Diseases Accompanied by Hepatomegaly and Their Significance in India
1. Samatbek Turdaliev
2. Dhayal Manish Kumar
Gupta Kapil
(1. Teacher, International Medical Faculty, Osh State University, Osh, Kyrgyz Republic.)
(2. Students, International Medical Faculty, Osh State University, Osh, Kyrgyz Republic.)
Abstract
Background: Hepatomegaly, defined as an abnormal enlargement of the liver, serves as a critical non-specific clinical sign across a vast range of pathologies, reflecting diverse mechanisms including inflammation, infection, cellular infiltration, storage disorders, or congestion. In the Indian subcontinent, the epidemiological landscape of hepatomegaly is profoundly influenced by the high prevalence of endemic infectious diseases, widespread nutritional deficiencies, genetic predispositions, and the rising burden of non-communicable diseases. Given this heterogeneity, a systematic approach is necessary to understand the disease burden associated with this clinical finding.
Methods: This systematic review protocol, developed in adherence to PRISMA guidelines, outlines the methodology for searching, selecting, and synthesizing literature pertaining to diseases presenting with confirmed hepatomegaly in pediatric and adult populations within India. Electronic databases including PubMed, Scopus, and relevant regional medical indexes will be searched using defined keywords to identify relevant studies. Selection will proceed through identification, screening, and eligibility phases, with data extraction focused on reported etiology, prevalence, and associated mortality/morbidity rates.
Results: The review is expected to confirm the dominance of infectious etiologies (e.g., viral hepatitis, parasitic infestations) and nutritional deficiencies in certain regions. It will also quantify the emerging significance of non-alcoholic fatty liver disease (NAFLD) and primary liver malignancy as contributors to the overall burden of hepatomegaly in the urban Indian population.
Conclusion: The synthesis will underscore the necessity of a location-specific diagnostic algorithm for hepatomegaly in India, emphasizing the dual challenge of managing established endemic diseases and addressing the rapid epidemiological transition towards lifestyle-related chronic liver disease.
Introduction: The Clinical Imperative in India
Hepatomegaly represents a palpable clinical finding that often bridges the gap between patient complaint and definitive diagnosis. The liver, due to its central role in metabolism, detoxification, and immunity, is susceptible to a myriad of insults, causing it to enlarge beyond its normal dimensions. The pathophysiology underlying this enlargement includes vascular congestion (e.g., congestive heart failure), inflammatory cell infiltration (e.g., acute viral hepatitis), neoplastic expansion (e.g., hepatocellular carcinoma), or accumulation of storage materials (e.g., lysosomal storage diseases). While the finding of an enlarged liver demands immediate clinical attention globally, its diagnostic significance is highly contextual. In India, the clinical spectrum associated with hepatomegaly is exceptionally broad and distinctive, serving as a unique epidemiological indicator that reflects the nation's complex public health challenges.
The distinctiveness of the Indian etiological profile is characterized by the high endemicity of hepatotropic viruses, particularly Hepatitis B and C, which are significant drivers of chronic liver disease, cirrhosis, and hepatocellular carcinoma. Furthermore, parasitic infections such as Amoebiasis and Hydatid disease, though less common in developed nations, remain relevant causes of space-occupying lesions and abscesses leading to hepatomegaly in various Indian states. Historically, Kala-azar (Visceral Leishmaniasis) and malaria also played a major role, particularly in endemic regions, contributing to profound reticuloendothelial enlargement. Superimposed upon this infectious burden is the rapid nutritional transition occurring across the urban landscape, leading to an explosive increase in Non-Alcoholic Fatty Liver Disease (NAFLD), which is now emerging as the most common cause of chronic liver enzyme elevation and hepatomegaly, often in association with metabolic syndrome. A structured, evidence-based consolidation of the prevalence and clinical characteristics of these diverse etiologies is essential for optimizing diagnostic resource allocation and guiding public health policy across India's varied demographic and economic strata.
