Congenital porto-sinusoidal vascular disorder-induced portal hypertension: A comprehensive review based on a classic clinical case

Abstract

There are still debates on the pathogenesis and classification of congenital porto-sinusoidal vascular disorder (PSVD) with portal hypertension, which makes numerous challenges in treatment. This review provides a focused exploration of the disease, highlighting its clinical implications through a detailed case study. We offer a comprehensive on aspects of underlying pathophysiology, epidemiological trends, diagnostic methodologies, clinical therapeutic and management strategies of PSVD, furthermore critically examines ongoing controversies within the field and suggests future research directions as well. We present a special case of congenital PSVD in a 15-year-old child. In the treatment of clinical cases of PSVD, it is essential for comprehensive synthesis of the disease, formulate an individualized treatment plan, and closely monitor the patient’s biochemical indices and clinical symptoms to ensure treatment efficacy and prognosis.

Key Words: Porto-sinusoidal vascular disorder; Portal hypertension; Pathophysiology; Epidemiology; Diagnosis and treatment

Core Tip: Our review initiated a comprehensive exploration of congenital porto-sinusoidal vascular disorder through a representative clinical case. By incorporating recent and relevant findings, this review aims to deepen the understanding of porto-sinusoidal vascular disorder in etiology, pathology, and treatment approaches, in order to enhance both clinical decision-making and the framework for future investigative efforts in this complex condition.

INTRODUCTION

Idiopathic noncirrhotic portal hypertension is an intrahepatic pre-sinusoidal portal hypertension disease that has become increasingly common clinically in recent years[1]. Its defining feature is the presence of significant clinical symptoms of portal hypertension (such as splenomegaly and esophageal/gastric varices) without cirrhosis[2]. Porto-sinusoidal vascular disorder (PSVD) is a newly proposed disease designation that serves as an important complement to idiopathic noncirrhotic portal hypertension. It encompasses patients with pathologic findings consistent with the condition but without portal hypertension symptoms, those with concomitant portal vein thrombosis, and those with viral hepatitis[2]. This paper systematically reviews the epidemiology, etiology, pathophysiology, histology, clinical manifestations, treatment approaches, and prognostic management of PSVD through in-depth analysis of classic cases and integration of current research findings, aiming to enhance clinicians’ understanding of this condition.

CASE PRESENTATION

Chief complaints

Upper gastrointestinal bleeding accompanied by thrombocytopenia for 10 days.

History of present illness

A 15-year-old female was admitted for upper gastrointestinal bleeding.

History of past illness

Deny a history of past illness.

Personal and family history

Deny a family history of genetic diseases. No history of alcohol consumption or drug exposure for liver injury, and no viral hepatitis or other common risk factors for cirrhosis.

Physical examination

General appearance: The patient appears fatigued but conscious and cooperative. No acute distress is observed.

Skin and mucous membranes: Moderate to severe anemia without jaundice, palmar erythema and spider angiomas are absent.

Abdomen: Soft and non-tender on palpation. The lower edge of the spleen extends beyond the umbilical level without hepatomegaly. No abdominal masses are palpable. Bowel sounds are normal. No ascites is detected by shifting dullness or fluid wave.

Other systems: No lymphadenopathy is found. Cardiopulmonary auscultation reveals no abnormalities. Neurological examination shows no signs of encephalopathy.

Laboratory examinations

Bone marrow aspiration (local hospital, February, 2025) showed no hematopoietic abnormality. Laboratory tests (during hospitalization at our hospital) revealed anemia (67 g/L) and thrombocytopenia (47 × 10⁹/L), while liver function remained within normal parameters. The hepatitis virus markers and autoimmune liver disease antibodies were negative.

Imaging examinations

Abdominal imaging revealed normal liver morphology with smooth margins, a dilated portal vein trunk with an internal diameter of 11 mm, multiple neoplastic dilatations of the intrahepatic portal vein, an enlarged spleen (length 214 mm, thickness 63 mm), and esophagogastric fundic vein varices.

Genetic test

There was no cirrhosis-related gene mutation in the whole exon gene test, and both parents were not heterozygous mutation carriers (Supplementary material).

Histopathological findings

The pathology of the liver biopsy (Figure 1) revealed lymphocytic infiltration in the hepatic sinusoids, fibrosis in the confluent zone, and partially stenosed and occluded portal veins with partially tortuous dilatation.

