Definition and Nomenclature
The term porto-sinusoidal vascular disease (PSVD) regroups several conditions characterized by alterations of the small branches of portal veins previously named from an histological point of view as “obliterative portal venopathy”, “nodular regenerative hyperplasia”, “hepato-portal sclerosis”, “non-cirrhotic portal fibrosis” and “incomplete septal fibrosis” or from a clinical point of view as “idiopathic portal hypertension” and “idiopathic non-cirrhotic portal hypertension (INCPH)” [
3•].
Almost recently, new diagnostic criteria have been proposed by the European Association for the Vascular Liver Disease (VALDIG) [
4••] that defines the diagnosis of PSVD in the presence of one of the three following features:
i)
Absence of cirrhosis at an adequate liver biopsy and at least one specific sign of portal hypertension
ii)
Absence of cirrhosis at an adequate liver biopsy and at least one specific histological sign of PSVD
iii)
Absence of cirrhosis at an adequate liver biopsy and at least one non-specific sign of portal hypertension and at least one non-specific histological sign of PSVD
Specific and non-specific clinical and histological signs are reported in Table
2.
Table 2
Diagnostical criteria for PSVD (VALDIG) [
4••]
Specific clinical signs of PH | Specific histological signs of PSVD |
Gastric-oesophagael, or ectopic varices Portal hypertensive bleeding Porto-systemic collaterals | Obliterative portal venopathy (thickening of vessel wall, occlusion of the lumen and vanishing of portal veins) Nodular regenerative hyperplasia Incomplete septal fibrosis or incomplete septal cirrhosis |
Unspecific clinical signs of PH | Unspecific histological signs of PSVD |
Ascites Spleen size ≥ 13 cm in the largest axis Platelet count < 150,000 per μL | Portal tract abnormalities (multiplication, dilation of arteries, periportal vascular channels and aberrant vessels) Architectural disturbance: irregular distribution of the portal tracts and central veins Non-zonal sinusoidal dilation Mild perisinusoidal fibrosis |
The term PSVD replaced the term INCPH in order to include the patients with specific histological features but no clinical signs portal hypertension.
When to Suspect PSVD?
There are two clinical scenarios in whom PSVD can be suspected: patients with chronic and unexplained alteration of liver enzymes without portal hypertension and patients with unexplained clinically evident portal hypertension. In both the cases, known causes of chronic liver disease or portal hypertension should be excluded.
The alterations of liver tests are various, and in particular they are represented by a mild elevation of ALT and AST, by an elevation of alkaline phosphatase 2 times upper the normal value or by an elevation of gamma-GT. These alterations are not associated to signs of portal hypertension [
5,
6].
Two recent European series showed that the histological lesions usually observed in patients affected by PSVD with portal hypertension (i.e. obliterative portal venopathy, OPV) were present in the 19% [
7] and 25% [
5] of the liver biopsies of patients with chronic elevation liver enzymes without cirrhosis and portal hypertension. Some of these patients developed clinical signs of portal hypertension during the follow-up. These observations suggest first of all that PSVD should be suspected and actively searched among the patients with chronic liver test abnormalities of unknown aetiology and no signs of portal hypertension and that, such conditions, PSVD with and without portal hypertension may be different stages of the same disease where histological PSVD might represent an “early” pre-symptomatic stage of PSVD with portal hypertension.
PSVD should be also suspected in patients with unexplained portal hypertension.
The absence of a cause of chronic liver disease together with the presence of a marked portal hypertension with normal or only mildly altered liver function tests should raise the suspicion of PSVD. If transaminases or cholestasis enzymes could sometimes be elevated, the liver synthetic capacity is usually preserved [
8••]. In fact, in these patients, bilirubin and albumin are quite normal, and prothrombin time is usually superior up to 50%. Moreover, other laboratory alterations such as anaemia, leukopenia and thrombocytopenia are the consequences of hypersplenism. On this basis, the distinction between PSVD and cryptogenic compensated cirrhosis may be very difficult and should always be supported by a liver biopsy. However, liver elastography may be helpful in this differential diagnosis at least to suspect PSVD and to select patients to be submitted to liver biopsy. In fact, the presence of a low liver stiffness (< 10 kPa) in patients with clinically evident portal hypertension may make the diagnosis of cirrhosis unlikely [
9].
Another challenge for the diagnosis of PSVD is with patients with chronic PVT. In fact, with new insights in the natural history of PSVD and its physiopathology, it is known that PSVD is frequently complicated by extrahepatic portal vein thrombosis [
6,
8••], and, hypothetically, if a certain patient is investigated after PVT occurs, it may be impossible to determine if a pre-existent PSVD is the cause of the vascular disease. In these cases, the only way to investigate PSVD might be performing a liver biopsy. Hence, the presence of a pre-existing, undiagnosed PSVD should be suspected in patients with acute or chronic PVT, and that is why, the criteria of the patency of the portal vein has been eliminated in the last definition of PSVD.
