A Tough Egg to Crack

Portal hypertension arises when there is resistance to flow in the portal venous system. It is defined as a pressure gradient greater than 5 mmHg between the portal vein and the intra-abdominal portion of the inferior vena cava.¹ Clinicians are familiar with the manifestations of portal hypertension – portosystemic shunting leading to encephalopathy and variceal hemorrhage, ascites, and splenomegaly with thrombocytopenia – because of their close association with cirrhosis. In developed countries, cirrhosis accounts for over 90% of cases of portal hypertension.¹ In the remaining 10%, conditions such as portal vein thrombosis primarily affect the portal vasculature and increase resistance to portal blood flow while leaving hepatic synthetic function relatively spared (Figure 3). Therefore, cirrhosis cannot be inferred with certainty from signs of portal hypertension alone.

Liver biopsy is the gold standard for the diagnosis of cirrhosis, but this method is increasingly being replaced by noninvasive assessments of liver fibrosis, including imaging and scoring systems.² Clinicians often infer cirrhosis from the combination of a known cause of liver injury, abnormal liver biochemical tests, evidence of liver dysfunction, and signs of portal hypertension.³ However, when signs of portal hypertension are present, but liver dysfunction cannot be established on physical exam (eg, palmar erythema, spider nevi, gynecomastia, and testicular atrophy) or laboratory testing (eg, low albumin, elevated INR, and elevated bilirubin), noncirrhotic causes of portal hypertension should be considered. In this case, the biopsy showed vascular changes that suggested impaired venous inflow without bridging fibrosis, which pointed to NCPH.

NCPH is categorized based on the location of resistance to blood flow: prehepatic (eg, portal vein thrombosis), intrahepatic (eg, schistosomiasis), and posthepatic (eg, right-sided heart failure).¹ In our patient, the dilated portal venules (inflow) in the presence of normal hepatic vein outflow suggested an increased intrahepatic resistance to blood flow. This finding excluded a causal role of the portal vein thrombosis and prompted testing for schistosomiasis.

Schistosomiasis affects more than 200 million people worldwide and is prevalent in Sub-Saharan Africa, South America, Egypt, China, and Southeast Asia.^4,5 Transmission occurs in fresh water, where the infectious form of the parasite is released from snails.^4,6 Schistosome worms are not found in the United States, but as a result of immigration and travel, more than 400,000 people in the United States are estimated to be infected.⁵

Chronic schistosomiasis develops from the host’s granulomatous reaction to schistosome eggs whose location (depending on the species) leads to genitourinary, intestinal, hepatic, or rarely, neurologic disease.⁶ Hepatic schistosomiasis arises when eggs released in the portal venous system lodge in small portal venules and cause granulomatous inflammation, periportal fibrosis, and microvascular obstruction.⁶ The resultant portal hypertension develops insidiously, but the architecture and synthetic function of the liver is maintained until the very late stages of disease.^6,7 Pulmonary hypertension can arise from the embolization of eggs to the pulmonary arterioles via portosystemic collaterals.

The demonstration of eggs in stool is the gold standard for the diagnosis of hepatic schistosomiasis, which is most commonly caused by Schistosoma mansoni and S. japonicum.⁷ Serologic assays provide evidence of infection or exposure but may cross-react with other helminths. Liver biopsy may reveal characteristic histopathologic findings, including granulomatous inflammation, distorted vasculature, and the deposition of collagen deposits in the periportal space, leading to “pipestem fibrosis.”^8,9 If eggs cannot be detected on stool or histology, then serology, secondary histologic changes, and sometimes PCR are used to diagnose hepatic schistosomiasis. In our patient, the epidemiology, Schistosoma antibody titer, pulmonary hypertension, and liver biopsy with granulomatous inflammation, periportal fibrosis, and intrahepatic portal venule dilation were diagnostic of hepatic schistosomiasis.

The recurrent episodes of confusion which resolved with lactulose therapy were suggestive of hepatic encephalopathy, which results from shunting and accumulation of neurotoxic substances that would otherwise undergo hepatic metabolism.¹⁰ Clinicians are most familiar with hepatic encephalopathy in cirrhosis, where multiple liver functions – synthesis, excretion, metabolism, and circulation – simultaneously fail. NCPH represents a scenario where only the circulation is impaired, but this is sufficient to cause the portosystemic shunting that leads to encephalopathy. Our patient’s recurrent hepatic encephalopathy, despite adherence to lactulose and rifaximin and its resolution after praziquantel treatment, underscores the importance of addressing the underlying cause of portosystemic shunting.Associating portal hypertension with cirrhosis is efficient and accurate in many cases. However, when specific manifestations of cirrhosis are lacking, clinicians must decouple this association and pursue an alternative explanation for portal hypertension. The presence of some intrahepatic pathology (from schistosomiasis) but no cirrhosis made this case a particularly tough egg to crack.