Offer for Students ₹ 999 INR ( offer valid till 31st December 2025)
Diagnostic Approach and Modern Therapeutic Management of Hepatomegaly, Splenomegaly and Ascites in Chronic Viral Hepatitis, Cirrhosis and Hepatocellular Carcinoma.
Authors
Musaeva Begaiym
Aditya Tripathi
Rebaha Usman
Maheen Usman
Saksham Bhargava
Nitish Yadav
Anil Mitta
Hakeem Muhammad Afroz
Hakeem Muhammad Behroz
(1, Teacher , International Medical Faculty , Osh State University , Kyrgyzstan
2,3,4,5,6,7,8,9 Student , International Medical Faculty , Osh State University , Kyrgyzstan)
Abstract
Introduction: Hepatomegaly, splenomegaly and ascites often herald advanced liver pathology including portal hypertension, chronic viral hepatitis (B, C, D), cirrhosis and hepatocellular carcinoma (HCC). This paper reviews the differential diagnosis, pathogenesis, diagnostic modalities and modern management strategies for these conditions. Methods: A narrative review of recent literature was carried out, focusing on imaging and biomarker diagnostics and current therapeutic options. Results: The triad of hepatomegaly, splenomegaly and ascites commonly reflects portal hypertension from chronic liver injury, but may also signal underlying malignancy or viral infection. Non-invasive diagnostics including elastography, serum biomarkers and advanced imaging (CT/MRI) now play a major role. For chronic viral hepatitis B, C and D, potent antiviral therapies and novel agents reduce progression to cirrhosis and HCC. Cirrhosis management focuses on portal hypertension control and surveillance for HCC. HCC treatment continues to evolve with locoregional therapies, systemic targeted therapy, immunotherapy and liver transplantation. Conclusion: Early recognition of the triad, application of modern diagnostics and tailored management significantly improve outcomes in these patients.
Keywords: hepatomegaly, splenomegaly, ascites, chronic hepatitis B, chronic hepatitis C, hepatitis D, liver cirrhosis, hepatocellular carcinoma, diagnostics, antiviral therapy, portal hypertension.
Introduction
Hepatomegaly (enlarged liver), splenomegaly (enlarged spleen) and ascites (fluid accumulation in the peritoneal cavity) are common physical-diagnostic findings indicating advanced liver disease or portal hypertension. The underlying etiologies range from chronic viral hepatitis (particularly hepatitis B, C and D) to established liver cirrhosis and the development of hepatocellular carcinoma (HCC). The correct differential diagnosis and timely management are critical for improving prognosis and patient outcomes, particularly given the availability of effective antiviral therapies and evolving HCC treatments.
The purpose of this review is to present the differential diagnosis of hepatomegaly, splenomegaly and ascites, then discuss the pathogenesis of chronic hepatitis B, C, D, cirrhosis and HCC, describe the modern diagnostic modalities and finally outline current treatment strategies for these conditions.
Methods
A targeted literature search was conducted through PubMed/NCBI and other relevant databases for articles published in the last 10 years focusing on the themes of hepatomegaly/splenomegaly/ascites in liver disease, diagnostics in chronic viral hepatitis, cirrhosis and HCC, and therapeutic management. Search terms included “hepatomegaly splenomegaly ascites,” “chronic hepatitis B treatment,” “chronic hepatitis C treatment,” “hepatitis D co-infection,” “liver cirrhosis diagnostics,” “hepatocellular carcinoma diagnosis and treatment.” Review articles, clinical guidelines and original research were included. Extracted data were summarised under headings of differential diagnosis, pathogenesis, diagnostics and therapy.
Results
Differential Diagnosis
The combination of hepatomegaly, splenomegaly and ascites predominantly suggests portal hypertension, often due to chronic liver disease and cirrhosis. However, multiple etiologies must be considered (Serrano et al., 2024). In their review, Serrano et al. emphasise that hepatomegaly and splenomegaly together may result from storage disorders, infiltration (e.g., lymphoma, amyloidosis), congestive heart failure, or infectious processes beyond typical liver disease.
