Portal Sinusoidal Vascular Diseases: Assessment and Therapy Notes

Portal Sinusoidal Vascular Diseases (PSVD): Assessment and Therapy

Visual Abstract Overview

  • PSVD is part of non-cirrhotic portal hypertension disorders.
  • It sits within a spectrum that includes:
    • Parenchymal liver diseases.
    • Hepatic vein obstruction.
    • Extrahepatic portal vein obstruction.
  • It's associated with unexplained liver enzyme abnormalities and risks for chronic liver diseases.
  • Possible scenarios for PSVD include:
    • Presence of PSVD-associated conditions.
    • Thrombocytopenia.
    • Family history of PSVD.
  • Laboratory work-up involves assessing liver function and enzymes (which may be normal or marginally abnormal).
  • Non-invasive assessment:
    • Radiology: Smooth liver surface, Segment IV preservation, portal vein dilation, collaterals/varices, splenomegaly.
    • Liver and splenic stiffness measurements: LSM < 10 kPa in 65% of cases, SSM/LSM > 2.
  • Invasive assessment:
    • Liver biopsy REQUIRED: No cirrhosis + NRH, OPV, incomplete septal fibrosis, or nonspecific changes.
    • EGD: varices and portal hypertensive gastropathy.
    • HVPG: < 10 mmHg in 40-60% of cases.
  • PSVD-associated disorders include vasculopathies, inborn errors of immunity, genetic disorders, autoimmune disorders, and exposure to toxins/drugs.

Introduction to PSVD

  • PSVD was introduced in 2019 to define liver conditions leading to portal hypertension (PH) without cirrhosis or portal vein thrombosis (PVT).
  • PSVD can occur with or without specific histological findings.
  • Nomenclature consolidates knowledge from diseases previously known as Banti disease, noncirrhotic portal hypertension, noncirrhotic portal fibrosis, and idiopathic portal hypertension.
  • Excludes etiologies like sarcoidosis, congenital hepatic fibrosis, and Budd-Chiari syndrome.
  • Prevalence and recognition of PSVD are increasing.
  • Advances in diagnostics and treatment improve life expectancy for patients with associated conditions (immunodeficiencies, autoimmune diseases).
  • Similar to cirrhosis, PSVD patients may experience complications like variceal bleeding and ascites.
  • Less is known about natural history, screening strategies, prognosis, and treatment options.
  • This review discusses methods for assessing PSVD (clinical, histological, imaging) and available treatments.
  • It also addresses challenges posed by new nomenclature and remaining questions in disease assessment.
  • Keywords: common variable immunodeficiency, liver stiffness measurement, liver transplant, pregnancy in liver disease