Figure 1 Occlusive portal vein lesions accompanied by nodular regenerative hyperplastic changes. A: Hepatic sinusoidal lymphocytic infiltration and stromal fibrosis in the confluent zone of the portal vein; B: Portal vein was partially narrowed and occluded, partially tortuous and dilated; C: Peri-sinusoid fibrosis (Masson trichrome); D: Nodular disorganization with hepatocyte plate atrophy (reticulin); E: Immunohistochemical staining showed positivity for CD10, CD38, CK19, and CK7. Scale bars = 100 μm.

Final diagnosis

Based on all the data, the final diagnosis is PSVD.

Treatment

Upon admission, we provided patients with administer gastric mucosal protective medication and administer platelet transfusion therapy.

Outcome and follow-up

The patient has recovered well after the transjugular intrahepatic portosystemic shunt procedure and has been followed up to the present day without any incident of gastrointestinal bleeding.

BASIC THEORIES OF CONGENITAL PSVD CAUSING PORTAL HYPERTENSION

Pathophysiology of congenital PSVD

The pathogenesis of congenital portal hypertension fundamentally involves structural or hemodynamic abnormalities within the portal venous system. Such abnormalities include congenital venous developmental defects, congenital hepatic fibrosis, and perinatal venous thrombosis[2]. These underlying pathological changes elevate portal venous resistance, leading to clinical manifestations of portal hypertension - such as esophageal and gastric varices and splenomegaly - without diffuse hepatocyte injury or cirrhosis.

In some patients with congenital portal hypertension, angiography or multimodal imaging studies reveal congenital hypoplasia of venous trunks or portal vein anomalies, such as extrahepatic portal vein obstruction (EHPVO) and portal vein thrombosis[3]. These anomalies may impair portal venous blood flow, leading to increased vascular resistance within the portal venous system and consequently triggering portal hypertension. Specifically, peripheral portal vein obstruction typically originates from perinatal or neonatal portal vein thrombosis, leading to the formation of collateral circulation within the portal venous system. While these lesions generally do not cause significant liver damage, they result in complications such as splenomegaly, esophageal and gastric varices, and recurrent bleeding. Through analysis of imaging and genomic data from EHPVO patients, researchers discovered that this disease is closely associated with certain genetic predispositions. For instance, specific gene variants may influence vascular development and repair processes, thereby increasing the risk of developing portal hypertension.

Congenital hepatic fibrosis is another significant cause of congenital portal hypertension. This condition typically presents with marked hepatic fibrosis accompanied by portal hypertension. Although symptoms are often insidious, patients commonly develop liver failure and splenomegaly as the disease progresses. The pathogenesis of congenital hepatic fibrosis frequently involves abnormal development of hepatic tubules. The dilation of these tubules may elevate intrahepatic pressure, subsequently leading to increased portal vein pressure. Studies indicate that approximately 70%-80% of congenital hepatic fibrosis patients will develop portal hypertension[3].

Another aspect is the role of porphyria in PSVD. Congenital erythropoietic porphyria results from profound uroporphyrinogen III synthase deficiency. In documented cases, it is associated with hepatobiliary complications, characterized by different levels of liver fibrosis. A unique case of congenital erythropoietic porphyria developing PSVD with portal hypertension necessitating liver transplantation was reported[4]. This shows the complex relationship between porphyria-related liver disorders and PSVD (Figure 2).

Figure 2 The potential pathophysiological mechanisms of congenital portal hypertension essentially involve abnormalities in the structure or hemodynamics of the portal venous system. Including: Congenital venous developmental defects, congenital hepatic fibrosis, perinatal venous thrombosis, molecular genetic factors such as gene mutations, and environmental factors such as perinatal infections and drug exposure. Additionally, complications arising in related sites due to congenital portal hypertension may occur. FBN1: Fibrillin 1; NOTCH1: Notch receptor 1; ACVRL1: Activin A receptor like type 1; MRI: Magnetic resonance imaging.

