo. Leiper, working in Egypt from 1913 to 1918, established the connection between skin exposure to canal water and infection, confirmed the life cycle with the snail as the intermediate host, and that the terminal and lateral spine eggs came from separate species. The association of chronic liver disease, characterized by hepatosplenomegaly and portal hypertension with schistosomiasis mansoni was first made by William St. Claire Symmers, also while working at Kasr El Aini Hospital in Cairo, when he described clay pipe stem fibrosis in 1904.3

Urinary schistosomiasis due to S. haematobium was the predominant form in Egypt until 35 or 40 years ago. This species was found in ancient mummies, and 200 years ago Napoleonic documents mentioned “menstruating males of Egypt,” attesting to the frequency of hematuria.1 During his extensive country-wide survey for schistosomiasis 70 years ago, John A. Scott showed that S. haematobium was the only species transmitted in Middle and Upper Egypt, south of Cairo, and both it and S. mansoni were endemic in the Nile delta (Fig. 1).4 With the completion of the Aswan High Dam in the 1960s, the flow of the Nile was controlled and summer floods no longer occurred. This provided a selective advantage to the intermediate host for S. mansoni, Biomphalaria alexandrina, over the host for S. haematobium, Bulinus truncatus. By 1979, an inversion from Scott's survey 50 years earlier in prevalence of S. mansoni and S. haematobium (from 3% and 73% to 74% and 2%) along with the snail intermediate hosts in a Nile delta community was reported.5 Increased prevalence and intensity of infection with S. mansoni in the populous Nile delta where exposure to canal water was occurring in several million farmers and their families resulted in an increase in schistosomal periportal fibrosis.

Figure 1.

Map of Egypt showing prevalence (in percentages) of Schistosoma haematobium (Sh), S. mansoni (Sm) infection in the upper-central and northeast Nile Delta, the western and southern Nile Delta (both Lower Egypt); Middle Egypt, along the Nile Valley south of Cairo to Assiut; and Upper Egypt along the Nile from Assiut to Aswan during J. A. Scott's nation-wide survey in 1935/64 and during the SRP nation-wide survey during 1991-1992.7 The prevalence of anti-HCV during 1991/2 in these same areas is also shown as adapted from Frank et al.6 and other sources.

The first effective therapy for schistosomiasis, using multiple intravenous injections of tartar emetic, was introduced in 1918. This was the treatment of choice for American troops infected with S. japonicum during the re-invasion of the Philippines in 1944; tartar emetic remained the standard therapy for S. mansoni and S. japonicum for over 60 years.3 The single-dose, safe and effective oral drug, praziquantel, did not become readily available in Egypt until the 1980s.3, 6

The Outbreak: Extensive Campaigns to Control Schistosomiasis

Egypt has had strong academic tropical medicine programs. Because many “tropical” medical problems confronting physicians were due to complications of hepatic fibrosis and cirrhosis due to schistosomiasis and chronic viral infections, some prominent Egyptian hepatologists established clinical liver centers. Their influence focusing attention on the national importance of schistosomiasis led to organized programs to control the trematode's transmission and the disease it causes.

Intravenous tartar emetic was used in large campaigns to control schistosomiasis as early as 1921. The Egyptian Ministry of Health (MOH) during an assessment of the country's health problems in the mid-20th century decided they had the resources to undertake large mass treatment campaigns in rural communities in which a large proportion of the population were screened for parasites and treated. A 10- to 12-dose course of tartar emetic intravenous injections was offered to everyone detected to have Schistosoma ova in stool or urine during these community screening campaigns.6 During these community-based treatment campaigns, as well as in rural health clinics and other health facilities, millions of Egyptians were treated with intravenous tartar emetic from the 1950s until the 1980s. The dangers of exposure to human blood were unappreciated, and disposable needles and syringes were unavailable 40 to 50 years ago. Emphasis was placed on control of what the Egyptian MOH thought was their biggest health problem, schistosomiasis.