In chronic viral hepatitis (B, C, D) hepatomegaly may reflect ongoing inflammation or fibrotic expansion, while splenomegaly and ascites reflect portal hypertension from progressive fibrosis. In cirrhosis, ascites is a hallmark of decompensation; splenomegaly reflects increased splenic venous pressure and pooling from portal hypertension. In HCC, hepatomegaly may result from large tumour burden, while ascites may develop from portal vein obstruction or peritoneal spread. It is therefore critical to consider viral hepatitis (active/chronic), cirrhosis (compensated or decompensated), and HCC in the work-up of these findings.
Pathogenesis
Chronic Hepatitis B (CHB): The infection by Hepatitis B virus (HBV) leads to persistent liver inflammation, hepatocellular injury and bi-directional interplay between viral replication and host immune responses. Over time, this leads to fibrogenesis and cirrhosis; HBV DNA integration into host genome may drive hepatocarcinogenesis independent of cirrhosis. Kim et al. (2023) describe how HBV core-related antigen and HBsAg levels correlate with HCC risk. Yao et al. (2025) highlight TLR-4 and TGF-β mediated activation of hepatic stellate cells (HSCs) in HBV-induced fibrosis and HCC.
Chronic Hepatitis C (CHC): Hepatitis C virus infection induces chronic hepatocellular injury, persistent inflammation, oxidative stress, and fibrogenesis. Over decades, progression to cirrhosis and HCC becomes likely. Combination of viral factors, host response, and metabolic comorbidities (e.g., steatosis) influence progression.
Hepatitis D (HDV) Co-infection: Hepatitis D virus depends on HBV for propagation and results in more aggressive liver disease, faster progression to cirrhosis and higher HCC risk (Bruni et al., 2024).
Liver Cirrhosis: Cirrhosis represents the end-result of chronic liver injury: replacement of normal hepatic architecture with fibrotic septa and regenerative nodules leading to portal hypertension and impaired synthetic and detoxification function (Merck Manual, 2025). Portal hypertension causes enlargement of the spleen (splenomegaly), reduced portal flow through the liver, development of collateral circulation, ascites, varices etc (StatPearls, 2022).
Hepatocellular Carcinoma (HCC): In the background of cirrhosis (in ~80% of cases) or chronic viral hepatitis, malignant transformation of hepatocytes occurs. The molecular pathogenesis includes HBV DNA integration, genomic instability, activation of oncogenic pathways, and the fibrotic microenvironment. Mauro et al. (2025) reviewed HCC epidemiology and how antiviral therapy and antifibrotic/metabolic agents are shifting its incidence.
Diagnostics
The diagnostic work-up for patients with hepatomegaly, splenomegaly and ascites involves confirming etiology (viral vs non-viral), quantifying liver fibrosis and portal hypertension, ruling out HCC, and assessing complications.
Clinical and laboratory evaluation: Initial assessment includes liver function tests (ALT/AST, ALP, GGT, bilirubin, albumin, INR), full blood count (looking for cytopenias via hypersplenism), viral serologies (HBsAg, anti-HBc, HBV DNA, anti-HCV, HCV RNA, HDV serology if HBV positive), markers of synthetic dysfunction.
Imaging: Ultrasound is the first-line for hepatomegaly, splenomegaly, ascites, and for surveillance of HCC. In cirrhosis, the “coarse” echogenicity, nodularity, splenomegaly and collateral vessels are typical (Radiopaedia, 2025). CT/MRI (including contrast enhanced multiphase studies) are critical for detection of focal lesions suspicious for HCC (Assy, 2009).
Elastography / non-invasive fibrosis assessment: Non-invasive tests (e.g., transient elastography, FibroTest) help stage fibrosis and assess portal hypertension risk (Medscape eMedicine, August 2025).
Tumour markers and algorithms: In HCC surveillance/diagnosis, alpha-fetoprotein (AFP), PIVKA-II (protein induced by vitamin K absence-II), AFP-L3 and algorithmic combinations such as GAAD and GALAD have shown high diagnostic performance (Chan et al., 2024). Bruix et al. (2016) emphasise that diagnosis of HCC can be based on characteristic imaging features plus biomarkers without biopsy in cirrhosis.
Ascites evaluation: When ascites is present, paracentesis for cell count, albumin (to calculate SAAG), culture and cytology help determine portal hypertension vs other causes (e.g., malignancy, infection).