Genetic and molecular mechanisms in congenital PSVD

The molecular mechanisms of portal hypertension are complex. However, recent studies have further revealed the crucial role of genetic and molecular mechanisms in congenital portal hypertension. Through genomic analysis of multigenerational families, researchers have identified key gene mutations closely associated with the development of congenital portal hypertension[1]. Particularly in patients with peripheral portal vein obstruction, mutations in certain thrombosis-related genes may represent a significant cause of portal vein thrombosis. Furthermore, genes associated with liver fibrosis and angiogenesis are also implicated in the development of congenital liver fibrosis. Gene mutations have been linked to isolated cases, as reported, an investigation revealed 34 genes and one chromosomal abnormality implicated in PSVD[2]. For example, mutations in genes such as potassium calcium-activated channel subfamily N member 3, deoxyguanosine kinase, familial obliterative portal venopathy, GTPase IMAP family member 5, FCH and double SH3 domains 1, tRNA methyltransferase 5, and histidine-rich glycoprotein are associated with isolated PSVD. Immune cells predominantly express these genes, which suggests they might have a more vital role in PSVD development than previously considered. Additionally, pathway analyses indicated two kinds of PSVD related to gene mutations: Those driven by morphogenetic disorders and those secondary to immunological alterations.

Regarding genetic mechanisms, we offered an extensive summary of genetic mutations linked to PSVD in patients without extrahepatic symptoms using whole-genome sequencing (Figure 2; Table 1).

Table 1 Genetic mutations associated with isolated porto-sinusoidal vascular disease.

Genes	Chromosome	Mutation	Transmission	Ref.
KCNN3	1	c.1348G>C	Autosomal dominant	[33]
DGUOK	2	c.l37A>G-c.831_832del	Autosomal recessive	[34,35]
FOPV	4	c.1783G>A-c.4895C>T	Autosomal dominant	[36]
GIMAP5	7	pI47T-p.P109 L-p.L204P-p.L223F	Autosomal recessive	[37]
FCHSD1	5	c.547C>T	Autosomal dominant	[38]
TRMT5	14	c.617T>C-c.899A>T	Autosomal recessive	[39]
HRG	3	c.545G>C-p.R182T	Autosomal dominant	[40]

KCNN3: Potassium calcium-activated channel subfamily N member 3; DGUOK: Deoxyguanos kinase; FOPV: Familial obliterative portal venopathy; GIMAP5: GTPase, IMAP family member 5; FCHSD1: FCH and double SH3 domains 1; TRMT5: TRNA methyltransferase 5; HRG: Histidine-rich glycoprotein.

Historical perspectives on congenital PSVD

Although there is limited literature directly on the historical perspectives of congenital PSVD, studies on other congenital vascular disorders can offer some insights. For example, Since the first report of afibrinogenemia in 1920, substantial breakthroughs in congenital fibrinogen disorders[5]. The discovery of three pathogenic mutations in fibrinogen genes has advanced our understanding of fibrinogen biosynthesis mechanisms and elucidated fundamental processes in fibrin polymerization and fibrinolysis. This historical development in understanding congenital fibrinogen disorders may parallel the potential historical evolution in the understanding of congenital PSVD, highlighting the significance of long-range research and discovery in elucidating the nature of such rare congenital vascular-related conditions (Figure 2).

Environmental factors contributing to congenital PSVD

In addition to genetic factors, environmental factors also play a role in the development of congenital portal hypertension. For example, perinatal infections and drug exposure may be potential triggers for portal vein thrombosis (Figure 2).

EPIDEMIOLOGY AND GLOBAL TRENDS OF CONGENITAL PSVD-INDUCED PORTAL HYPERTENSION

Previous epidemiological evidence indicates that although the overall incidence of congenital portal hypertension is low and lacks rigorous national/international registry systems, non-cirrhotic/congenital portal hypertension (NCPH) constitutes a significant proportion in pediatric populations, particularly manifestations such as congenital liver fibrosis and congenital EHPVO[6]. Its etiological composition, clinical presentation, and natural history exhibit marked geographical and etiological variations. Therefore, more systematic cohort studies are needed in the future to accurately assess incidence rates and genetic/environmental influences.

According to the latest review, NCPH in pediatric portal hypertension patients is primarily attributed to the following etiologies: Extrahepatic portal venous obstruction: Account for the majority of NCPH cases[7]. Congenital hepatic fibrosis and non-cirrhotic portal fibrosis: Typically, due to congenital/developmental causes. These etiologies differ markedly from the distribution of causes of adult portal hypertension in developed countries; EHPVO accounts for a higher proportion in developing nations, whereas portal hypertension associated with cirrhosis is more prevalent overall in European and American countries[8].

Based on previously reported multicenter cohort and retrospective analyses[2], patients with EHPVO typically present during childhood or adolescence with symptoms including splenomegaly, gastrointestinal varices, and recurrent bleeding. Most retain well-preserved liver function, but complications are significant.

