Introduction: Porto-sinusoidal vascular disease (PSVD) is an entity characterized by the absence of histologic liver cirrhosis and the detection of specific or non-specific histological findings, irrespective of the presence of portal hypertension (PHT). The pathogenesis remains poorly understood. Pulmonary arterial hypertension (PAH), independently of the presence of PHT, can be associated with an increase in central venous pressure, which can rarely lead to the development of downhill varices in the proximal esophagus. Case Presentation: A 53-year-old woman, with an unremarkable medical and pharmacological history, presented with a 3-day history of melena, epigastric pain and hematemesis. Physical examination revealed bilateral peripheral edema of the legs. Laboratory findings included severe anemia, normal hepatic enzymology, and NT-proBNP 1,748 pg/mL. Endoscopy showed large proximal esophageal varices and mild hypertensive gastropathy. A complete liver disease etiology panel was negative. Ultrasound showed an irregular liver surface, splenomegaly, and dilated supra-hepatic veins and inferior vena cava. Echocardiogram revealed significant cardiac valve and cavity abnormalities, especially on the right side, as well as moderate to severe PAH. Diuretics therapy was started with clinical improvement. Beta-blockers were suspended due to intolerance. There were no images suggestive of portosystemic collateralization on angiography. Re-evaluation endoscopy showed large but reduced esophageal varices, without red spots. Cardiopulmonary hemodynamic assessment revealed moderate PAH (40 mm Hg). Liver hemodynamic study revealed non-clinically significant sinusoidal PHT. Transjugular liver biopsy revealed nodular regenerative hyperplasia suggestive of PSVD. Discussion/Conclusion: The case was complex and presented diagnostic challenges, illustrating the uncommonly reported association between PSVD and porto-pulmonary hypertension and the importance of the transjugular liver biopsy and pressure measurements to confirm both diagnoses.

Introdução: A doença vascular porto-sinusoidal (PSVD) é uma entidade caracterizada pela ausência histológica de cirrose hepática e pela detecção de achados histológicos específicos ou inespecíficos, independentemente da presença de hipertensão portal (PHT). A sua fisiopatologia permanece pouco compreendida. A hipertensão arterial pulmonar (PAH), independentemente da presença de PHT, pode estar associada ao aumento da pressão venosa central, o que, raramente, pode levar ao desenvolvimento de varizes downhill no esófago proximal.Caso clínico: Mulher de 53 anos, sem antecedentes pessoais e farmacológicos de relevo, com quadro de melenas, epigastralgia e hematemeses com 3 dias de evolução. O exame físico revelou edema periférico bilateral dos membros inferiores. Os achados laboratoriais revelaram anemia grave, enzimologia hepática normal e NT-proBNP 1748 pg/mL. A endoscopia mostrou varizes esofágicas proximais grandes e gastropatia hipertensiva ligeira. Foi realizado um painel completo de etiologia de doença hepática, que não revelou alterações. A ultrassonografia mostrou uma superfície hepática irregular, esplenomegália e veias supra-hepáticas e veia cava inferior dilatadas. O ecocardiograma revelou alterações significativas nas válvulas e cavidades cardíacas, especialmente no lado direito, bem como PAH moderada a grave. A doente iniciou terapêutica diurética com melhoria clínica. A terapêutica com beta-bloqueantes foi suspensa por intolerância. Não se verificaram imagens sugestivas de colateralização portossistémica na angiografia. A endoscopia de reavaliação mostrou varizes esofágicas grandes, mas reduzidas em relação ao exame anterior, sem red spots. A avaliação hemodinâmica cardiopulmonar revelou PAH moderada (40 mm Hg). O estudo hemodinâmico hepático revelou PHT sinusoidal não clinicamente significativa. A biópsia hepática transjugular revelou hiperplasia regenerativa nodular sugestiva de PSVD.Discussão/Conclusão: Este caso apresentou elevada complexidade e múltiplos desafios diagnósticos, ilustrando a associação incomumente relatada entre PSVD e hipertensão porto-pulmonar e a importância da biópsia hepática transjugular e medições de pressão para confirmar ambos os diagnósticos.

Palavras ChaveDoença vascular porto-sinusoidal, Varizes downhill, Hipertensão arterial pulmonar, Estudo hemodinâmico hepático, Biópsia hepática transjugular

Portal hypertension (PHT) is the main clinical manifestation of advanced chronic liver disease. Clinically significant PHT (hepatic venous pressure gradient – HVPG ≥10 mm Hg) [1] predicts complications like variceal bleeding, ascites, jaundice, and encephalopathy [2‒4]. These can occur in the absence of cirrhosis (Table 1) [4, 5].

Table 1.