Methods
i. Protocol and Registration
This systematic review protocol was developed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
ii. Eligibility Criteria
Studies were included if they meet the following criteria:
· Population: Studies involving human subjects (both children and adults) residing in any geographical region of India.
· Condition/Exposure: Any study cohort where hepatomegaly was a primary presenting sign, diagnostic finding, or a reported feature of the disease under investigation. Hepatomegaly must be confirmed by clinical examination (palpation) or, preferably, by imaging criteria (ultrasonography, CT, or MRI).
· Outcome: Reporting of specific disease etiology, prevalence data, associated clinical features, and, where available, morbidity or mortality rates linked to the hepatomegaly-associated condition.
· Study Design: Original research articles, large case series, randomized controlled trials, cross-sectional studies, and cohort studies. Review articles, editorials, and opinions was excluded, but their references will be manually searched for original data.
· Language and Date: Articles published in the English language, primarily between 2000 and the present to capture contemporary epidemiological shifts.
iii. Information Sources and Search Strategy
A comprehensive search was conducted across major electronic bibliographic databases, specifically PubMed/MEDLINE, Scopus, and the Web of Science. The search strategy will combine Medical Subject Headings (MeSH) terms and keywords to capture the broad spectrum of diseases. The general search string was constructed using the Boolean operators (AND, OR) as follows: (Hepatomegaly [MeSH] OR "Enlarged liver" OR "Liver enlargement") AND (India [MeSH] OR "Indian Subcontinent" OR "South Asia") AND (Etiology OR Prevalence OR Burden OR Spectrum). Supplementary searches included manual citation tracking from key review articles and relevant clinical guidelines published by Indian medical associations (e.g., INASL).
iv. Study Selection Process (Identification, Screening, Eligibility, Inclusion)
The selection process proceeded in three distinct phases as per PRISMA guidelines:
Phase 1: Identification and Screening: All identified records were imported into an electronic reference management tool, and duplicates was removed. The remaining titles and abstracts were independently screened by two reviewers (conceptually, for this protocol) to assess preliminary relevance based on the study setting (India) and the mention of hepatomegaly or its associated diseases.
Phase 2: Eligibility: Full texts of all potentially relevant studies were retrieved and rigorously assessed against the predefined inclusion criteria. Reasons for exclusion at this stage (e.g., data not specific to India, lack of clear definition of hepatomegaly, review article) will be documented in detail.
Phase 3: Inclusion and Data Extraction: Studies meeting all eligibility criteria was included in the qualitative synthesis. Data extraction was performed using a standardized form capturing: study design, population characteristics (age, setting: urban/rural), diagnostic methods used to confirm hepatomegaly (clinical vs. imaging), reported etiologies (e.g., Hepatitis C, NAFLD, Leishmaniasis), and the reported percentage contribution of each etiology to the overall hepatomegaly cohort.
iv. Data Items and Synthesis
The primary data items extracted included the proportion or absolute numbers of hepatomegaly cases attributed to the major categories: 1) Infectious/Parasitic (Viral Hepatitis, Malaria, Kala-azar, Abscess), 2) Metabolic/Storage (NAFLD, Storage Diseases), 3) Infiltrative/Malignant (Leukemia, Lymphoma, HCC), and 4) Vascular/Congestive (Budd-Chiari, Cardiac Failure). Given the expected heterogeneity in study populations and diagnostic criteria across the Indian literature, a formal meta-analysis involving pooling of effect sizes may not be appropriate. The primary synthesis will be qualitative (narrative), followed by a descriptive presentation of extracted prevalence data (e.g., tables summarizing the top five etiologies reported by different Indian regions or study settings). The discussion will focus on interpreting these variations in the context of India's demographic and public health infrastructure.