Examples of typical congenital-related etiologies: (1) Congenital fibrosis of the superior portal vein represents a manifestation of congenital structural abnormalities within the portal venous system, potentially leading to increased portal venous resistance and hypertension[9]; (2) Peripheral portal vein obstruction (portal cavernoma) often originates from perinatal portal vein thrombosis[10]; and (3) Peripheral portal vein obstruction (portal cavernoma) often originates from perinatal portal vein thrombosis, subsequently forming complex collateral circulation.

For PSVD-induced portal hypertension, although specific global trends are not well-established, understanding the trends in related liver diseases can be informative. Monitoring global trends in PSVD-induced portal hypertension, if established, would be crucial for international health policy-making and resource allocation[11].

DIAGNOSTIC TECHNIQUES FOR CONGENITAL PSVD-INDUCED PORTAL HYPERTENSION

Imaging modalities and innovations

Imaging modalities play a crucial role in diagnosing congenital PSVD causing portal hypertension. Cross-sectional imaging modalities, such as computed tomography and magnetic resonance imaging, can deliver essential diagnostic information. In a comparative study of histologically confirmed cases, intrahepatic portal system abnormalities were observed in 49% of PSVD patient’s vs 15% of cirrhotic controls (P < 0.001), while focal nodular hyperplasia-like lesions occurred in 30% of PSVD cases compared to 1% in non-cirrhotic parenchymal liver disease (P < 0.001). Liver morphological abnormalities, characterized by peripheral parenchymal atrophy and central segmental vicarious hypertrophy, showed a significantly higher prevalence in PSVD patients (32% vs 7%; P < 0.001)[12].

Furthermore, on gadoxetic acid-enhanced magnetic resonance imaging hepatobiliary phase, a characteristic imaging finding - periportal hyperintensity - was identified in 42% (14/33) of PSVD patients. This finding was absent in cirrhotic controls (1/95, 1.1%) and non-cirrhotic parenchymal disease controls (0/41, 0%; P < 0.001). These findings suggest that cross-sectional imaging can help in the diagnosis of PSVD, especially in differentiating it from cirrhosis. Future imaging innovations may further improve the diagnostic accuracy, similar to the advancements in other fields such as the development of new imaging techniques for bone metastasis detection, which offer unique advantages in different aspects of diagnosis[13].

Biomarkers and laboratory assessments

Biomarkers and laboratory assessments can potentially aid in the diagnosis of congenital PSVD with portal hypertension. Although specific biomarkers for this disorder are not well-defined, in other diseases, biomarkers have proven useful. For example, in paroxysmal nocturnal hemoglobinuria, various biomarkers can be utilized to track complement pathway inhibition and assess the effectiveness of treatment[14].

In the context of PSVD, some studies have explored related factors. Research indicates that PSVD patients exhibit increased copper content in the liver, with 32% having moderate (≥ 50 μg/g) and 4% having significant (≥ 250 μg/g) elevations[15]. Increased levels correlated with younger age, while hepatic copper content was notably tied to liver-related outcomes. This indicates that laboratory assessments of hepatic copper and potentially other biomarkers could be relevant in the diagnosis and prognosis of PSVD-induced portal hypertension.

Histopathology confirmation

Liver biopsy is of significant value in confirming PSVD. The patient’s liver tissue typically shows portal fibrosis, sinusoidal endothelial proliferation, and intact lobular architecture, without the typical pseudo-lobular formation seen in cirrhosis. Non-specific pathological findings include: Abnormal portal vein branches (arterial proliferation, dilation, and anomalous vessels closely connected to the portal vein within the confluence area), vascular structural disorganization (such as irregular distribution of the portal and central veins), non-band-like sinusoidal dilatation, and mild perisinusoidal fibrosis[16].

Differential diagnosis challenges

Differentiating congenital PSVD causing portal hypertension from other conditions presenting with portal hypertension is challenging, the lack of specific diagnostic criteria is the primary challenge in confirming the disease at present. Clinicians often need to integrate multiple diagnostic tools for comprehensive assessment rather than relying on a single indicator for confirmation. This may further complicate early diagnosis in resource-constrained areas.