History and Terminology

  • PSVD is a relatively new term, but the condition has been recognized for a long time.
  • 19th Century: Portal hypertension without cirrhosis was first mentioned. Gretzel and then Banti described "splenic anemia".
    • "Splenic anemia:" characterized by spleen enlargement, frequent hemorrhages, and congestion of visceral organs. Splenectomy was thought to be curative.
    • The disease was believed to prevail in children and young adults.
    • Speculation that splenomegaly resulted from infectious toxin or vasomotor paresis in the splanchnic area.
    • The possibility of the liver, not the spleen, being the driver of the condition was also recognized.
  • Banti disease represents a spectrum of diseases of various etiologies and without a typical course, suggesting the term “complex” or “syndrome” instead of “disease”.
  • 1960s: Mikkelsen introduced "hepatoportal sclerosis" to describe histological findings in patients with PH without cirrhosis.
  • "Idiopathic portal hypertension," "noncirrhotic portal fibrosis," and "noncirrhotic portal hypertension" were also used interchangeably.
  • Increased prevalence of IPH in India was hypothesized to be due to exposure to certain toxins, bacteria, parasites, or herbal substances.
  • Following the establishment of the National Research Committee on Aberrant Portal Hemodynamics in 1975, increased recognition of IPH in Japan.
  • Nationwide epidemiological surveys in Japan estimated IPH prevalence to be 7.9 per one million in 2014.
  • The terms NCPF and IPH are still used alongside PSVD. The recently published APASL guidelines retained NCPF and IPH as the preferred terms in Asia.
  • Like NCPF/IPH, PSVD excludes certain diseases, such as sarcoidosis, congenital hepatic fibrosis, and primary PVT.
  • One significant advantage of the new terminology is the inclusion of conditions without PH, which are excluded by the terms "IPH" or "idiopathic noncirrhotic portal hypertension (INCPH)," and it avoids the assumption that the etiology is idiopathic.
  • The presence of nodular regenerative hyperplasia (NRH) or obliterative portal venopathy (OPV) without clinical signs of PH may represent an early form of PSVD, allowing for longitudinal assessment and disease staging.
  • In 1989, Sarin introduced the concept of “early” or “pre-NCPF”.
  • Another advantage of the PSVD spectrum is that it allows for the coexistence of risk factors for other chronic liver diseases, such as alcohol use or metabolic syndrome, provided that the liver biopsy confirms PSVD.
  • PSVD unites several different entities under one term, certain challenges remain.
  • PSVD encompasses multiple pathologies, some diagnosed by specific histological or clinical features, with or without PH.
  • The diversity within this spectrum suggests that terms like “porto-sinusoidal vascular complex” or “syndrome” might be more appropriate.
  • The histological findings reported along the diagnosis of PSVD, such as “PSVD with NRH,” may be helpful as it will allow for transferability of the findings across studies.
  • PSVD allows only categorization based on the presence or absence of PH, the APASL guidelines propose categorizing NCPF/IPH into 4 stages based on the presence of PH and associated complications, allowing for a more nuanced and gradual assessment.
  • The proposed nonspecific histological features, even when combined with nonspecific features of PH, may be insufficient to diagnose PSVD.
  • Portal tract abnormalities, including herniation of the portal vein, are observed in COVID-19 infection, while perisinusoidal fibrosis can occur in steatotic liver disease.
  • The new nomenclature also excludes pathologies affecting the central vein.
  • Abnormally dilated central veins are among the features frequently found in NCPF.
  • In chronic granulomatous disease, which is often associated with PH without cirrhosis, central vein venopathy was the second most common abnormality after portal vein venopathy (63% and 80%, respectively), and was linked to the number of hepatic abscesses.
  • Pericentral fibrosis is also commonly found in diseases related to telomere gene abnormalities.

Pathophysiology

  • Histological changes in PSVD that eventually lead to PH are thought to result from disruptions in hepatic blood flow.
  • The hypercoagulability and vasculopathy theories are perhaps the most studied mechanisms in PSVD.
  • A proportion of patients with PH have no histological abnormalities, suggesting that there may be other mechanisms involved in PSVD pathogenesis, presenting opportunities for future research. An example of this is massive splenomegaly.
  • Associations between PSVD and certain conditions may shed light on the pathophysiological processes leading to liver disease.

Hypercoagulability and Vasculopathy

  • Hillaire et al. study: Up to half of all patients with NCPH have underlying prothrombotic disorders, such as protein C and S deficiencies, or polycythemia vera.
  • Patients with PSVD have elevated markers of hypercoagulability and platelet aggregation, such as factor VIII, von Willebrand factor, p-selectin, prothrombin fragments, along with decreased ADAMTS13 levels.
  • Secreted by HSC, ADAMTS13 is a metalloproteinase responsible for the cleavage of von Willebrand factor multimers and thrombosis prevention.
  • Decreased levels of ADAMTS13, alongside the absence of fibrosis in PSVD, may be related to abnormal function of HSC.
  • Compared to other liver diseases, patients with IPH demonstrated higher serum levels of vascular cell adhesion molecule-1 and increased expression of this marker in sinusoidal cells.
  • Activation of the coagulation system by proinflam- matory cytokines in inflammatory bowel disease may explain the association of PSVD with Crohn disease and ulcerative colitis, and it may also predispose patients to PSVD due to thiopurine toxicity.
  • Hernandez-Gea et al. analyzed the transcriptome and identified several genes potentially involved in PSVD pathogenesis, including SERPINC1, apolipoproteins, genes encoding fibrinogen (FGB and FGA), and alpha-2 macroglobulin, all of which may contribute to vasculopathy.
  • Vasculopathy due to direct damage from recurrent infections, abscesses, and granulomas and continuous exposure to antibiotics with hepatotoxic potential may cause OPV and NRH in chronic granu- lomatous disease.
  • Portal venous obliteration is often found near the abscesses on liver biopsy.