Frank et al.6 reported a direct relationship between parenteral treatment of schistosomiasis from 1961 to 1985 and the country-wide prevalence of antibodies to hepatitis C (anti-HCV) in 1995. Prevalence of anti-HCV was higher in Lower Egypt, where tartar emetic was used more extensively and several years longer to treat schistosomiasis mansoni, than it was in Upper Egypt, where the switch to oral drugs for schistosomiasis hematobia began in the 1970s (Fig. 1). As many people were infected with hepatitis B virus (HBV) as with HCV during these schistosomiasis control campaigns. However, HBV caused chronic infections in 5% or less of infected children and adults, whereas HCV infection persisted in 70% to 80%.6 Egypt has universal childhood immunization for HBV, and an estimated 2% or fewer Egyptians currently have chronic HBV infections.

Abbreviations

MOH, Ministry of Health; HBV, hepatitis B virus; PPF, periportal fibrosis; HCV, hepatitis C virus; anti-HCV, antibodies to hepatitis C virus; Th1 and Th2, SRP, Schistosomiasis Research Project; CMI, cell-mediated immunity; PY, patient-years; HCC, hepatocellular carcinoma; NHL, non-Hodgkin's lymphoma.

The Switch: from Schistosomiasis to Hepatitis C

In the mid-1990s, the United States Agency for International Development funded a very large nation-wide project to conduct research on schistosomiasis in Egypt: The Schistosomiasis Research Project (SRP).7 The SRP included basic research on snails; immune responses and vaccine development; health education, sociological and ecological factors associated with transmission; diagnosis and clinical management of complications; and epidemiology. American “schistosomologists” worked alongside Egyptian scientists to better understand and develop mechanisms to control schistosomiasis in the country. These scientists examined 89,180 subjects from nine rural governorates in their communities. The most important morbidity assessment tool was abdominal ultrasound.

What was learned from these studies? S. haematobium had left the Nile delta, retreating to Middle and Upper Egypt, and the prevalence, intensity, and morbidity of infection with that species was low in these endemic areas (Fig. 1).7S. mansoni had spread into Middle Egypt to the Fayoum oasis8, 9 and Minya.10 However, although prevalence of S. mansoni was not much lower in many areas (Fig. 1), the intensity of infection and morbidity was much less. Because morbidity is directly related to intensity of infection, more advanced stages of the characteristic ultrasound lesion of schistosomal hepatic fibrosis (Fig. 2)11, 12 was present less frequently than expected.7

Figure 2.

Abdominal ultrasound showing hepatic periportal fibrosis in a patient with S. mansoni infection on the left as drawn on the right.

A simplified explanation for the hepatic pathology caused by schistosomiasis is that eggs are swept into and trapped in the portal triads. Cell-mediated immunity (CMI) triggered by soluble egg antigens led to formation of granulomas and fibrosis almost exclusively in portal tracks (Fig. 3). The less than expected ultrasound prevalence of periportal fibrosis was believed to result from the availability and use of the antischistosomal drug, praziquantel, in the MOH's health units since 1982.13 Infected people were regularly receiving praziquantel that either cleared or markedly reduced the intensity of their infections. This, in turn, prevented development of hepatic lesions. However, these people often were reinfected. Therefore, many had a few Schistosoma ova in their stools in the absence of the complications of schistosomiasis.3

Figure 3.

Schistosoma mansoni egg granuloma in the liver. The tissue reaction around an ova trapped in the portal triad consists of macrophages, lymphocytes, and fibroblasts.

However, many persons with enlarged livers and spleens, portal vein dilatation, and bright or coarse echo patterns compatible with chronic hepatitis and fibrosis were detected during ultrasound.7 By that time many in these rural villages were known to have chronic HCV infections.14–16

Now: the Large Reservoir of Chronic Hepatitis C Infection

Estimates of HCV prevalence in Egypt range from 11% to 14% with 8 to 10 million having anti-HCV and 5 to 7 million having active infections (i.e., HCV-RNA positive). HCV prevalence is directly associated with the amount of intravenous tartar emetic used to control schistosomiasis in the geographic areas (Fig. 1). The lowest rates are in Cairo and Alexandria (<8%), highest in rural areas of the Nile Delta [Lower Egypt (>15%)], and intermediate (8%-16%) in rural areas along the Nile south of Cairo (Middle and Upper Egypt).6, 14–18 Prevalence increases with age and is higher in males. This “cohort effect” provides further evidence that inhabitants of rural communities endemic for schistosomiasis had exposures leading to HCV infections more than 20 years ago (Fig. 4).