As demonstrated by this patient’s clinical course, most patients may experience a period of “cirrhosis” or other related syndromes without an identifiable primary cause. Therefore, reevaluating the medical history and liver biopsy specimens is crucial prior to definitive diagnosis. Imaging evaluations should be performed early to guide clinical practice. According to a systematic review, elastography and cross-sectional imaging are effective non-invasive methods for accurately distinguishing PSVD from cirrhosis[17]. In PSVD, both transient elastography and magnetic resonance elastography demonstrate significantly reduced liver stiffness measurements and elevated spleen stiffness measurements, resulting in higher spleen stiffness measurement/Liver stiffness measurement ratios compared to cirrhosis.

Among imaging features, signs such as focal nodular hyperplasia-like lesions, irregular portal veins (both intra-hepatic and extra-hepatic), and splenomegaly suggest PSVD. In contrast, nodular changes and atrophy on the surface of segment IV are different from the signs that suggest the diagnosis of cirrhosis.

The definitive diagnosis of PSVD still relies on liver biopsy, but this invasive procedure carries a risk of bleeding. Furthermore, histological findings may lack specificity in some patients, leading to misdiagnosis or missed diagnosis. Additionally, sampling errors may result in patients undergoing liver biopsy failing to reveal positive pathological changes[18].

TREATMENT STRATEGIES FOR CONGENITAL PSVD-INDUCED PORTAL HYPERTENSION

Pharmacological interventions and efficacy

For portal hypertension, whether congenital NCPH or acquired cirrhosis-related hypertension, the goals of drug intervention are: (1) Reduce portal vein pressure and decrease the risk of variceal bleeding; (2) Improve portal venous hemodynamics and related pathologies (e.g., splenomegaly, visceral complications); and (3) Delay the onset of complications and mortality risk[19]. Current mainstream clinical drug strategies include: (1) Non-selective beta-blockers: Drugs like propranolol and nadolol reduce portal pressure by decreasing cardiac output and portal venous flow, thereby lowering the risk of variceal bleeding. In pediatric portal hypertension, β-blockers are used for secondary prevention (i.e., in patients with existing variceal bleeding risk) based on adult data, though standalone evidence is limited; (2) Vasoconstrictive peptide analogues: Octreotide can reduce portal venous flow by inhibiting splenic and gastrointestinal blood flow, serving as a short-term bridging therapy during acute bleeding episodes; and (3) Targeted endothelial function modulation drugs (exploratory in adult studies): Drugs targeting pathways such as NO and endothelin have been studied in adults, but evidence in pediatric congenital portal hypertension remains extremely limited and is primarily in the research phase. It is important to note that most evidence for drug interventions originates from adult cirrhotic portal hypertension or small pediatric cohorts. High-quality randomized controlled trials specifically targeting congenital NCPH remain scarce (Figure 3)[20].

Figure 3 Treatment approaches for congenital portal hypertension. Including pharmacological interventions, endoscopic therapy during acute bleeding episodes, and surgical/interventional procedures to improve long-term prognosis.

Endoscopic and surgical treatment

Beyond pharmacological interventions, comprehensive supportive management forms the cornerstone of congenital portal hypertension management. Interventions are typically individualized based on clinical stage and complications: (1) Endoscopic procedures[21]: Endoscopic variceal ligation or sclerotherapy are the primary methods for controlling gastrointestinal bleeding. Unlike adults, pediatric patients with EHPVO require regular follow-up evaluations to assess long-term compliance with endoscopic treatments and monitor for the development of complications; (2) Surgical procedures[22]: Physiological bypass procedure - Meso Rex bypass. For patients with EHPVO, it serves as a physiological portal vein re-establishment pathway that restores normal hepatic blood flow. It is currently the preferred long-term intervention recommended in international consensus guidelines. Percutaneous interventional and reconstructive approaches; (3) Portal vein recanalization: Recent studies[23] indicate that interventional portal vein recanalization techniques can restore hepatic portal venous blood flow in a proportion of pediatric patients who are ineligible for Meso Rex bypass, suggesting these techniques may serve as adjunctive or alternative solutions in the future; and (4) Liver transplantation: For patients who fail to respond to medication and various interventional therapies, or who develop liver failure or severe complications from portal hypertension, liver transplantation remains the ultimate treatment option. It fundamentally alleviates portal hypertension and improves quality of life (Figure 3).

Supportive treatment

Nutritional support and growth monitoring: Pediatric patients often present with malnutrition or growth retardation, necessitating systematic strategies for protein, caloric, and micronutrient supplementation.