Bacterial Translocation

  • Bacterial translocation may contribute to the progression of liver disease in PSVD, similar to mechanisms identified in cirrhosis.
  • Gioia and colleagues studied the markers of intestinal translocation; patients with PSVD had higher levels of zonulin and lipopolysaccharide compared to controls.
  • Increased levels of toll-like receptor 4 macrophages in liver tissue correlated with inflammation.
  • Previous studies have shown an inverse correlation between lipopolysaccharide and ADAMTS13 levels in alcohol-associated liver disease, suggesting a role for endotoxemia in hypercoagulability.
  • In cystic fibrosis (CF), bacterial translocation may also contribute to PSVD: mutations in CFTR gene may indirectly lead to imbalance in toll-like receptor 4–associated inflammation due to self-activation of Src oncogene and disruption of the epithelial intestinal barrier.
  • Patients with CF with liver disease have a higher abundance of potential pathogens like S.salivarius and V.parvula compared to those without liver disease, supporting the role of the microbiome in hepatic pathogenesis.
  • Poor sanitation and a high prevalence of intestinal infections are factors thought to contribute to the increased prevalence of NCPH and PSVD in low- and middle-income countries, including India.

Autoimmune Conditions

  • Histological features of PSVD have been described in association with various autoimmune conditions, including scleroderma, systemic lupus erythematosus, and rheumatoid arthritis.
  • Several studies on autoimmunity and PSVD come from Japan.
    • Terada and colleagues showed that patients with IPH had higher expression of HLA-DR compared to those with other liver diseases, including cirrhosis.
    • Sato demonstrated the presence of anti-endothelial cell antibodies in the sera of patients with IPH, which may induce elastin production in portal tracts.
  • Recent study by Cerda Reyes et al compared the prevalence of autoimmune markers in people with PSVD and cirrhosis, finding that 92% of patients with PSVD had at least 1 autoantibody, including antiendothelial cell antibodies, suggesting vasculopathy may be a driver in PSVD.

Genetic Predisposition

  • PSVD has been identified in several disorders of inborn errors of immunity, many of them being monogenic disorders such as common variable immunodeficiency (CVID) with mutations in PI3KCD and PI3KR1 or TACI, or X-linked agammaglobulinemia with mutations in BRT.
  • Up to half of the patients with germline mutations in telomere-related genes and liver disease were found to have PSVD.
  • Missense variants in ADAMTS13, von Willebrand factor, and genes associated with alternative complement pathways, CFH, CFB, and CFI, were identified in a patient with IPH.
  • Previous association of the variant found in ADAMTS13 with cerebral aneurysms and complement gene variants with thrombotic microangiopathy further underscores the role of vascular abnormalities in PSVD.
  • Whole-exome sequencing of families affected by PSVD enabled the discovery of variants associated with familial, isolated forms of the disease.
  • A heterozygous variant in FOPV, or Familial Obliterative Portal Venopathy gene, has been linked to an autosomal dominant inheritance pattern and is also found in nonfamilial OPV cases.
  • Vilarinho and colleagues studied 2 consanguineous families affected by PH without cirrhosis and identified a homozygous mutation in the DGUOK gene, which encodes deoxyguanosine kinase.
  • DGUOK insufficiency leads to mitochondrial DNA depletion and has been previously observed in cases of liver failure associated with mitochondrial disease.
  • This finding bridges a knowledge gap about the role of didanosine in PSVD pathogenesis: didanosine treatment downregulates mitochondrial deoxyguanosine kinase in vitro, and it can potentially lead to DGUOK insufficiency in vivo.
  • A study by Shan and colleagues identified the variant FCHSD1R183W, which is inherited in autosomal dominant pattern with variable expressivity. FCHSD1R183W is a gain-of-function mutation, potentially involved in the mTOR regulated pathway.
  • Previous animal models have suggested mTOR pathway activation in the spleens of portal hypertensive rats, with improvement in PH after mTOR blockade using rapamycin.
  • A recent comprehensive review of genetics in PSVD analyzed the expression of previously identified genes associated with the condition in various cell types. The study found that most of these genes are expressed in immune cells, particularly myeloid cells, highlighting the role of immune disorders and autoimmunity in the pathophysiology of PSVD.