Moreover, PSVD is frequently associated with several systemic conditions and with the chronic exposition to various drugs and toxins (Table
3) that may play a direct role in the pathophysiology of the liver alterations. It has been reported that more than a half of PSVD patients have an associated disease [
2,
6,
10]. As a practical consequence, in patients affected by these diseases or exposed to these drugs, the searching of signs of portal hypertension is suggested. In particular, physicians should be aware of the possibility to develop PSVD, and they should be careful about the presence of liver tests alteration, of indirect signs of portal hypertension such as thrombocytopenia and of splenomegaly or portal vein dilatation, when an imaging technique is performed. When one of these alterations is present, the patient should be referred to a hepatologist.
Table 3
Diseases and drugs associated to porto-sinusoidal vascular disease (PSVD)
Thrombophilia | Hematologic disease |
Protein S, protein C, antithrombin deficiency Antiphospholipid syndrome Factor V Leiden Prothrombin mutation | Myeloproliferative Neoplasm Myeloid metaplasia Lymphoproliferative disorders (Hodgkin’s disease, non-Hodgkin’s lymphoma, chronic lymphocytic leukaemia and multiple myeloma) Spherocytosis |
Genetic disorders | Gut Diseases |
Cystic fibrosis Adams Oliver syndrome Turner’s disease TERT/TERC mutation | Celiac disease Inflammatory bowel disease |
Autoimmune disease | Acquired and congenital immunodeficiency |
Rheumatoid arthritis Systemic lupus erythematosus Systemic sclerosis Scleroderma | HIV infection Primary antibody-deficiency syndrome |
Drug and toxics | |
Oxaliplatin Azathioprine, 6-thioguanine Cytosine arabinoside Cyclophosphamide Bleomycin Chlorambucil Doxyrubicin Carmustine |
Diagnosis
For the diagnosis of PSVD, a combination of histological and radiological findings is necessary.
Biopsy remains mandatory to confirm the diagnosis of PSVD. Since the typical histological lesions cannot be all always contemporary present and they are distributed in a focal way, it is necessary to have an adequate liver specimen (Table
2) [
4••,
11•]. The optimal sample should measure more than 20 mm of length and contain at least 10 portal spaces, and it should be low fragmented. It is equally important that the liver biopsy would be referred to an expert pathologist.
Unfortunately, there are not specific radiological signs of PSVD, but the combination of several findings may suggest the diagnosis of PSVD.
Doppler ultrasound is frequently the first examination performed in patients with suspicion of PSVD. In these patients, the liver aspect may be either normal or inhomogeneous with irregular surface due to the micronodular transformation, rendering very difficult to differentiate it from cirrhosis, and caudal lobe hypertrophy and right hepatic lobe atrophy are present. In PSVD the main findings are the signs of portal hypertension such as splenomegaly, even more marked than in patients with cirrhosis, and portal venous axis dilatation. Moreover, in PSVD, the portal vein may appear markedly thickened with hyperechoic walls, anomalies that are found also in its intrahepatic branches, probably indicating periportal fibrosis.
Computed tomography (CT) would reveal vascular abnormalities especially on the peripheral intrahepatic portal branches (i.e. heterogeneous hepatic enhancement, abrupt narrowing of second-degree intrahepatic portal vein branches, paucity of the medium size portal branches). Moreover, CT has a better performance than Doppler ultrasound once a portal vein thrombosis is found, in order to assess its extension and duration but also for the evaluation of porto-systemic shunts. Finally, CT may be helpful to assess the presence of benign hypervascular nodules due to the haemodynamic abnormalities [
12,
13].
Liver stiffness may have a role in the diagnosis of PSVD at least to rule out the presence of cirrhosis. In these patients, liver stiffness can be normal or slightly elevated but surely lower than cirrhosis [
9]. The presence of clinically relevant portal hypertension with normal or moderate elevated values of liver stiffness should lead to exclude cirrhosis and to suspect PSVD. Furthermore, liver stiffness measurement would be helpful also in the distinction between patients with PVT caused and not caused by PSVD being it higher in patients with PVT secondary to PSVD [
14,
15].
Owing to the fact that patients with PSVD have a pre-sinusoidal type of portal hypertension, the HVPG is normal or slightly elevated, frequently < 10 mmHg [
9,
16,
17]. Moreover, the presence of vein-to-vein communications, often seen in these patients with a frequency higher than in cirrhotic patients, may further underestimate the value of HVPG. Hence, contrarily to cirrhosis, haemodynamic studies have scarce utility to indirectly evaluate the severity of portal hypertension in patients with PSVD where the HVPG is not correlated with clinical events such as the development of oesophageal varices, variceal bleeding or ascites.