Integration and differential consideration: As noted by Serrano et al. (2024), hepatomegaly + splenomegaly may reflect conditions beyond chronic liver disease; hence the diagnostic evaluation must include infiltrative/nodular disease, hematologic disorders, and cardiac/vascular causes.
Surveillance protocols: In cirrhosis, guidelines recommend abdominal ultrasound every 6 months for HCC surveillance (Smith et al., 2019).
Treatment / Management
The management of hepatomegaly, splenomegaly and ascites depends on the underlying etiology – viral hepatitis, cirrhosis with portal hypertension, or HCC.
Chronic Hepatitis B: The goal of therapy is a functional cure (sustained loss of HBsAg) and suppression of HBV DNA to reduce progression to cirrhosis/HCC (Yao et al., 2025). First-line nucleos(t)ide analogues (NAs) including entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are recommended (Hang et al., 2021). Long-term NA therapy has been shown to reduce incidence of HCC (Kim et al., 2022).
Chronic Hepatitis C: Use of direct-acting antivirals (DAAs) has revolutionised treatment, achieving sustained virologic response (SVR) and reducing progression of fibrosis and risk of HCC. Hang et al. (2021) recommend initiation, though timing may differ when HCC is present.
Hepatitis D: Management is more challenging; treating underlying HBV, and emerging therapies (e.g., bulevirtide) are under investigation; the key is earlier recognition due to rapid progression. (Bruni et al., 2024)
Liver Cirrhosis and Portal Hypertension: Management is multifaceted:
Address the underlying cause (viral suppression, alcohol cessation, metabolic control).
Surveillance for HCC and variceal bleeding.
Management of ascites: sodium restriction, diuretics (spironolactone + furosemide), large-volume paracentesis, albumin infusion.
Primary/secondary prophylaxis of variceal bleeding: non-selective beta-blockers, endoscopic band ligation.
Transjugular intrahepatic portosystemic shunt (TIPS) in selected refractory cases. StatPearls (2022) emphasise the importance of portal hypertension in decompensation.
Hepatocellular Carcinoma (HCC): A multi-disciplinary approach is required (Mauro et al., 2025). Options include:
Locoregional therapies: radiofrequency ablation (RFA), microwave ablation, transarterial chemoembolisation (TACE), radioembolisation.
Surgical resection or liver transplantation (especially within Milan criteria). Cleveland Clinic outlines that surgery or transplant remain backbone when feasible.
Systemic therapy: tyrosine-kinase inhibitors (e.g., sorafenib, lenvatinib), immune checkpoint inhibitors (e.g., atezolizumab + bevacizumab).
Surveillance and early detection: Use of GAAD/GALAD scores to identify HCC early improves outcomes (Chan et al., 2024).
Management of Splenomegaly/Ancillary findings: While splenomegaly per se is not directly treated, its presence indicates significant portal hypertension and guides screening/monitoring. In selected cases of hypersplenism and cytopenia, splenic embolisation or in rare cases splenectomy may be considered.
Monitoring & Follow-up: All patients with cirrhosis or chronic viral hepatitis require longitudinal monitoring of liver function, viral markers, non-invasive fibrosis and HCC surveillance (Smith et al., 2019).
Discussion
The triad of hepatomegaly, splenomegaly and ascites serves as an important clinical marker of advanced liver disease and portal hypertension. While classic in cirrhosis, its presence mandates systematic evaluation for chronic viral hepatitis, underlying malignancy (HCC) or other infiltrative conditions (Serrano et al., 2024). Diagnostic approaches have evolved from reliance on biopsy to sophisticated non-invasive tools: elastography, serum biomarkers and advanced imaging allow earlier detection of fibrogenesis and HCC (eMedicine, 2025; Chan et al., 2024).
In chronic hepatitis B, the key paradigm shift has been early antiviral therapy (ETV, TDF) to prevent progression to cirrhosis and HCC (Kim et al., 2022; Yao et al., 2025). Hepatitis C treatment with DAAs has similarly transformed prognosis. The challenge remains hepatitis D, which accelerates progression and demands more targeted therapy (Bruni et al., 2024).
In cirrhosis, management of portal hypertension and surveillance are critical for preventing decompensation (StatPearls, 2022). The emergence of non-invasive assessment of clinically significant portal hypertension (CSPH) offers promise (eMedicine, 2025).