Drug and Environmental Toxicity

  • The evolution of therapeutic options for previously fatal conditions, such as immunodeficiencies and cancer, has increased survival rates, yet many medications have been associated with the development of NRH and OPV.
  • The first reports of NCPH with didanosine appeared over a decade after its approval for HIV treatment. Didanosine use was linked with hypercoagulability and drug-induced microvascular liver injury, which was not always reversible after cessation.
  • This ultimately led to medication withdrawal in many countries, including the United States.
  • Chemotherapy is another known risk for PSVD.
  • Vigano and colleagues analyzed 82 paired biopsies from patients during and after chemotherapy, primarily with oxaliplatin, and found that 57% of patients developed sinusoidal dilation or NRH during chemotherapy. However, 88% of patients showed reversal of NRH 9 months after completing chemotherapy.
  • Liver transcriptome analyses of patients treated with oxaliplatin revealed upregulation of genes involved in angiogenesis, such as VEGF, and cellular adhesion molecules like VWH and THBS2.
  • Arsenic toxicity, frequently associated with NCPH in India, induces hepatotoxicity through oxidative stress-induced activation of HSC and subsequent portal fibrosis.
  • NCPF was also identified as a dominant liver pathology preceding angiosarcoma after occupational exposure to vinyl chloride (VC).
  • The injury occurs at the sinusoidal level, leading to dilation and fibrosis.
  • In the study by Lelbach, features of NCPF/PSVD were identified in at least 48% of workers with heavy exposure to VC, with cases associated with angiosarcoma, HCC, and cholangiocarcinoma.

Histopathology

  • A liver biopsy is required to diagnose PSVD, and there are certain quality requirements for the biopsy.
  • A specimen is considered adequate if it is at least 20 mm in length, is not overly fragmented, and contains 10 or more complete portal tracts. Alternatively, a biopsy may be considered adequate by an expert hepatopathologist.
  • Transjugular liver biopsy is often the safest approach for patients with thrombocytopenia, providing an opportunity for simultaneous portal pressure measurement.
  • In PSVD, in the absence of complications such as VB or ascites, the most common indications for liver biopsy are abnormalities of serum tests or noninvasive tests and imaging suggestive of PH.
  • The diagnostic histological features of PSVD can appear in isolation or in combination, with a significant heterogeneity even within the same liver.
  • Studies from Japan suggested that OPV, NRH, and incomplete septal fibrosis or cirrhosis (ISF) share common features of portal fibrosis with portal venous obliteration and may represent stages in the chronological progression of NCPH.
  • Histological diagnosis of PSVD is challenging, as interobserver agreement on diagnosing NRH/ PSVD is poor, even among experienced pathologists, and it does not improve with the provision of clinical histories.

Nodular Regenerative Hyperplasia (NRH)

  • NRH involves the transformation of normal hepatic parenchyma into regenerative nodules no more than 3 mm, usually with little or no fibrosis.
  • It is thought to result from an imbalance between arterial and portal venous flow.
  • The term “NRH” was first introduced by Steiner in 1959. He described small nodules composed of new liver cells that distorted the lobular architecture and compressed portal and central veins.
  • Unlike cirrhosis, NRH lacks fibrous bands, scars, or septae, but exhibits pseudo-septae or band-like zones, likely produced by the compressive effects of nodules in areas of atrophy. Perisinusoidal fibrosis between nodules is common.
  • Steiner described NRH as a regenerative process typically occurring in the presence of a systemic condition, such as cardiac congestion.
  • The hepatocytes within the nodules are organized in 2- cell thick plates, and compressed central veins may have a slit-like appearance.
  • Although NRH may resemble cirrhosis, there are no fibrotic bands between the nodules, which can be confirmed by Masson trichrome staining. Regeneration may be less evident on hematoxylin and eosin staining; reticulin staining is usually needed for diagnosis.
  • In 1990, Wanless proposed a histological classifi- cation of micronodular transformation: it was graded as 3+ and referred to as NRH only if nodules were present in most distinct areas, whereas grades 1+ or 2 + were referred to as focal atrophy with hyperplasia when nodules were indistinct or occasional.
  • In a study of 2500 autopsies, NRH was present in 2.6% of cases, while focal atrophy with hyperplasia occurred in 10.2%. All cases were associated with obliterative changes in the portal veins.
  • The presence of NRH is associated with higher odds of major complications, such as bleeding or perforation, following per- cutaneous liver biopsy compared to viral hepatitis, likely due to the presence of underlying systemic disease in patients with NRH.