Figure 4.

Age- and gender adjusted prevalence of anti-HCV among 4,000 inhabitants of a community in the Nile delta having an overall 24% prevalence of HCV antibodies.17 This curve is typical for cohort effect in which adults over the age of 25, having steep increases in anti-HCV rates, were exposed during previous campaigns to control schistosomiasis with intravenous tartar emetic.

The huge reservoir of HCV among older Egyptians makes exposure to human blood and blood products much more dangerous than in the United States. Blood transfusion, before screening for HCV was started in the early 1990s, infected many Egyptians, and accidental needle sticks of health care workers and the reuse of needles and syringes are much more likely to transmit HCV in Egypt than in most circumstances in the United States. In addition, because of its expense, prolonged course, toxicity, and difficulty taking the treatment regimen, and low therapeutic response rate, only a small proportion of Egyptians with chronic HCV have received antiviral therapy. The sustained viral response rate to pegylated interferon and ribavirin in Egyptians infected with genotype 4 HCV, which causes approximately 90% of infections in the country, ranges between 29% and 69%, with the better response in those treated 36 weeks or longer.19, 20 Therefore, current antiviral treatment regimens will have little impact on the HCV reservoir of infection.

Risk Factors for Hepatits C Infection in Egypt

Extensive studies of both prevalent (in the past) and incident (present) transmission of HCV have been conducted. Cross-sectional studies of 10,000 subjects living in two rural communities with 9% and 24% prevalence of anti-HCV showed that age, male sex, parenteral therapy for schistosomiasis, blood transfusion, invasive medical procedures, injections, circumcision of boys by “informal” health care providers, and complicated birth deliveries were all risk factors for HCV in the past.17, 18, 21, 22 HCV infections congregated within families, with children being at increased risk if their parents were infected and spouses being at greater risk if their partner was infected, particularly in the case of husbands with HCV-infected wives.23 The risk of HCV infection was higher for children when their mothers were anti-HCV positive than when their fathers were positive and was higher when the parent had circulating HCV-RNA. For instance, 14 % (87/612) of children whose mothers had HCV-RNA were positive for anti-HCV, in comparison with 7% (28/401) whose parents only had anti-HCV, and 2.6% (38/1,537) whose parents were seronegative. Sequencing isolates from 13 families with parent(s) and children having HCV-RNA showed 10 of 18 had genetically similar viruses (Mohamed MK et al., unpublished observations).

The Egyptian MOH has initiated a countrywide program to prevent transmission of HCV and other blood-borne infections. Serological screening of all blood transfusions and health education efforts have reduced HCV transmission. A prospective study of current risk of infection has shown the strongest predictor of incident HCV was having an anti-HCV-positive family member. Among those that did, incidence was 5.8/1,000 person years (PY) compared (P < .001) with 1.0/1,000 PY. Twenty-seven of the 33 incident cases had an anti-HCV-positive family member. Parenteral exposures increased the risk of HCV but were not statistically significant; 67% of seroconverters were younger than 20 years old, and the highest incidence rate (14.1/1,000 PY) was in children younger than 10 living in households with an anti-HCV-positive parent in a Nile Delta village having a 24% anti-HCV prevalence.24 The mechanism for this increased risk in children of infected mothers is unknown. A hypothesis that needs testing is that a proportion of this transmission is due to some types of mother-to-child exposures, possibly from viral contaminated saliva, but these studies have yet to be done.

Magnitude of HCV-Caused Chronic Liver Disease in Egypt

Several clinical studies have demonstrated the importance of HCV in the causality of chronic liver disease in Egypt. Among 1,023 outpatients in the National Liver Institute, 73.5% had anti-HCV, compared with 16.4% with hepatitis B surface antigen.25 In the 100 among these patients who had liver biopsies, 89% had chronic hepatitis, cirrhosis, or hepatocellular carcinoma (HCC), and 84.3% of these had anti-HCV. A case-control study that compared 237 outpatients seen at the National Liver Institute (cases) with 212 gender- and age-matched neighbors who denied liver disease (controls) supported this belief that HCV is the predominant cause of liver disease and that there is a large occult reservoir of HCV-caused chronic liver disease in the country.26 Others also reported that HCV infection with genotype 4a was the main cause of chronic liver disease in 135 adult patients living in Alexandria27 and in 801 residents of a Nile Delta community.28

