Diseases Accompanied by Hepatomegaly and Hepatosplenomegaly: A Structured Clinical Review
1. Abdirasulova Zhainagul Abdirasulovna
(The supervising faculty member contributed through academic guidance, critical review of the manuscript, and overall supervision of the study)
2. Aishwarya, Nivi, Prakash, Rachit
(Formulation of research goals, final reviewing and editing)
3. Atul, Aditya, Shivraj, Nijamuddin Ansari
(Article draft preparation)
4. Onkar, Vedant, Kazim, Khalid
(Investigating and researching ideas)
5. Anantharaj, Aman, Ali Masavwar
(Reviewing methods for the article and supervision)
Abstract: Hepatomegaly and Hepatosplenomegaly reflect a wide range of systemic diseases which includes infectious, metabolic, hematological, and other related vascular conditions. These clinical manifestations may arise from various infectious, metabolic, hematological, vascular, neoplastic, and immune-mediated conditions. This structured review article, systematically analyzes the etiological spectrum, underlying mechanisms, and diagnostic approaches associated with these findings. We authors have used a narrative methodology which was employed using standard medical textbooks and peer-reviewed literature. We’ve used a structured clinical approach integrating all the history, examination, and targeted investigations which is essential for exact diagnosis and proper management. This review summarizes etiologies, mechanisms, and diagnostic approaches based an IMRAD structure. And finally, as authors, we also suggest early recognition improves outcomes.
Keywords: Hepatomegaly, metabolic, vascular, neoplastic, peer-reviewed, diagnosis.
Introduction
Hepatomegaly and hepatosplenomegaly are two significant clinical findings that are indicators of an underlying pathology, from benign, self-limited disorders to threatening, life-threatening disease. This overview presents a comprehensive account of the significant disease’s accompaniment of liver and spleen enlargement [1]. Among the other metabolic diseases, lysosomal storage diseases are a group of rare conditions with a collective incidence of 1 in 5000 live births. LSDs are caused by genetic variants affecting the lysosomal enzymes, transporters, or integral membrane proteins. As a result, abnormal metabolites accumulate in the organelle, leading to dysfunction. Clinical advances, includes early diagnosis and targeted management against specific diseases, they have improved the life expectancy and also the quality of life of people affected by certain LSDs [2].
Materials and methods
In this review article we have used necessary information from the STAR Protocols and STAR contents which promotes transparent reporting of experimental design and methodological details. Out of 400 resulted journals, which are dated from 1980 – 2026, we chose 12 results dated from 2000 – 2024 which are very recent, for our review paper based on our required criteria, out of which 10 are research-based articles, 1 letter-based article and 1 discussion article and we collected and formatted every single detail according to IMRAD structure with expanded clinical explanations, subheadings, and numbered citations [3-4]. Based on which we found etiologies, which are included with clinically relevant conditions associated with organ enlargement and hence we classified it into;
A. Infectious causes
B. Metabolic and storage disorders
C. Hematological disorders
D. Congestive and vascular causes
E. Additional categories: neoplastic, autoimmune causes [5-6].
We took selected reviews from standard references.
Results
INFECTIOUS CAUSES- Infectious diseases are one of the most common causes of hepatomegaly or hepatosplenomegaly, especially in tropical regions where these conditions are more prevalent. This enlargement mainly happens because infections stimulate the immune system and the reticuloendothelial system (RES), which includes the liver and splenic organs responsible for filtering blood and hosting immune cells. In viral infections such as hepatitis, liver damage is largely immune-mediated rather than directly caused by the virus. The immune system attacks infected hepatocytes, leading to inflammation and enlargement of the liver. During acute infection, this often presents as a tender hepatomegaly. If the infection persists, chronic inflammation can result in fibrosis and eventually cirrhosis. [5 – 8]. Parasitic infections frequently cause hepatosplenomegaly. In malaria, infected red blood cells are sequestered in the spleen, and macrophages become highly active, leading to splenic enlargement. The liver may also enlarge due to increased clearance activity and immune response. [6 – 9]. In visceral leishmaniasis (kala-azar), the enlargement can be massive because parasites live inside macrophages, which accumulate in large numbers in the liver and spleen. Bacterial infections affect the liver differently. Tuberculosis leads to granuloma formation in the liver, contributing to hepatomegaly. Typhoid fever causes hyperplasia of the reticuloendothelial system, leading to mild to moderate enlargement of both liver and spleen [10].