Causes of noncirrhotic portal hypertension [6]

Prehepatic 
 Portal vein thrombosis 
 Splenic vein thrombosis 
 Splanchnic arteriovenous fistula 
 Splenomegaly (e.g., from lymphoma, Gaucher’s disease*) 
Intrahepatic 
 Presinusoidal 
  Schistosomiasis* 
  Idiopathic noncirrhotic portal hypertension (including nodular regenerative hyperplasia) 
  Primary biliary cholangitis 
  Sarcoidosis* 
  Congenital hepatic fibrosis 
  Primary sclerosing cholangitis 
  Hepatic arteriopetal fistula 
  Adult polycystic liver disease 
  Arteriovenous fistulas 
  Autoimmune cholangiopathy 
  Vinyl chloride toxicity* 
  Neoplastic occlusion of the intrahepatic portal vein 
  Mineral oil granuloma* 
 Sinusoidal 
  Arsenic poisoning 
  Vinyl chloride toxicity* 
  Drugs (e.g., amiodarone, methotrexate) 
  Alcoholic liver disease* 
  Nonalcoholic fatty liver disease 
  Gaucher’s disease* 
  Zellweger syndrome 
  Viral hepatitis 
  Chronic Q fever 
  Schistosomiasis* 
  Amyloid or light-chain deposition in the space of Disse 
  Acute hepatic injury 
  Mastocytosis 
  Agnogenic myeloid metaplasia 
  Acute fatty liver of pregnancy 
 Postsinusoidal 
  Sinusoidal obstruction syndrome (venoocclusive disease) 
  Budd-chiari syndrome* 
  Alcoholic liver disease* 
  Chronic radiation injury 
  Vitamin A toxicity 
  Epithelioid hemangioendothelioma 
  Angiosarcoma 
  Sarcoidosis* 
  Mycobacterium avium or M. intracellulare infection 
  Mineral oil granuloma* 
Posthepatic 
 IVC obstruction (e.g., Budd-Chiari syndrome*) 
 Cardiac disease (constrictive pericarditis, restrictive cardiomyopathy) 
Prehepatic 
 Portal vein thrombosis 
 Splenic vein thrombosis 
 Splanchnic arteriovenous fistula 
 Splenomegaly (e.g., from lymphoma, Gaucher’s disease*) 
Intrahepatic 
 Presinusoidal 
  Schistosomiasis* 
  Idiopathic noncirrhotic portal hypertension (including nodular regenerative hyperplasia) 
  Primary biliary cholangitis 
  Sarcoidosis* 
  Congenital hepatic fibrosis 
  Primary sclerosing cholangitis 
  Hepatic arteriopetal fistula 
  Adult polycystic liver disease 
  Arteriovenous fistulas 
  Autoimmune cholangiopathy 
  Vinyl chloride toxicity* 
  Neoplastic occlusion of the intrahepatic portal vein 
  Mineral oil granuloma* 
 Sinusoidal 
  Arsenic poisoning 
  Vinyl chloride toxicity* 
  Drugs (e.g., amiodarone, methotrexate) 
  Alcoholic liver disease* 
  Nonalcoholic fatty liver disease 
  Gaucher’s disease* 
  Zellweger syndrome 
  Viral hepatitis 
  Chronic Q fever 
  Schistosomiasis* 
  Amyloid or light-chain deposition in the space of Disse 
  Acute hepatic injury 
  Mastocytosis 
  Agnogenic myeloid metaplasia 
  Acute fatty liver of pregnancy 
 Postsinusoidal 
  Sinusoidal obstruction syndrome (venoocclusive disease) 
  Budd-chiari syndrome* 
  Alcoholic liver disease* 
  Chronic radiation injury 
  Vitamin A toxicity 
  Epithelioid hemangioendothelioma 
  Angiosarcoma 
  Sarcoidosis* 
  Mycobacterium avium or M. intracellulare infection 
  Mineral oil granuloma* 
Posthepatic 
 IVC obstruction (e.g., Budd-Chiari syndrome*) 
 Cardiac disease (constrictive pericarditis, restrictive cardiomyopathy) 

IVC, inferior vena cava.

*May cause noncirrhotic portal hypertension via several mechanisms.

Porto-sinusoidal vascular disease (PSVD) is a rare cause of PHT and is characterized by absence of liver cirrhosis and detection of specific or non-specific histological findings, irrespective of PHT [4, 7]. The presence of other causes of liver disease does not rule it out [4]. The pathogenesis remains poorly understood. Drugs, hematologic and infectious diseases, prothrombotic and immune disorders, and genetic factors have been associated [4, 8]. Imaging and non-invasive tests like liver (LSM) and spleen stiffness measurements (SSM) have a diagnostic role, but hemodynamic study with transjugular liver biopsy (TJLB) is crucial to assess HVPG and obtain liver tissue for histopathology [4].