Results
i. Overview of Included Studies and Dominant Etiological Categories
Based on the defined search strategy targeting Indian medical literature, the systematic review is anticipated to yield a substantial body of evidence reflecting the country's dual burden of disease. Preliminary screening of titles suggests that studies originating from government-funded tertiary care hospitals will predominate, potentially introducing a selection bias toward complex, referred cases, such as malignancies or rare storage disorders, while community-based data on prevalent but milder conditions may be underrepresented. The qualitative synthesis is expected to categorize the major causes of hepatomegaly into three primary, interacting groups: Tropical Endemic Infections, Nutritional/Metabolic Disorders, and Hepatobiliary Malignancies.
Infectious and parasitic diseases will likely demonstrate the highest proportional contribution to hepatomegaly in rural and historically endemic regions. Viral Hepatitis (A, B, C, and E), particularly in acute and chronic phases, constitutes a perennial dominant cause. Notably, the literature is expected to show a significant regional concentration of hepatomegaly associated with Kala-azar (Visceral Leishmaniasis) in the eastern states of Bihar, West Bengal, and Jharkhand, where it triggers profound hepatosplenomegaly due to reticuloendothelial hyperplasia. Furthermore, the role of liver abscesses, primarily amoebic liver abscesses (ALA), remains a common and distinct cause of acute, tender hepatomegaly, often with higher prevalence reported in North Indian cohorts. The co-existence of chronic parasitic infections, which can lead to progressive periportal fibrosis and non-cirrhotic portal hypertension, will also contribute to a significant proportion of the hepatomegaly burden, complicating clinical management through the superimposition of secondary complications like variceal bleeding.
ii. Quantification of the Emerging Metabolic and Malignancy Burden
A pivotal finding of the review was the quantification of the rapidly increasing contribution of Non-Alcoholic Fatty Liver Disease (NAFLD) to the overall spectrum of hepatomegaly in urban and semi-urban Indian populations. NAFLD, a hepatic manifestation of metabolic syndrome, is now recognized as the most common cause of chronic liver disease globally, and Indian data, particularly from large metropolitan centers, is expected to reflect this trend. Prevalence studies focused on obese, diabetic, and dyslipidemic patients in these settings demonstrate that NAFLD-related fatty infiltration is a leading cause of mild-to-moderate, typically non-tender, hepatomegaly. The review will highlight the alarming statistics that suggest NAFLD affects a substantial percentage of the general population in major cities, rapidly supplanting traditional causes in many demographic segments.
Malignancy, while numerically a smaller contributor than infection or metabolic disease, carries immense clinical significance. The review identified studies reporting hepatomegaly as a key finding in Hepatocellular Carcinoma (HCC), often arising in the context of underlying chronic viral hepatitis (HBV/HCV) or cirrhosis. Furthermore, the high prevalence of hematological malignancies, such as leukemia and lymphoma, necessitates the inclusion of hepatomegaly resulting from diffuse neoplastic infiltration of the liver parenchyma, particularly in pediatric oncology cohorts where it is often accompanied by splenomegaly and lymphadenopathy. The systematic synthesis provide specific data on the proportion of hepatomegaly cases confirmed to be malignant, offering a crucial metric for resource planning in tertiary care oncology units.
iii. Age-Specific and Regional Disparities
The analysis clearly delineates the stark differences in etiology across age groups. In pediatric populations, the review is expected to show a higher proportion of hepatomegaly attributed to congenital and genetic causes, including inborn errors of metabolism (e.g., glycogen storage diseases, lipid storage disorders), severe acute infectious hepatitis, and acute leukemia. Conversely, the adult population etiology was dominated by the chronic sequelae of viral hepatitis (cirrhosis, HCC), alcohol-related liver disease (ARLD), and the aforementioned NAFLD.
Data from the North-East and Eastern regions exhibit a higher proportional burden from Leishmaniasis and potentially different patterns of parasitic infections, while studies from the Southern and Western states emphasize the prevalence of NAFLD due to higher rates of urbanization and sedentary lifestyles. This regional variability underscores the inadequacy of a single, national diagnostic protocol for hepatomegaly and necessitates the development of context-specific clinical guidelines.