Obliterative Portal Venopathy (OPV)

  • OPV, also known as hepatoportal sclerosis, phlebo- sclerosis, or noncirrhotic portal fibrosis, affects small and medium-sized portal veins.
  • A marked patchy subendothe- lial thickening of intrahepatic branches of the portal vein was observed in association with IPH, but not with cirrhosis or extrahepatic portal vein obstruction. At that time, the first hypothesis emerged, suggesting that OPV, similar to schistosomiasis, was the primary process leading to portal stasis and hypertension, rather than a consequence.
  • Livers with OPV may appear atrophic on gross examination.
  • Lobular architecture is typically significantly deranged, with portal areas irregularly distributed in the parenchyma, and portal veins are often missing or compressed. Residual portal veins may be dilated and acquire a thin layer of smooth muscle cells. The sinusoids may show vessel-like dilation.
  • Since vein obliteration or sclerosis is not consistently present in this condition, the term “portal vein stenosis” has been proposed as an alternative to OPV.

Incomplete Septal Fibrosis (ISF)

  • The term "incomplete septal fibrosis,” sometime used interchangeably with “incomplete septal cirrhosis,” was introduced by Rubin and Popper in 1965 to describe a final, macronodular stage of primary biliary cholangitis, characterized by thin incomplete septae that demarcate large, ill-defined nodules.
  • The gross appearance of the liver surface may be normal.
  • In ISF, the portal tracts are hypoplastic, with abnormal spacing between portal tracts and veins.
  • Veins are usually located near the portal tracts or septae.
  • Diagnosis of ISF generally requires an intraoperative liver biopsy or liver explant, as findings on needle biopsy are often only suggestive.
  • ISF is not easily identified on hematoxylin and eosin staining, reticulin staining is helpful in recognizing this feature.
  • The term is sometimes applied to cases of regressed cirrhosis, in which the septae become attenuated as the fibrosis gradually disappears, but this should be distinguished from cases of NCPH that develop bridging fibrosis as part of fibrosis progression.

Nonspecific Features of PSVD

  • Nonspecific features of PSVD can be subtle, present in various combinations, and found in normal livers or other liver disorders. These features include portal tract abnormalities, architectural disturbance, nonzonal sinusoidal dilation, and mild perisinusoidal fibrosis.
  • It is possible that they may present early stages of NRH or OPV, the most distinct histological features of PSVD.
  • In a study by Verheij et al, 94% and 97% of patients with INCPH exhibited sinusoidal dilation and perisinu- soidal fibrosis, respectively.
  • Specific staining may aid in identifying subtle features of PSVD.
    • Cytokeratin 7 defines the phenotype of cholangiocytes and is not expressed in normal hepatocytes. Hematological disturbances and hypoxic changes, thought to play an etiological role in PSVD, lead to cytokeratin 7 expression in atrophic hepatocytes at the periphery of regenerative nodules in NRH, potentially representing adjustment to a hypoxic environment.
    • Abnormal CD34 staining in sinusoidal endothelial cells suggests sinusoidal capillarization.
    • Bakshi et al study: Nearly all cases of NRH demonstrated cytokeratin 7 and CD34 positivity.
    • Glutamine synthetase, a marker of benign liver neoplasms that is normally positive only in hepatocytes around hepatic veins, may demonstrate irregular patterns in cases of NRH, such as periportal, pericentral, or multizonal positivity.