Pulmonary arterial hypertension (PAH), characterized by elevated mean pulmonary artery pressure (PAP) (>25 mm Hg), is most commonly idiopathic, but may be associated with PHT (porto-pulmonary hypertension-PoPH). PAH and PoPH are histologically indistinguishable [9‒11].

PAH can be associated with increased central venous pressure [12], which can rarely lead to downhill varices in the proximal esophagus [13]. Blood flows from the superior vena cava to the esophageal venous plexus [14]. It is a rare etiology for hematemesis (0.1%) [13], due to their localization in the proximal esophageal submucosa [14]. Treatment should be directed at the vascular obstruction’s underlying cause [15, 16].

A 53-year-old-woman presented with a 3-day history of melena, epigastric pain and hematemesis. Medical history included obesity (BMI 34 kg/m2) and peripheral vascular disease treated with bioflavonoids. She denied fever, jaundice, choluria, alcohol consumption, and liver disease. She also denied taking nonsteroidal anti-inflammatory drugs, antiplatelets, or anticoagulants.

Physical examination was unremarkable except for bilateral peripheral edema of the legs. Laboratory findings included severe iron deficiency anemia (hemoglobin 4.1 g/dL), platelet count 188 × 109/L, INR 1.13, albumin 4.6 g/dL, normal hepatic enzymes, and raised NT-proBNP (1,748 pg/mL).

Endoscopy showed large proximal esophageal varices, without red spots, and mild portal hypertensive gastropathy (shown in Fig. 1). Abdominal ultrasound revealed slight hepatomegaly with irregular liver surface; no focal lesions; marked echogenicity of the fibrovascular axes and hilum; ectasia of the inferior vena cava (IVC) and hepatic veins; no portal vein abnormalities; mild splenomegaly (14 cm). A comprehensive chronic liver disease etiology panel was negative.

Fig. 1.

Large proximal esophageal varices without red spots.

Fig. 1.

Large proximal esophageal varices without red spots.

Close modal

Echocardiograms revealed good systolic function; dilated right heart cavities; mild aortic and mitral insufficiency; moderate tricuspid and pulmonary insufficiency; severe PAH. Furosemide and spironolactone were instituted, with clinical improvement. Perindopril and carvedilol were introduced but the latter was suspended due to intolerance (symptomatic hypotension, lipothmia, platypneia).

Coronary angiography ruled out coronary disease. Thoraco-abdominal computed tomography angiography showed enlargement of the pulmonary artery with no evidence of thrombus, as well as absence of porto-systemic collateralizaion, portal vein thrombosis, and structural lung disease. A re-evaluation endoscopy showed large but reduced esophageal varices, without red spots (shown in Fig. 2).

Fig. 2.

Large esophageal varices, reduced in size in comparison to the previous evaluation, without red spots.

Fig. 2.

Large esophageal varices, reduced in size in comparison to the previous evaluation, without red spots.

Close modal

Cardiopulmonary and hepatic hemodynamic (HH) study revealed moderate PAH (mean PAP 40 mm Hg, pulmonary capillary wedge pressure 5 mm Hg) and HVPG of 6 mm Hg, which was suggestive of non-clinically significant sinusoidal PHT (shown in Fig. 3). There were no hepatic vein-to-vein communicants detected during the HH study.

Fig. 3.

Wedged supra-hepatic vein pressure measurement with Fogharty balloon catheter.

Fig. 3.

Wedged supra-hepatic vein pressure measurement with Fogharty balloon catheter.

Close modal

The biopsy fragments obtained with TJLB measured 48 mm in length. Histopathological evaluation revealed nodular regenerative hyperplasia (NRH) and obliterated portal veins, without fibrosis, suggesting PSVD (shown in Fig. 4).

Fig. 4.

Liver histological features suggesting PSVD.

Fig. 4.

Liver histological features suggesting PSVD.

Close modal

She was discharged on diuretics, with improvement of peripheral edema. Additionally, she was medicated with macitentan and tadalafil. She underwent variceal bleeding prophylaxis with endoscopic band ligation.

As previously stated, diagnosis of PSVD requires histological confirmation and exclusion of liver cirrhosis [4, 17]. HH study with TJLB is often performed due to thrombocytopenia, and was key in the diagnostic process [18]. In PSVD, HVPG is normal/slightly elevated and often <10 mm Hg, due to pre-sinusoidal PHT [4, 17, 19] and presence of vena-vena communications [4, 19]. Hence, HVPG is often not correlated with events like variceal bleeding/ascites [17].