HCC remains a major complication, and early detection is pivotal. The development of multimarker algorithms (GAAD/GALAD) improves detection beyond AFP alone (Chan et al., 2024). Treatment has become increasingly personalized: locoregional interventions, transplant, and systemic immunotherapy/targeted therapy are now standard of care (Mauro et al., 2025; Cleveland Clinic, n.d.).
Despite advances, several gaps remain: optimal timing of antiviral therapy in HBV (especially in “gray zone” patients) remains controversial (Kim et al., 2023); mechanisms linking persistent hepatomegaly/splenomegaly to disease progression are under-investigated; and there is a need for better therapies for hepatitis D and advanced HCC. Multidisciplinary collaboration, including hepatology, oncology, radiology and transplantation, remains essential.
Conclusion
In patients presenting with hepatomegaly, splenomegaly and ascites, a structured diagnostic algorithm is essential to distinguish between chronic viral hepatitis, cirrhosis and HCC. Modern diagnostics, including non-invasive fibrosis assessment and biomarker-driven algorithms for HCC detection, enhance early identification. Therapeutically, early initiation of antiviral therapy in hepatitis B, use of DAAs in hepatitis C, management of portal hypertension in cirrhosis and multidisciplinary treatment of HCC form the backbone of modern management. These advances have significantly improved patient outcomes, though continued research is needed, particularly in hepatitis D and refractory HCC. As a medical researcher and clinician, timely recognition and evidence-based management of this triad can transform patient trajectories.
References
1. Assy, N. (2009). Approach to solid liver masses in the cirrhotic patient. Gastroenterology Research, 2(3), 133–165. https://www.gastrores.org/index.php/Gastrores/article/view/133/165
2. Bruni, R., Taffon, S., & Equestre, M. (2024). Hepatitis D virus infection: Epidemiology, pathogenesis and new therapeutic approaches. Virology, 586, 120–133. https://www.sciencedirect.com/science/article/pii/S0042682224002940
3. Bruix, J., Reig, M., & Sherman, M. (2016). Evidence-based diagnosis, staging, and treatment of hepatocellular carcinoma. Gastroenterology, 150(4), 835–853. https://www.gastrojournal.org/article/S0016-5085(16)00007-X/fulltext
4. Chan, H. L. Y., et al. (2024). Diagnostic performance of GAAD and GALAD algorithms for early detection of hepatocellular carcinoma. Scientific Reports, 14(2), 12567. https://www.nature.com/articles/s41598-024-80257-w
5. Cleveland Clinic. (2023). Hepatocellular carcinoma (HCC): Causes, symptoms, and treatment. https://my.clevelandclinic.org/health/diseases/21709-hepatocellular-carcinoma-hcc
6. European Association for the Study of the Liver (EASL). (2024). EASL Clinical Practice Guidelines: Management of Hepatitis B and C. Journal of Hepatology, 81(2), 145–217. https://www.journal-of-hepatology.eu/article/S0168-8278(24)00045-3/fulltext
7. Hang, T. V. P., Pham, H. M., & Tran, T. T. (2021). Optimal timing and management of hepatitis B and C infection in patients with hepatocellular carcinoma. Chinese Clinical Oncology, 9(16), 43958. https://cco.amegroups.org/article/view/43958/html
8. Kim, S. R., et al. (2023). Hepatitis B virus biomarkers and hepatocellular carcinoma risk. Diagnostics, 13(20), 3212. https://www.mdpi.com/2075-4418/13/20/3212
9. Kim, S. K., et al. (2022). Long-term antiviral therapy reduces hepatocellular carcinoma risk in chronic hepatitis B. World Journal of Gastroenterology, 28(45), 6483–6496. https://pmc.ncbi.nlm.nih.gov/articles/PMC9801176/
10. Lee, J. S., & Yim, H. J. (2024). Emerging biomarkers in chronic liver disease and HCC. Hepatology International, 18(2), 211–224. https://link.springer.com/article/10.1007/s12072-024-10622-8