Case-control studies have shown that both HBV and HCV infection increase the risk of HCC (adjusted odds ratios of 3-13). Because the prevalence of infections with HCV in the country is so much higher than the prevalence of HBV infections, the attributable fraction of HCV (60%-70%) and the anti-HCV rate (75%-90%) has become the greatest risk factor for HCC in Egypt.29, 30 Just as is happening in the United States,31 prevalence of HCC is increasing in Egypt along with this increasing association with HCV.29,30 HCC is now one of the three most frequently diagnosed cancers in Egypt.32 Chronic HCV infection has also been associated with increased risk for B-cell non-Hodgkin's lymphoma (NHL). Egyptian patients with NHL were 2.3 times more likely to have HCV-RNA in their sera than matched controls.33

Concomitant Schistosomiasis and Hepatitis C Infections

As early as the 1970s, Egyptian tropical medicine physicians began to note almost half of their patients with schistosomiasis mansoni who developed cirrhosis with jaundice or ascites also had chronic infections with HBV.34 The relationship between HBV and hepatosplenic schistosomiasis was initially reported from Brazil, Egypt, and the Philippines.35–38 Ghaffar and colleagues39 reported a 12-month follow-up of adults from an area endemic for schistosomiasis mansoni admitted to a fever hospital with acute viral hepatitis.39 Among the 126 patients who had acute HBV infections, 19% having co-infections with S. mansoni were positive for hepatitis B surface antigen at 12 months, and many also had persistent splenomegaly. The authors proposed that chronic schistosomiasis favored the persistence of the HBV (and non-A, non-B hepatitis) infections, resulting in splenic enlargement.

Studies by Kamal and colleagues reported that Egyptian patients with co-infections have higher HCV-RNA titers, more advanced liver disease, more hepatic complications, and a greater mortality rate than those infected with only HCV.40 They also noted that patients with co-infections responded poorly to interferon therapy and had a higher relapse rate and higher HCV-RNA titers and more severe hepatic lesions than HCV patients not having concomitant schistosomiasis.41

Immune Responses Associated With Concomitant Infections

The clinical observations that chronic schistosomiasis may favor persistence of other infections led to a series of experiments in animal models that showed schistosomiasis upregulated thymus-dependent type 2 responses (Th-2) while downregulating Th-1 responses, leading to persistence of concomitant viral infections.42–44

Because resolution of HCV infections has been associated with a strong CD4+ and CD8+ Th-1 immune response,45, 46 it was reasonable to assume active schistosomal infections might lead to viral persistence and accelerated progression of hepatic complications caused by the cytokine imbalance in the microenvironment around the schistosomal hepatic granulomas (Fig. 3).

The reports by Kamal and colleagues support this.40, 41 She and her colleagues also conducted a prospective study of the HCV-specific CD4+ and cytokine responses in patients with acute HCV hepatitis, with or without S. mansoni co-infection. HCV-specific CD4+ proliferative responses and cytokine production in peripheral blood mononuclear cells were correlated with liver biopsy results. Whereas 5 of 15 patients with HCV alone recovered from acute HCV, all 17 patients with S. mansoni co-infection progressed to histologically proven chronic hepatitis. This was more rapid in co-infected patients who had strong Th-2 immune responses.47 In another publication, she and her colleagues compared HCV-specific peripheral CD4+ T-cell responses and cytokines in patients with chronic HCV alone with those with S. mansoni co-infection.48 An HCV-specific CD4+ proliferative response to at least one HCV antigen was detected in 73% of patients having only HCV infections, in comparison with only 8.6% of those with co-infections. Stimulation with HCV antigens produced a Th-1 cytokine profile in patients infected with HCV alone compared with a Th-2 predominance in patients co-infected with HCV and S. mansoni. In contrast, there was no difference in response to schistosomal antigens in patients infected with only S. mansoni or co-infected with both HCV and S. mansoni. The findings in these last two publications suggest the inability to generate an HCV-specific CD4+ Th-1 leads to persistence and severity of HCV in patients with S. mansoni co-infection.