METABOLIC AND STORAGE DISORDERS- Metabolic disorders are becoming an increasingly important cause of hepatomegaly, especially with the rising prevalence of lifestyle-related diseases. Unlike infections, these conditions typically result from abnormal accumulation of substances within liver cells or the reticuloendothelial system. One of the most common causes today is non-alcoholic fatty liver disease (NAFLD). It occurs due to insulin resistance, which leads to excessive fat accumulation in hepatocytes. Initially, this may cause simple hepatomegaly, but in some patients, it progresses to non-alcoholic steatohepatitis (NASH), fibrosis, and eventually cirrhosis if not addressed.
In genetic metabolic disorders, abnormal storage of metals or lipids plays a key role. In Wilson’s disease, defective copper metabolism leads to accumulation of copper in hepatocytes, causing oxidative injury, inflammation, and liver enlargement. Similarly, hemochromatosis results from excessive iron deposition in the liver, leading to progressive fibrosis and cirrhosis over time. Lysosomal storage disorders are another important group, particularly in children. In Gaucher disease, lipid-laden macrophages accumulate in the liver and spleen, resulting in often massive hepatosplenomegaly. These conditions highlight the role of the reticuloendothelial system in organ enlargement. Overall, metabolic causes of hepatomegaly tend to be progressive and may remain asymptomatic in early stages, making early detection crucial to prevent irreversible liver damage [11].
HEMATOLOGICAL DISORDERS- Hematological disorders are important causes of hepatomegaly and hepatosplenomegaly. These conditions typically lead to enlargement through mechanisms such as increased red blood cell destruction (hemolysis), infiltration of abnormal cells, and extramedullary hematopoiesis. In hemolytic anemias such as thalassemia and sickle cell disease, there is excessive destruction of red blood cells. To compensate, the body increases blood cell production outside the bone marrow, particularly in the liver and spleen, leading to their enlargement. In leukemias and lymphomas, abnormal malignant cells infiltrate the liver and spleen. Acute leukemias tend to present with rapid enlargement, while chronic leukemias and lymphomas usually show a more gradual progression. This infiltration disrupts normal organ architecture and function.
Myeloproliferative disorders also contribute by causing uncontrolled proliferation of blood cells. As the bone marrow becomes insufficient or fibrotic, blood cell production shifts to the liver and spleen (extramedullary hematopoiesis), resulting in hepatosplenomegaly. In many of these conditions, hypersplenism can develop. This leads to increased sequestration and destruction of blood cells within the spleen, causing pancytopenia (anemia, leukopenia, and thrombocytopenia) [12 – 13].
CONGESTIVE AND VASCULAR CAUSES- Congestive and vascular disorders can also lead to hepatomegaly and hepatosplenomegaly mainly by affecting blood flow and causing congestion within the liver and spleen. In these conditions, the problem is not inflammation or infiltration, but impaired venous drainage and increased vascular pressure. In congestive heart failure, elevated central venous pressure leads to passive congestion of the liver. Over time, this chronic congestion can cause structural damage to the liver, sometimes progressing to what is known as cardiac cirrhosis. Patients may have a firm, enlarged, and sometimes tender liver due to venous stasis. Budd–Chiari syndrome is another important vascular cause, resulting from obstruction of the hepatic veins. This blockage prevents blood from draining out of the liver, leading to hepatomegaly, abdominal pain, ascites, and liver dysfunction. The severity depends on how complete and rapid the obstruction is. And most importantly portal hypertension, is the most commonly due to cirrhosis, leads to increased pressure in the portal venous system. This contributes to splenomegaly due to congestion of the spleen and increased pooling of blood. Portal vein thrombosis and other vascular abnormalities can also impair normal blood flow and contribute to similar findings [14].
