Deadly intersection: Schistosomiasis, hepatopulmonary syndrome, and cirrhosis

Abstract

In this editorial, we comment on the article by Rolim et al in World Journal of Hepatology, which highlights the impacts of hepatopulmonary syndrome (HPS) related to schistosomiasis in patients with and without cirrhosis. Schistosomiasis, a parasitic disease affecting millions worldwide, frequently leads to portal hypertension. Its outcomes are more devastating in cirrhosis than in non-cirrhotic portal hypertension, due to the complex interplay between cirrhosis and HPS, a severe pulmonary vascular complication. Cirrhosis distorts hepatic architecture, impairs portal blood flow, and triggers systemic vascular changes. Schistosomiasis exacerbates portal hypertension and inflammation, further injuring the liver. In non-cirrhotic portal hypertension, significant vascular resistance occurs, but preserved liver function mitigates systemic effects. In contrast, cirrhosis amplifies hypoxia, worsens pulmonary shunting, and predisposes patients to respiratory failure, infection, and death. In a retrospective study of 113 patients, Rolim et al found that cirrhosis had an impact on mortality, yet the presence of HPS did not significantly affect survival. While cirrhosis worsening outcomes are anticipated, HPS should theoretically worsen survival by impairing oxygenation. Early diagnosis, parasite control, and managing cirrhosis-related complications are critical for schistosomiasis-related liver disease. Understanding these differences underscores the importance of integrating liver health into global schistosomiasis management strategies.

Key Words: Schistosomiasis; Portal hypertension; Hepatopulmonary syndrome; Survival; Mortality; Non-cirrhotic portal hypertension

Core Tip: Schistosomiasis, hepatopulmonary syndrome, and cirrhosis represents a perfect storm of pathophysiological complexity which can significantly worsen survival in those infected and with liver disease. Diagnostic and therapeutic challenges abound in disproportionately affected resource-limited settings where advanced imaging, pulmonary function testing, and liver transplantation may be scarce or unavailable.

INTRODUCTION

Schistosomiasis is one of the most prevalent parasitic diseases worldwide, disproportionately affecting populations in resource-limited settings[1-3]. As a chronic infection caused by Schistosoma species, it may lead to complications such as portal hypertension in the absence of cirrhosis, known as non-cirrhotic portal hypertension (NCPH). Although NCPH is an expected complication of chronic schistosomiasis, the prognosis becomes markedly worse when schistosomiasis coexists with cirrhosis and hepatopulmonary syndrome (HPS)[4,5].

THE PATHOPHYSIOLOGICAL COMPLEXITY OF SCHISTOSOMIASIS AND PORTAL HYPERTENSION

As highlighted by Rolim et al[6], schistosomiasis-induced portal hypertension primarily arises from granulomatous inflammation and fibrosis surrounding the presinusoidal portal veins. Eggs from S. japonicum and S. mansoni can travel from the mesenteric veins to the portal circulation, lodging in smaller portal branches and inciting periportal granuloma formation. In early stages, the hepatic venous pressure gradient remains normal, but in severe cases, extensive periportal fibrosis develops, leading to complications such as portal hypertension, varices, and splenomegaly. Unlike cirrhosis, which is characterized by widespread architectural distortion of the liver, NCPH allows for relatively preserved hepatic synthetic function. However, in endemic regions, patients with chronic schistosomiasis often face additional liver insults, including viral hepatitis, alcohol use, or metabolic disorders, which accelerate the progression to cirrhosis[1-5].

When cirrhosis develops alongside schistosomiasis, the liver’s ability to compensate for vascular resistance becomes severely impaired. This exacerbates portal hypertension, leading to a higher rate of complications such as variceal bleeding, ascites, and encephalopathy[5,6]. Moreover, cirrhosis is associated with systemic inflammation, oxidative stress, and endothelial dysfunction, creating a fertile ground for the development of HPS[7,8].

HPS IN SCHISTOSOMIASIS

As Rolim et al[6] describe, HPS is a severe pulmonary vascular disorder characterized by intrapulmonary vasodilation and impaired oxygenation in the context of chronic liver disease or portal hypertension. The development of HPS in schistosomiasis-related cirrhosis significantly worsens the clinical course. Several pathophysiological mechanisms converge to drive this progression:

First, cirrhosis increases systemic inflammatory cytokine release, which leads to an overproduction of nitric oxide overproduction. This, in turn, leads to pulmonary vasodilation and increases intrapulmonary shunting, severely compromising oxygen exchange[7,8].

Second, the chronic hypoxia observed in HPS triggers compensatory mechanisms that further strain both the pulmonary and cardiovascular systems. Hypoxia-induced angiogenesis exacerbates shunting and perpetuates oxygenation deficits[9].

Finally, Schistosomiasis-induced immune activation and granulomatous inflammation intensify the systemic inflammatory burden, which further amplifies the respiratory and vascular challenges posed by HPS[10].

In non-cirrhotic schistosomiasis, while portal hypertension is present, the liver’s preserved function mitigates systemic inflammation and hypoxia, reducing the likelihood of HPS progression. By contrast, in cirrhotic patients, impaired hepatic clearance of inflammatory mediators exacerbates vascular dysfunction, creating a deadly feedback loop between the liver and lungs[5-10].

CLINICAL AND PUBLIC HEALTH IMPLICATIONS

The findings from Rolim et al[6] emphasize the profound implications that schistosomiasis, cirrhosis, and HPS have on patient outcomes and healthcare systems in endemic regions. Current therapeutic options for schistosomiasis focus on antiparasitic agents like praziquantel, which effectively eliminates the parasite but does not reverse established fibrosis or portal hypertension[3]. For HPS, oxygen therapy and liver transplantation remain the only definitive treatments, with transplantation offering the dual benefit of resolving both HPS and advanced liver disease[11].

One unexpected finding from Rolim et al[6] was that cirrhosis had an impact on mortality, while HPS did not. This is inconsistent with existing knowledge of the effect of HPS on mortality, which suggests that mortality rates are significantly higher in patients with cirrhosis-related HPS compared to those with NCPH. This discrepancy highlights the importance of early detection and aggressive management of complications. As the authors explain, several factors may explain this incongruent finding, such as retrospective data collection, small sample size, and potential inaccuracies in diagnostic criteria for HPS. Future studies addressing these limitations are needed to better understand the impact of HPS in the presence of cirrhosis and schistosomiasis.

THE WAY FORWARD: INTEGRATED MANAGEMENT STRATEGIES

A multidisciplinary approach is essential to address the deadly intersection of schistosomiasis, HPS, and cirrhosis. Public health initiatives aimed at reducing schistosomiasis transmission, such as mass drug administration, improved sanitation, and safe water access, remain critical[3]. Additionally, enhanced screening for portal hypertension, liver dysfunction, and early HPS in schistosomiasis patients could enable timely intervention, potentially reducing morbidity. Research into anti-fibrotic agents, immunomodulators, and pulmonary vasodilators offers hope for improving outcomes in advanced cases. Furthermore, strengthening infrastructure and expanding access to transplantation in endemic regions could significantly alter the prognosis for patients with this lethal triad.

CONCLUSION

The intersection of schistosomiasis, HPS, and cirrhosis represents a perfect storm of pathophysiological complexity. Diagnostic and therapeutic challenges abound in disproportionately affected resource-limited settings where advanced imaging, pulmonary function testing, and liver transplantation may be scarce or unavailable, leaving many vulnerable patients without viable options. By advancing our understanding of these conditions and fostering global efforts to improve prevention, diagnosis, and treatment, we can mitigate the devastating impact of this deadly triad and save countless lives.