Splenic function monitoring: Significant splenomegaly may cause cytopenia and bleeding tendencies, requiring collaborative treatment adjustments with hematology.

Multidisciplinary team management: Involves collaboration among pediatric hepatology, interventional radiology, nutrition, anesthesia, and surgical teams to optimize individualized treatment pathways.

Emerging therapies and clinical trials

Despite ongoing advances in the treatment of congenital portal hypertension, numerous challenges persist in pharmacological interventions, supportive care, and surgical management. Particularly for portal hypertension arising from different etiologies, treatment strategies should be more individualized. Emerging therapies and clinical trials offer hope for improving the treatment of portal hypertension secondary to congenital PSVD. For example, specific targeted therapies such as endothelial function modulators; or direct intervention in the molecular mechanisms of portal hypertension through gene therapies like clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeats-associated protein 9, repairing relevant gene mutations or regulating the expression of genes involved in angiogenesis and thrombosis, thereby effectively treating or preventing congenital portal hypertension[24].

For PSVD-induced portal hypertension, emerging therapies could potentially target the specific genetic or molecular mechanisms identified in the disorder. Rigorous clinical trials are need to be conducted to assess the safety profile and therapeutic efficacy of these novel therapeutic agents. Nevertheless, conducting clinical trials for rare diseases like PSVD-induced portal hypertension faces challenges such as patient recruitment and the need for long-term follow-up, presenting challenges analogous to those encountered in spinal cord injury clinical trials (Figure 3)[25].

CLINICAL MANAGEMENT AND PRACTICE IN CONGENITAL PSVD-INDUCED PORTAL HYPERTENSION

Guidelines for monitoring and follow-up

Guidelines for monitoring and follow-up are essential in the clinical management of portal hypertension secondary to congenital PSVD. Long-term follow-up studies reveal that changes in liver function and spleen size serve as crucial indicators for clinical monitoring of portal hypertension[26].

In the case of PSVD-induced portal hypertension, esophageal and gastric varices along with recurrent gastrointestinal bleeding represent some of the most common clinical manifestations of this disease, significantly impacting patients’ quality of life and prognosis. Therefore, regular monitoring of liver function, portal pressure, and complication occurrence such as gastroesophageal varices is crucial. Imaging studies, laboratory tests, and clinical evaluations should be part of the follow-up protocol, and the frequency and type of monitoring may need to be individualized based on the patient’s condition[27].

Multidisciplinary care approaches

Multidisciplinary care approaches are beneficial in the management of congenital PSVD with portal hypertension. In other complex diseases, such as congenital central hypoventilation syndrome, a coordinated multidisciplinary approach involving pulmonologists, otolaryngologists, cardiologists, anesthesiologists, gastroenterologists, sleep medicine physicians, geneticists, surgeons, oncologists, and respiratory therapists can optimize care and improve patient outcomes[28].

For PSVD-induced portal hypertension, a multidisciplinary team may include hepatologists, radiologists, gastroenterologists, and surgeons. The team can work together to diagnose, treat, and manage the patients, taking into account the complex nature of the disorder, which involves both vascular and liver-related aspects. This approach can also help in addressing the various complications and comorbidities that may arise in these patients.

Patient quality of life and supportive care

Patient quality of life and supportive care are important aspects of managing congenital PSVD inducing portal hypertension. Supportive care requirements can be overwhelming for patients undergoing hematopoietic stem cell transplants, and quality of life can be significantly affected[29]. The most frequently utilized supportive care resources included information from doctors and nurses, support groups, and faith-based support.

In the context of PSVD-induced portal hypertension, patients may experience physical and psychological distress due to the disease and its complications. Providing supportive care, such as psychological counseling, nutritional support, and education about the disease, can enhance the patient’s quality of life. Additionally, ensuring proper pain management and addressing the social and emotional needs of the patients are essential components of comprehensive care.

DISCUSSION

Debates on pathogenesis and classification

There are debates on the pathogenesis and classification of congenital PSVD with portal hypertension, the exact pathogenesis is still not fully understood, and there may be different views on how to classify the disorder.

Some may argue that the classification should be based on genetic mutations, while others may consider the clinical manifestations and associated comorbidities. However, the penetrance of genetic mutations and congenital portal hypertension varies significantly among individuals, closely linked to genetic background and environmental factors. Not all individuals carrying the mutated gene will exhibit clinical symptoms. Furthermore, epigenetic modifications - such as DNA methylation and histone modifications - play crucial roles in regulating gene expression. These modifications may be activated or suppressed under specific environmental or external stimuli, thereby influencing disease onset. Therefore, while certain gene mutations are associated with congenital portal hypertension, their penetrance is not 100% and may be influenced by environmental factors, epigenetic modifications, and interactions with other genes[30].