Clinical Manifestations and Natural History of the Disease

  • PSVD without PH is typically asymptomatic. In the absence of other causes of liver disease, mild eleva- tions in liver enzymes or increases in liver stiffness measurements (LSM) are the most common reasons for a liver biopsy.
  • The presence of associated disorders, family history with PSVD, or exposure to certain toxins may raise suspicion of PSVD, although an ultimate diagnosis is impossible without histological confirmation.
  • As the disease progresses, patients may develop nonspecific clinical features, such as splenomegaly, thrombocytopenia, and ascites, and specific features like esophageal, gastric and ectopic varices, portal hypertensive bleeding, and portosystemic shunting, which can be identified on imaging.
  • Cytopenias are often more severe than found in cirrhosis.
  • Portal hypertensive gastropathy (PHG) is a common endoscopic finding in both children and adults with PSVD and may result in massive diffuse bleeding in severe cases.
  • PHG is associated with decreased survival in cirrhosis, and in PSVD, it may be the first sign of PH, even preceding the development of varices. This suggests that PHG should be considered one of the specific features of PH contributing to the diagnosis of PSVD.
  • PSVD with PH is frequently misdiagnosed as cirrhosis in 70%–80% of cases, while the correct diagnosis of cirrhosis is made in up to 98% of cases.
  • Krasinkas et al study: 13 out of 16 patients (81%) with PSVD, confirmed on explants, were incorrectly diagnosed with cirrhosis prior to liver transplantation (LT), based on clinical criteria, imaging, and even pretransplant histology.
  • The most common initial clinical finding in PSVD is varices on esophagogastroduodenoscopy, followed by abnormal liver tests and VB. In contrast, the initial findings in cirrhosis are usually liver nodularity on imaging, followed by abnormal function tests and varices.
  • A nationwide survey in Japan showed that splenomegaly and esophageal varices are the presenting symptoms in 80% of cases, with approximately one-third of patients experiencing VB at the time of presentation.
  • HE and cognitive impairment are less common in PSVD compared to cirrhosis. Cognitive impairment correlates with the presence of large portosystemic shunts, and it is likely due to the decreased clearance of gut-derived toxins from the circulation.
  • Overt HE has been reported in up to 7% of patients with PSVD.
  • Lattanzi and colleagues used the skeletal muscle index to assess sarcopenia, finding that despite higher albumin levels than in cirrhosis, the prevalence of sarcopenia and cirrhosis was similar in patients with INCPH. The presence of sarcopenia was associated with an increased risk of refractory bleeding, although the analysis included a mixed cohort of patients with INCPH and PVT.
  • Cardiopulmonary complications, such as hepatopulmonary syndrome (HPS), portopul- monary hypertension (PoPH), and cardiomyopathy, are well described with cirrhosis and can occur regardless of the underlying etiology, contributing to morbidity and mortality. Similar complications have been observed in PSVD, although they are less extensively studied.
  • Intrahepatic malignancies, including HCC, cholangiocarcinoma, and angiosarcoma, have been reported in both adults and children, occurring in 0.5%–3.3% of cases after a median follow-up of 4.2–5.7 years. This underscores the importance of regular imaging surveillance.
  • PSVD is a progressive disease.
  • In a Japanese cohort, 10% of patients experienced decompensation or death within 10 years after the initial presentation.
  • Mironova et al study: 20% of patients with no signs of PH developed varices or PHG over a median of 50 months. All patients had CVID and NRH, suggesting that the presence of an underlying disorder may accelerate disease progression, and different underlying conditions confer different risks for mortality.
  • Severe conditions such as CVID and autoimmune diseases were associated with poor prognosis and were included in the nomogram to predict survival in PSVD. Similarly, severe associated disorders, elevated serum creatinine, and the presence of ascites were linked to unfavorable outcomes following TIPS and abdominal surgery.
  • One of the potential explanations of progression is increase in liver fibrosis over time. Hercun et al showed that nearly one-third of patients with CVID with NRH had fibrosis progression in the repeat liver biopsy performed after a median of 3 years.

Specific Populations

Pediatric Population

  • Splenomegaly, abnormal liver tests, and VB are the most common presenting symptoms in the pediatric population.
  • VB is observed in up to half of the children at presentation.
  • Overt HE has not been reported in children with NCPH, although the rate of minimal HE is similar to that in adults and can reach up to 33%.
  • Symptom onset typically occurs between the ages of 6 and 10 years; however, it may take 3–4 years before a diagnosis is made.
  • In a study of 48 children with OPV, familial cases manifested earliest, at a mean age of 2.5 years. The 20-year probability of survival and survival without bleeding in the whole cohort was 93% and 27%, respectively.
  • The presence of PH at diagnosis determines the outcomes in children with PSVD. In the study by Di Giorgio et al, all children without PH survived with no progression to PH, while 19% of children with PH required a LT. In another study of 30 children with PSVD, 2 out of 12 children without PH at the beginning (16.7%) progressed to PH over a median follow-up of 4.5 years. Among all children with PH, 2 (10%) required LT for HCC or HPS, and 6 (30%) underwent surgical shunting.
  • NRH is the predominant histological feature in children with CF who underwent LT, seen in 94% of all explants.