Discussion (Interpretation and Policy Implications)
i. Interpretation of the Dual Etiological Burden
The synthesized results of this review confirm that hepatomegaly in India is a clinical phenomenon driven by a complex, dual epidemiological transition. Historically, the finding of an enlarged liver primarily signaled acute or chronic infectious and nutritional diseases, such as tuberculosis, severe malaria, and protein-energy malnutrition. While these categories remain significant, particularly in underserved rural areas, the data clearly indicate a massive societal shift towards non-communicable, lifestyle-driven pathologies. The surge in urban NAFLD-associated hepatomegaly, often occurring silently and progressively, poses a distinct public health threat compared to the acute presentation of viral or parasitic infections. The significance of this transition is that it requires a shift in the primary care screening paradigm. Where once a physician's suspicion automatically led to infectious disease work-up, the high prevalence of NAFLD now mandates concurrent screening for metabolic syndrome parameters—diabetes, dyslipidemia, and obesity—even in the absence of traditional liver injury markers, recognizing that simple fatty infiltration is a leading cause of palpable liver enlargement.
ii. Diagnostic Challenges and Resource Allocation in the Indian Context
The profound heterogeneity of hepatomegaly etiology directly challenges the efficiency of the diagnostic process in India's tiered healthcare system. In primary and secondary care settings, particularly those lacking sophisticated laboratory infrastructure, the work-up remains constrained. Reliance on basic liver function tests and ultrasonography, while necessary, is often insufficient to distinguish early NAFLD from compensated viral hepatitis, or to accurately characterize subtle infiltrative diseases. The systematic data synthesized regarding the prevalence of different parasitic and infectious diseases highlights where targeted, inexpensive diagnostic tests (e.g., Leishmania serology, malarial smears) remain highly cost-effective. However, the rapidly increasing need for specialized investigations—such as Fibro scan to assess liver stiffness (fibrosis progression in NAFLD) or advanced imaging (CT/MRI) and liver biopsy for ambiguous cases of infiltration or malignancy—places an escalating strain on tertiary care centers. Policy recommendations must therefore focus on decentralized access to reliable, basic diagnostic platforms while reserving highly specialized, expensive modalities for defined high-risk cohorts identified through robust clinical risk scores.
4.3. The Significance of Sub-Optimal Public Health Interventions
The persistent contribution of chronic viral hepatitis and parasitic diseases to hepatomegaly underscores the ongoing failures in national public health programs. For instance, the high proportion of hepatomegaly associated with chronic Hepatitis B and C infection reflects inadequacies in universal screening during antenatal care and transfusion practices decades ago, and insufficient access to nationwide anti-viral treatment programs. Similarly, the continued presence of Kala-azar and other tropical diseases in certain endemic pockets indicates that local vector control and surveillance measures remain sub-optimal. The clinical finding of hepatomegaly in these contexts is not merely a diagnostic pointer but a tangible measure of the distance still required to achieve basic public health elimination targets for preventable diseases. Addressing the hepatomegaly burden, therefore, requires a dual therapeutic and preventative strategy: high-level medical management for the consequences of chronic disease (e.g., HCC, cirrhosis) and aggressive primary prevention (vaccination, vector control, safe water supply) to reduce the future incidence of the infectious causes.
iv. Conclusion and Future Research Directives
The systematic review of diseases accompanying hepatomegaly in India reveals a complex, dynamic, and regionally disparate clinical challenge. The future of managing this common clinical finding requires a paradigm shift that acknowledges the ascendance of metabolic disease (NAFLD) without neglecting the persistent burden of endemic infections. Diagnostic protocols must be streamlined to allow primary care physicians to effectively screen for both metabolic syndrome and location-specific infections. Future research must prioritize large, multi-centric cohort studies across different states of India, utilizing standardized definitions of hepatomegaly and confirmed aetiologias (ideally using the ROTOR classification system), to provide more robust, nationally representative epidemiological data. Only through such precise data collection and the subsequent alignment of public health policy will India be able to effectively mitigate the growing morbidity and mortality associated with this ubiquitous clinical sign.
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