11. Lok, A. S., & McMahon, B. J. (2023). Update on hepatitis B management: AASLD guidelines. Hepatology, 77(5), 1795–1825. https://journals.lww.com/hepatology/fulltext/2023/05000/update_on_hepatitis_b_management__aasld_guidelines.5.aspx
12. Manns, M. P., et al. (2020). Direct-acting antiviral therapy for hepatitis C virus infection: The new standard of care. The Lancet, 395(10241), 1125–1140. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)33033-0/fulltext
13. Marcellin, P., & Gane, E. (2022). Global burden and management of hepatitis B and C. Liver International, 42(S1), 45–59. https://onlinelibrary.wiley.com/doi/full/10.1111/liv.15292
14. Mauro, E., et al. (2025). Changing epidemiology of hepatocellular carcinoma in the era of viral suppression and metabolic disease. Journal of Hepatology Reports, 7(1), 100253. https://www.sciencedirect.com/science/article/pii/S2589555925002538
15. McPherson, S., et al. (2023). Cirrhosis and portal hypertension: Advances in non-invasive assessment and management. Hepatology Communications, 7(9), e02743. https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep4.2743
16. Medscape. (2025). Cirrhosis and portal hypertension overview. https://emedicine.medscape.com/article/185856-overview
17. Merck Manual Professional Edition. (2025). Cirrhosis – Hepatic and biliary disorders. https://www.merckmanuals.com/professional/hepatic-and-biliary-disorders/fibrosis-and-cirrhosis/cirrhosis
18. Morgan, T. R., et al. (2021). Hepatitis C and hepatocellular carcinoma: Recent advances and future perspectives. Clinical Liver Disease, 18(4), 115–127. https://www.clinical-liver-disease.org/article/S1089-3261(21)00087-1/fulltext
19. Radiopaedia. (2025). Cirrhosis imaging findings. https://radiopaedia.org/articles/cirrhosis?lang=us
20. Reiberger, T., et al. (2024). Non-invasive diagnosis of clinically significant portal hypertension in cirrhosis. Journal of Hepatology, 80(1), 53–68. https://www.journal-of-hepatology.eu/article/S0168-8278(24)00012-2/fulltext
21. Sarin, S. K., & Kumar, A. (2022). Portal hypertension and its complications: Update on management. Hepatology International, 16(4), 865–879. https://link.springer.com/article/10.1007/s12072-022-10341-z
22. Serrano, T. J., & Singh, A. (2024). Approach to hepatomegaly and splenomegaly: Diagnostic considerations and clinical approach. Cureus, 16(2), e53245. https://pmc.ncbi.nlm.nih.gov/articles/PMC10932313/
23. Sharma, B., & John, S. (2022). Hepatic cirrhosis. In StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK482419/
24. Sherman, M., & Forner, A. (2023). Management of hepatocellular carcinoma: From surveillance to systemic therapy. New England Journal of Medicine, 389(12), 1040–1056. https://www.nejm.org/doi/full/10.1056/NEJMra2210806
25. Singal, A. G., & Llovet, J. M. (2022). Screening and early detection strategies for hepatocellular carcinoma. Nature Reviews Gastroenterology & Hepatology, 19(7), 424–438. https://www.nature.com/articles/s41575-022-00593-0
26. Smith, A., Jones, P., & Patel, S. (2019). Cirrhosis: Diagnosis and management. American Family Physician, 100(7), 759–770. https://www.aafp.org/pubs/afp/issues/2019/1215/p759.html
27. Terrault, N. A., et al. (2021). Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2021 practice guidance. Hepatology, 74(2), 1041–1092. https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.31802
28. Villanueva, A. (2019). Hepatocellular carcinoma. New England Journal of Medicine, 380(15), 1450–1462. https://www.nejm.org/doi/full/10.1056/NEJMra1713263
29. Yao, J., Zhang, L., & Lin, W. (2025). Hepatitis B virus–induced cirrhosis and hepatocarcinogenesis: Mechanistic insights and therapeutic targets. Exploration of Digestive Diseases, 100565. https://www.explorationpub.com/Journals/edd/Article/100565
30. Zhang, W., & Lin, C. (2023). Advances in the management of refractory ascites and hepatorenal syndrome in cirrhosis. Hepatology International, 17(3), 320–335. https://link.springer.com/article/10.1007/s12072-023-10490-5