Pregnancy

  • Compared to cirrhosis, PSVD may be associated with better fertility due to the preserved synthetic function of the liver.
  • Pregnancy causes a physiological increase in blood volume and a hyperdynamic state, which in PSVD can further increase portal venous flow and the risk of complications.
  • Women with noncirrhotic causes of PH may experience higher rates of VB compared to those with cirrhosis, but they tend to tolerate VB better. At the same time, they have lower rates of postpartum hemorrhage compared to women with cirrhosis.
  • Maternal mortality is lower in NCPH compared to cirrhosis (0.7% vs. 0.89%).
  • Andrade and colleagues studied 24 spontaneous pregnancies in patients with INCPH: 25% of pregnancies were nonviable, and of the viable pregnancies, 50% resulted in preterm deliveries. Two women developed VB (8.3%), and one developed PVT. All women were alive after 27 months of follow-up.
  • An earlier study by Aggarwal et al reported a higher incidence of VB, up to 26%; this difference from the findings by Andrade et al. may be partially explained by advancements in prevention and screening over time.
  • Current guidelines recommend that women with noncirrhotic forms of PH, including PSVD, undergo variceal screening and prophylaxis similar to patients with cirrhosis. Small varices should be treated with nonselective beta-blockers (NSBB), while for medium or large varices NSBB or prophylactic esophageal variceal ligation should be considered.
  • The frequent association of hypercoagulable conditions with PSVD may warrant consideration of prophylactic anticoagulation during pregnancy, including the postpartum period. Low molecular weight heparin is the preferred anti- coagulant in pregnancy.
  • Endoscopic treatment of VB during pregnancy appears to be well tolerated.
  • Successful pregnancies have been reported after surgical shunting or TIPS.

SARS-CoV-2 Infection

  • Patients with PSVD have been shown to experience a more severe course of SARS-CoV-2 infection, with a greater need for ICU care compared to the general population.
  • Infected patients had significantly higher serum bilirubin levels compared to noninfected.
  • The high risk of severe SARS-CoV-2 infection suggests the importance of better vaccination planning for this patient group.
  • Recent study from the Vascular Liver Diseases Group: SARS-CoV-2 vaccines elicited a strong immune response and had low rates of adverse events, including thrombotic complications.
  • Cossiga et al study: The presence of PSVD, among other liver diseases, was associated with a better immunogenic response to a SARS-CoV-2 booster dose.

Assessment of Portal Hypertension in PSVD

Challenges of PSVD Assessment

  • Assessment of PSVD severity remains problematic, as no staging system is currently available.
  • The heterogeneity of histological findings in PSVD makes it challenging to consolidate all features into a single scoring system.
  • The MELD or Child-Pugh score depend on parameters of synthetic liver function, such as bilirubin, albumin, and INR, which typically remain normal in PSVD until the late stages. However, bilirubin and INR at the upper limit of normal may suggest the presence of PH.
  • Scores based on platelet count, such as Fibrosis-4, do not always reflect liver disease severity in PSVD. Thrombocytopenia may result from massive splenomegaly in immunodeficiencies, underlying disorders associated with bone marrow failure, or platelet count may be increased in myeloproliferative disorders or following splenectomy.
  • Non-invasive tools for evaluating fibrosis, screening for PH, identifying patients at risk for VB, and determining the need for intervention are well-established in chronic liver diseases, such as alcohol-associated liver disease and viral hepatitis. In PSVD, however, the appropriate cut-offs are still being established.