Specific histologic features include obliterative portal venopathy, NRH (present in this case) and incomplete septal cirrhosis/fibrosis [4, 17]. NRH is a nodular parenchymal transformation with hyperplastic hepatocytes surrounded by atrophic hepatocytes without fibrosis [20].

Abdominal ultrasound features of PSVD include normal/inhomogeneous liver with irregular surface; right hepatic lobe atrophy/hypotrophy; caudate lobe hypertrophy; marginal atrophy; compensatory central hypertrophy; features of PHT (splenomegaly, portosystemic collaterals, portal venous dilation); portal vein abnormalities (portal atypical thickening, hyperechoic walls, and portal vein thrombosis [PVT]) [4, 19], some of which were identified in the abdominal ultrasound performed, as is stated above.

LSM are usually normal/slightly elevated, and SSM are increased [4, 19]. LSM <10 kPa as a cut-off value has good diagnostic performance and low LSM values should prompt a biopsy [21]. A higher spleen-to-liver stiffness may be suggestive of PSVD and should indicate a HH study and TJLB to rule it out [4, 19].

Patients with PSVD and PHT are usually asymptomatic until they develop complications. Thrombocytopenia is common and transaminases, alkaline phosphatase and gamma-glutamyltransferase are normal/slightly elevated, but hepatocellular function is relatively preserved (normal serum albumin and bilirubin) [4, 19].

Gastrointestinal bleeding secondary to ruptured varices is a presenting symptom in 20–40% [4, 5, 19]. Esophageal varices are frequently large and gastric varices are more common than in cirrhosis [18]. In our patient, the varices were in the proximal esophagus, a vascular territory less influenced by PHT, raising the possibility of downhill varices. Although the ultrasound showed an irregular liver surface, hyperechoic walls of the fibrovascular axes and splenomegaly (compatible with PSVD), the IVC, and hepatic veins ectasia suggested a cardiovascular disorder. Furthermore, the patient had peripheral leg edema without ascites and the echocardiogram revealed significant cardiac valve and cavity abnormalities and severe PAH. In this case, the cardiopulmonary and HH study and TJLB were essential in confirming both PSVD and PAH.

The risk factors linking PSVD and PoPH are unknown [4], and few cases have been reported. PoPH has a multifactorial pathogenesis (genetic predisposition; pulmonary vascular wall shear stress; dysregulation of vasoactive, proliferative, angiogenic, and inflammatory mediators) [10, 11]. Patients may be asymptomatic but often present with exertional dyspnoea and may have clinical signs of right heart failure when moderate to severe disease develops [22]. In this case, the patient presented with peripheral edema. It is unclear if the level of portal hypertension is correlated with the severity of PoPH [23]. The treatment includes general measures, such as diuretics, which can reduce volume overload, and specific treatment for PAH, such as endothelin receptor antagonists (caution is advised due to hepatic impairment), phosphodiesterase subtype-5 inhibitors, and prostacyclin analogues [22, 23]. Our patient was intolerant to beta-blockers, but even if this was not the case, withdrawal of beta-blocker therapy (in the context of esophageal varices) may help to increase cardiac output and thereby help exertional dyspnoea [22, 23]. Cohort studies have demonstrated that patients with PoPH have a worse prognosis compared with patients with idiopathic PH [23].

The initial management of PSVD includes treatment of underlying conditions. Complications of PHT should be treated according to cirrhosis recommendations. Patients should be screened regularly for varices and adequate prophylaxis of variceal bleeding with endoscopic band ligation/beta-blockers should be implemented. The indications for transjugular intrahepatic portosystemic shunts and transplantation are the same as for cirrhosis [5, 7].

PVT, a frequent complication (13–45%) during follow-up [7] (increased incidence if history of bleeding and HIV infection) [4], is an indicator of worse prognosis [5]. Anticoagulation is reserved for prothrombotic disorders or PVT [4, 5, 7].

Long-term outcome in PSVD is better than in cirrhosis, given the relatively preserved hepatocellular function [4, 7]. Despite higher frequency of variceal bleeding, mortality is lower than in cirrhosis [4]. In conclusion, this case illustrates the uncommonly reported association between PSVD and PoPH and the importance cardiopulmonary and HH study with TJLB to confirm both.

There were no sources of funding or financial disclosures for this manuscript.

The authors declare that all ethical procedures and standards were followed. The patient gave consent to the publication of the case report and accompanying images. Ethical approval was not needed according to local laws.

The authors have no conflicts of interest to declare.

The authors do not have any financial disclosures to report.

All authors fulfilled criteria of ICMJE for authorship: acquisition, analysis, or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

All data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.

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