Although genetic testing plays a crucial role in revealing the genetic background of congenital portal hypertension, many patients may receive “negative” results - meaning no known genetic mutations associated with portal hypertension are detected. This outcome does not imply the absence of genetic factors and requires careful interpretation. Polygenic and complex genetic background: Congenital portal hypertension typically results from polygenic inheritance and may be closely associated with epigenetic modifications. In such cases, single-gene testing may fail to capture all relevant genetic variations. Therefore, a negative result does not imply the absence of genetic predisposition. Clinicians should interpret negative results as a negation within the scope of currently known genes, not as a comprehensive exclusion of genetic factors. Novel genes and unknown mutations: The limitations of genetic testing also extend to identifying unknown genes or novel mutations. With ongoing advances in genomics, additional genes associated with congenital portal hypertension may be discovered in the future. This implies that a negative genetic test result cannot completely rule out the role of hereditary factors. Clinicians should remain attentive to new research and technologies to update the reference databases for genetic testing.

When faced with negative genetic test results, clinicians should adopt the following strategies: Integrate clinical presentation and family history: Although genetic testing provides insights into hereditary background, clinical diagnosis still requires comprehensive evaluation of clinical symptoms, family history, and imaging findings. In the clinical management of portal hypertension, medical history collection and familial genetic information are particularly crucial, as some genetic disorders may exhibit incomplete penetrance or phenotypic diversity due to genetic variations. Dynamic follow-up and multidisciplinary collaboration: Patients with negative results still require long-term follow-up to promptly detect early clinical signs of portal hypertension.

Resolving these debates is crucial for accurate diagnosis, treatment, and research. For example, a clear understanding of the pathogenesis can help in developing targeted therapies, and a standardized classification system can facilitate communication among researchers and clinicians.

Innovations in personalized medicine

Innovations in personalized medicine have the potential to transform the treatment of congenital PSVD inducing portal hypertension. In the oncological field, precision medicine, which integrates molecular profiling of individual tumors with established clinicopathological parameters, has facilitated the formulation of personalized and tumor-specific therapeutic regimens[31].

For PSVD-induced portal hypertension, personalized medicine could involve using genetic and molecular information to guide treatment decisions. For example, if specific gene mutations are identified in a patient, targeted therapies can be developed or selected. Additionally, understanding the individual patient’s immune response and other physiological characteristics can help in optimizing treatment. However, implementing personalized medicine in PSVD-induced portal hypertension faces challenges such as the need for advanced diagnostic technologies and the high cost of personalized treatments.

Future research priorities and technological advances

Future research priorities for congenital PSVD with portal hypertension should focus on several aspects. Firstly, more in-depth studies on the pathophysiology and genetic mechanisms are needed to fully understand the disorder. This could involve large-scale genetic studies to identify more genes associated with PSVD and to clarify the molecular pathways involved. Secondly, developing accurate and non-invasive diagnostic tools is crucial. Technological advances in imaging and biomarker discovery, similar to the progress in liquid biopsies and DNA sequencing in precision medicine[32], could lead to earlier and more accurate diagnosis. Furthermore, the translational significance of genetic research lies in enhanced multidisciplinary collaboration. For instance, in the management of patients with portal hypertension, cooperation among geneticists, pediatric hepatologists, and genetic counselors can effectively facilitate the translation of research findings into clinical practice. Thirdly, clinical trials should be conducted to appraise the safety and availability of newly-developing therapies, both pharmacological and non-pharmacological. Finally, improving the understanding of the long-term outcomes and quality of life of patients with PSVD-induced portal hypertension is essential for comprehensive management.

CONCLUSION

The clinical manifestations of PSVD patients exhibit significant heterogeneity. When accompanied by portal hypertension, the condition can easily be confused with cirrhosis. Therefore, enhancing comprehensive understanding of the disease’s clinical characteristics and refining the diagnostic and treatment protocols are crucial for clinicians.

ACKNOWLEDGEMENTS

We extend our gratitude to the departmental staff for their assistance in data collection and to our pathologists for preparing the microscopic slides essential.