Invasive Assessment: HVPG

  • HVPG is the gold standard method for evaluating PH.
  • HVPG ≥ 10 mmHg indicates clinically significant PH and related complications in chronic liver disease.
  • HVPG < 10 mmHg in a patient with clinical features of PH suggests PSVD.
  • Seijo and colleagues study: The mean HVPG in 39 patients with IPH was 7.0 ± 3.0 mmHg. All patients had either varices, ascites, or history of VB.
  • HVPG may be an indicator of esophageal varices: in a study by Da et al patients with varices had higher HVPG compared to those without, with a mean HVPG 10.3 (4.3) mmHg versus 8.1 (5.4) mmHg, respectively.
  • Magaz and colleagues study: 36% of patients with PSVD had an HVPG > 10 mmHg.
  • The presence of hepatic vein-to-vein communications may prevent the accurate measurement of wedged hepatic venous pressure.
  • HVPG tends to underestimate the degree of PH in PSVD due to the presinusoidal nature of the disease.
  • Direct portal pressure measurements, via transhepatic or endoscopic approaches, may provide more accurate information in cases of PH at the presinusoidal level, although these methods require specialized expertise.

Noninvasive Assessment

  • Liver biopsy remains the gold standard for differentiating between PSVD and cirrhosis.
Liver Stiffness Measurement (LSM)
  • LSM is commonly used for prognostication in advanced chronic liver disease.
  • Elkrief and colleagues study: The median LSM by vibration-controlled transient elastography (VCTE) in PSVD was 7.9 kPa, compared to 33.8 kPa in alcohol-associated cirrhosis and 18.2 kPa in HCV-related cirrhosis. Despite these lower LSM values in PSVD, the number of patients with specific signs of PH, such as varices needing treatment, was higher in PSVD.
  • In patients with PH, an LSM < 10 kPa had a specificity of 93%–96% for diagnosing PSVD, while an LSM > 20 kPa had high sensitivity and negative predictive value to rule out PSVD.
  • LSM values with ≥ 6.2 kPa by VCTE may be useful for diagnosing NRH in patients with CVID.
  • Mironova et al prospective cohort of people with NCPH, predominantly PSVD, LSM ≥ 10 kPa was identified as a useful predictor of poor outcomes, death, LT, or decompensation.
  • Liver stiffness measured by acoustic radiation force impulse in combination with superior mesenteric vein diameter may be useful for identifying PSVD in patients with PVT and determining who requires a liver biopsy.
  • Patients with NRH have higher LSM values by magnetic resonance elastography compared to those without NRH, suggesting that parenchymal changes in NRH contribute to increased stiffness.
Splenic Stiffness Measurement (SSM)
  • PSVD is characterized by increased splenic size and stiffness, making splenic stiffness measurement (SSM) by VCTE a useful tool for evaluating and diagnosing PSVD.
  • Ferreira-Silva and colleagues study: Patients with PSVD had a higher SSM compared to those with cirrhosis, with values of 59.4 versus 47.3 kPa, respectively.
  • The authors proposed splenic-hepatic elastography index.
  • The diagnostic accuracy of LSM alone for predicting PSVD was 77.9%, the ratio of SSM/LSM > 2 had a significantly higher diagnostic accuracy of 89.7%.
  • Moga et al proposed an algorithm where an SSM ≤ 40 kPa measured by VCTE and bilirubin < 1 mg/dL identify patients with a low probability of HRV, potentially sparing an endoscopy. When measured by two-dimensional shear wave elastography (2D-SWE), SSM outperforms both LSM and SSM/LSM for predicting HRV in IPH.
  • A combination of SSM/ LSM > 1.23 and LSM ≤ 4.7 kPa measured by magnetic resonance elastography has been proposed to differentiate between NCPH and cirrhosis.

Imaging

  • Ultrasound is the most commonly used imaging modality and is helpful for evaluating signs of PH, measuring the size of the spleen and liver, assessing the diameter of the portal and splenic veins, and screening for PVT and liver masses. In OPV, increased echogenicity of the portal vein walls may be seen on ultrasound. However, ultrasound cannot consistently differentiate between PSVD and cirrhosis.
  • Cross-sectional imaging, such as CT and MRI, offers a more detailed morphological assessment of liver segments, lesions, vasculature, and volumetrics. Liver nodularity, caudate lobe hypertrophy, and segment IV atrophy may be seen in PSVD, although these findings are less frequent than in cirrhosis.
  • Lampichler and colleagues created a predictive model