Final clinical insights
a) Acute + fever + tenderness → think infections
b) Chronic + progressive + metabolic signs → think metabolic/storage disorders
c) Cytopenias + splenomegaly → think hematological causes
d) Edema/ascites + vascular history → think vascular/congestive causes
Acknowledgements
Dr. Abdirasulova Zhainagul Abdirasulovna, the supervising faculty member contributed to conceptualization, provided critical revision of the manuscript for important intellectual content, and supervised the overall development of the study. Students Aishwarya, Nivi, Prakash, Rachit focused on formulation of research goals, final reviewing and editing. Atul, Aditya, Shivraj, Nijamuddin Ansari helped in article draft preparation, Onkar, Vedant, Kazim, Khalid viewed on Investigating and researching ideas, Anantharaj, Aman, Ali Masavwar helped in Reviewing methods for the article and also focused on supervising the review preparation.
Overview
Hepatomegaly and hepatosplenomegaly are not diseases themselves but physical signs that reflect an underlying problem. In practice, the cause is often suggested by the context in which the enlargement occurs, whether it is acute or chronic, painful or painless, isolated or associated with systemic symptoms. A helpful way to think about these conditions is to remember that the liver and spleen are part of the body’s filtering and immune systems. Anything that increases workload, causes congestion, or leads to abnormal cell or substance accumulation can enlarge them.
Conflict of interest
The authors declare that there is no conflict of interest regarding the publication of this article.
References:
1. International Journal of Research Publication and Reviews, Vol (6), Issue (10), October (2025), Page – 3875-3883
2. Jerves Serrano T, Gold J, Cooper JA, et al. Hepatomegaly and Splenomegaly: An Approach to the Diagnosis of Lysosomal Storage Diseases. J Clin Med. 2024;13(5):1465. Published 2024 Mar 2. doi:10.3390/jcm13051465
5. Kumar V et al. Robbins & Cotran Pathologic Basis of Disease. 2021. Page- 3 – 431.
6. Harrison's Principles of Internal Medicine, 22nd Edition, Dan L. Longo, Anthony S. Fauci, Dennis L. Kasper, Stephen L. Hauser, J. Larry Jameson, Joseph Loscalzo, Steven M. Holland, Carol A. Langford, Part 11- Section 1 – 3.
7. Harrison's Principles of Internal Medicine, 22nd Edition, Dan L. Longo, Anthony S. Fauci, Dennis L. Kasper, Stephen L. Hauser, J. Larry Jameson, Joseph Loscalzo, Steven M. Holland, Carol A. Langford, Part 10, Section 3, Chapter 347 – 357.
8. Kumar V et al. Robbins & Cotran Pathologic Basis of Disease. 2021. Page 833 – 836.
9. Harrison's Principles of Internal Medicine, 22nd Edition, Page 1698 – 1692
10. Harrison's Principles of Internal Medicine
11. Viral hepatitis: Ch. 306–308, Page 2043 – 2065.
12. Malaria: Ch. 219, Page 1487 – 1495.
13. Visceral leishmaniasis: Ch. 220, Page 1496 – 1500.
14. Typhoid fever: Ch. 186, Page 1220 – 1225.
15. Tuberculosis: Ch. 165, Page 1088 – 1095.
16. Infectious mononucleosis (EBV): Ch. 187, Page 1226 – 1229.
17. HIV infection: Ch. 197, Page 1300 – 1315.
18. Powell, Lawrie W., and David M. Frazer. "Hemochromatosis." Harrison's Principles of Internal Medicine, 21e Eds. Joseph Loscalzo, et al. McGraw-Hill Education, 2022, Ch- 307, 310, 406. Harrison's Principles of Internal Medicine, Hemolytic anemias (thalassemia, sickle cell disease): Ch. 126 – 127, Page- 890 – 905.
19. Leukemia overview- https://www.ncbi.nlm.nih.gov/books/NBK560490/
20. Harrison's Principles of Internal Medicine, Congestive hepatopathy / cardiac cirrhosis: Ch. 309, Page- 2085 – 2092, Budd-Chiari syndrome: Ch. 314, Page- 2135 – 2140, Portal hypertension: Ch. 308, Page- 2079 – 2084.
21. Harrison's Principles of Internal Medicine https://accesspharmacy.mhmedical.com/book.aspx?bookID=3095.
22. Relevant sections/pages:
a) Infectious diseases: Page- 1088 – 1500.
b) Hematologic disorders: Page- 850 – 905.
c) Metabolic liver diseases: Page- 2066 – 2112.
d) Vascular/portal hypertension: Page- 2079 – 2140.
e) Infiltrative diseases: Page- 2890 – 2900.