This was further supported by a recent publication evaluating kinetics of intrahepatic HCV-specific CD4+ T-cell responses and their role in progression of fibrosis in both mono- and co-infected patients.49 As in the early studies, co-infected patients had a more rapid progression of HCV hepatic fibrosis than those infected with only HCV. Patients with HCV infection alone had stronger initial multispecific intrahepatic HCV-specific CD4+ Th-1 responses than the co-infected patients, who had either no responses or weak, narrowly focused responses. The rate of progression of fibrosis and the virus load inversely correlated with the intrahepatic HCV-specific CD4+ Th-1 responses. They concluded progression of liver fibrosis was also associated with failure to develop early, multispecific, HCV-specific CD4+ Th-1 responses.

We reported that immunosuppression with S. mansoni co-infections may not require this infection be active (i.e., having viable adult worms).50 We analyzed the core HCV-specific CD8+ T-cell responses in 44 donated blood units rejected because they had anti-HCV. Half also had anti-Schistosoma antibodies, which are more likely evidence of past, rather than present, infection in adult Egyptians who donate blood. HCV-specific CD8+ ELISPOT responses were examined using pools of 180 overlapping 9-mer peptides covering the core of HCV genotype 4a. Comparison of CD8+ T-cell responses in blood units positive for both anti-HCV and anti-Schistosoma with blood units positive only for anti-HCV showed a significant decrease in core-specific CD8+ T-cell interferon gamma, interleukin 4 (IL-4), and IL-10 responses. In contrast, there was no difference in CMI to PHA mitogen. We proposed antigens from hepatic schistosomal granulomas remaining in the liver after death of the adult worms (Fig. 3) could have stimulated the HCV-specific CMI suppression.

The Future: Hepatitis C in Egypt

Results of experiments in laboratory animals are often not repeated when studying humans. This was not the case in S. mansoni and HCV co-infections, because an imbalance in T-cell subsets with suppression of specific immune response to HCV antigens was detected in humans similar to that reported in coinfected animals. Furthermore, the immunological changes were directly associated with more severe and rapidly progressive HCV infections. However, these results need to be confirmed by others and accepted with caution before applying them to the general population. Although Egypt has a massive amount of morbidity associated with a very high prevalence of HCV and a large proportion of the population have been infected with both the virus and the trematode, complications of HCV do not appear to be as overwhelming as would be expected. In fact, many HCV-infected individuals were carrying out their daily activities in communities that were also endemic for schistosomiasis mansoni.14–18, 21, 22, 25–28

In conclusion, the large reservoir of infection in human blood increases the incidence of new HCV infections and encourages us to seek more information on how it is being transmitted to assist the Egyptian MOH in their preventive efforts. Children with HCV-infected parents are at particularly high risk and would benefit from both efforts to reduce exposure to HCV-contaminated blood and other biological fluids or to become immunized when a vaccine is available. Although the Egyptian HCV epidemic ended 25 years ago, the very high “silent” reservoir of infection makes HCV, instead of schistosomiasis, this country's most important public health problem. Clinical management of the estimated 5 to 7 million Egyptians with chronic HCV infections is also a national problem that will not be resolved until more effective, less toxic, and less expensive chemotherapeutic agents become available. Some HCV-infected Egyptians are paying for, or have insurance that covers, treatment with the currently available antiviral regimens. However, the Egyptian MOH has inadequate resources to provide treatment to the large segment of the population that would benefit from this therapy.

Acknowledgements

I am indebted to the several hundred Egyptian medical scientists, at all levels from student to professor, from whom I have learned a great deal. This includes in particular the late Professors Farid-Abdel-Wahab from Cairo University, Mohamed Ali Madwar and Yasin Ghaffar from Ain Shams University, and Professors Mohamed Nafeh and Ahmed Medhat from Assiut University, Gamal Esmat from Cairo University, Mohamed Abdel-Hamid from Minya University, Alaa Ismail from Ain Shams University, and the National Hepatology & Tropical Medicine Research Institute, and the former Minister and Undersecretary of Health, Ismail Sallam and Taha El-Khoby.

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