Idiopathic Non-Cirrhotic Portal Hypertension and Porto-Sinusoidal Vascular Disease: Review of Current Data

Abstract

Idiopathic non-cirrhotic portal hypertension (INCPH) is a clinicopathologic disease entity characterized by the presence of clinical signs and symptoms of portal hypertension (PH) in the absence of liver cirrhosis or known risk factors accountable for PH. Multiple hematologic, immune-related, infectious, hereditary and metabolic risk factors have been associated with this disorder. Still, the exact etiopathogenesis is largely unknown. The recently proposed porto-sinusoidal vascular disease (PSVD) scheme broadens the spectrum of the disease by also including patients without clinical PH who are found to have similar histopathologic findings on core liver biopsies. Three histomorphologic lesions have been identified as specific for PSVD to include obliterative portal venopathy, nodular regenerative hyperplasia and incomplete septal cirrhosis/fibrosis. However, these findings are often subtle, under-recognized and subjective with low interobserver agreement among pathologists. Additionally, the natural history of the subclinical forms of the disease remains unexplored. The clinical course is more favorable compared to cirrhosis patients, especially in the absence of clinical PH or liver dysfunction. There are no universally accepted guidelines in regard to diagnosis and treatment of INCPH/PSVD. Hence, this review emphasizes the need to raise awareness of this entity by highlighting its complex pathophysiology and clinicopathologic associations. Lastly, formulation of standardized diagnostic criteria with clinical validation is necessary to avoid misclassifying vascular diseases of the liver and to develop and implement targeted therapeutic strategies.

Keywords: Cirrhosis; Incomplete septal cirrhosis; Liver; Nodular regenerative hyperplasia; Non-cirrhotic; Portal hypertension; Porto-sinusoidal; Vascular injury.

Figure 1

(a) Liver biopsy from Budd-Chiari syndrome (BCS) shows venous outflow obstruction pattern injury with mild centrizonal sinusoidal dilatation and congestion (hematoxylin and eosin (H&E), × 100). (b) Chronic BCS with extensive sinusoidal dilatation, centrizonal hepatocyte atrophy and dropout and fibrosis. The portal tracts are relatively spared (H&E, × 100).

Figure 2

(a) Sinusoidal obstruction syndrome (SOS) associated with oxaliplatin chemotherapy. Marked centrizonal congestion and sinusoidal widening is noted (hematoxylin and eosin, × 100). (b) Trichrome stain shows perisinusoidal fibrosis (Masson-trichrome, × 200).

Figure 3

(a) Fatty liver disease without cirrhosis or advanced fibrosis, but with portal hypertension. Zonal steatosis is noted (hematoxylin and eosin (H&E), × 40). (b) Higher magnification view showing pericentral fibrosis (long arrow) probably secondary to fatty liver disease, and phlebosclerosis (obliterative portal venopathy, short arrow), possibly secondary to concurrent porto-sinusoidal vascular disease (H&E, × 100).

Figure 4

Etiopathogenic associations with porto-sinusoidal vascular disease. ^#Systemic lupus erythematosus, rheumatoid arthritis, scleroderma, Sjogren’s syndrome, inflammatory bowel diseases, celiac disease, autoimmune hepatitis, Felty’s syndrome. ^¥Protein C or S deficiency, factor V Leiden, factor II mutation, antithrombin III deficiency. ^±Antiphospholipid syndrome, malignancy, ADAMTS 13 deficiency, oral contraceptive use. *Turner syndrome, Adams-Oliver syndrome, cystic fibrosis, phosphomannose isomerase deficiency. NAFLD: non-alcoholic fatty liver disease; HIV: human immunodeficiency virus.

Figure 5

Magnetic resonance imaging with contrast shows mild nodular contour of the liver surface (arrows) and relative hypertrophy of the caudate lobe (*) in porto-sinusoidal vascular disease.

Figure 6

(a) Obliterative portal venopathy (also known as phlebosclerosis) with inconspicuous portal venous branch (arrow) (hematoxylin and eosin, × 200). (b) Incomplete septal fibrosis or cirrhosis (Masson-trichrome, × 150). (c) Nodular regenerative hyperplasia. The nodularity is highlighted by reticulin special stain (reticulin, × 30). (d) Trichrome stain shows the absence of cirrhosis in nodular regenerative hyperplasia (Masson-trichrome, × 30).

Figure 7

(a) Paraportal shunt vessel (arrow) in idiopathic non-cirrhotic portal hypertension/porto-sinusoidal vascular disease (INCPH/PSVD) (hematoxylin and eosin (H&E), × 200). (b) Irregularly distributed portal tracts and central veins in INCPH/PSVD. Non-zonal sinusoidal dilatation is also noted (H&E, × 50). (c) Mild perisinusoidal fibrosis (Masson-trichrome, × 130). (d) Rudimentary portal tract in INCPH/PSVD (H&E, × 250).

Figure 8

Diagram summarizing the diagnostic approach for idiopathic non-cirrhotic portal hypertension and porto-sinusoidal vascular disease. *Portal vein thrombosis may be seen along the natural disease course of idiopathic non-cirrhotic portal hypertension. ^#Biopsy adequacy criteria are available for porto-sinusoidal vascular disease (core liver biopsy ≥ 20 mm in length or featuring ≥ 10 portal tracts, or when considered adequate by an expert pathologist).