Changing Etiological Spectrum of Hepatocellular Carcinoma in India—A Systematic Review and Meta-analysis

Suprabhat Giri; Ashok Choudhury; Dibya L Praharaj; Ankita Singh; Arun Vaidya; Sidharth Harindranath; Prajna Anirvan; Shivam Kalia; Akash Shukla

doi:10.1016/j.jceh.2024.101391

. 2024 Mar 4;14(5):101391. doi: 10.1016/j.jceh.2024.101391

Changing Etiological Spectrum of Hepatocellular Carcinoma in India—A Systematic Review and Meta-analysis

Suprabhat Giri ^∗, Ashok Choudhury ^†, Dibya L Praharaj ^∗, Ankita Singh ^‡, Arun Vaidya ^‡, Sidharth Harindranath ^‡, Prajna Anirvan ^§, Shivam Kalia ^∗, Akash Shukla ^‡,^⁎

PMCID: PMC10979108 PMID: 38559423

Abstract

Background

Recent studies from both India and outside India have shown a change in the etiological profile of hepatocellular carcinoma (HCC). We aimed to analyze the etiological spectrum and changing trends of HCC etiology in India using a systematic review of current literature and meta-analysis.

Methods

Electronic databases of PubMed/Medline, Scopus, and Embase were searched from inception to July 2023 for studies reporting the data on the etiology of HCC from India. The pooled proportions with 95% confidence interval were calculated using summative statistics.

Results

A total of 60 studies (n = 12,327) were included in the final analysis. The pooled proportions of HCC cases with at least one positive and negative viral marker were 56.0 (49.5–62.6) and 43.1% (36.5–49.8), respectively. The pooled proportion of HCC cases with positive hepatitis B virus (HBV) markers was 41.0 (35.8–46.1), while those with positive markers for hepatitis C virus were 20.3 (17.0–23.6). The pooled proportion of cases with HCC with significant alcohol intake was 19.0% (15.6–22.4), and those related to nonalcoholic fatty liver disease (NAFLD) were 16.9% (12.1–21.7). Around 7.9% (5.8–10.0) of the cases had HCC with multiple etiologies. Subgroup analysis showed a significant variation with the location of the study based on zone. Meta-regression analysis based on publication year (1990–2023) showed a significant reduction in the proportion of cases with HBV and an increase in cases with NAFLD. In contrast, the proportion of cases with hepatitis C virus and alcohol did not change significantly.

Conclusion

Viral hepatitis is the most common etiology of HCC in India, predominantly HBV. The proportions of cases with HCC related to NAFLD are increasing, and those related to HBV are declining.

Keywords: hepatocellular carcinoma, hepatitis B, nonalcoholic fatty liver disease, hepatitis C, meta-analysis

Graphical abstract

Hepatocellular Carcinoma (HCC) is the most common primary liver cancer in India and constitutes a significant cause of morbidity and mortality in patients with cirrhosis.¹ The epidemiological profile of HCC in India is sparse and unreliable due to a lack of representative data. The fact sheet report by the National Cancer Registry Program, which coordinates with the Indian Council of Medical Research and National Care Center for Disease Informatics and Research covering 28 population-based and 58 hospital-based cancer registries, mentions about liver cancer but not specifically about HCC.² This may be because these cancer registries are maintained mainly by medical or surgical oncologists, while most patients with HCC are managed by gastroenterologists or hepatologists, and hence, data on HCC might not have been captured. Moreover, the cancer registry by the Indian Cancer Society includes only patients from greater Mumbai, Nagpur, Pune, and Aurangabad, thus presenting an incomplete database.

Nonalcoholic fatty liver disease (NAFLD) has been on the rise due to changes in dietary habits and lifestyle, and its prevalence in India is higher than the estimated global prevalence.³ With the availability of a highly effective and safe vaccine against the Hepatitis B virus (HBV) and directly acting antivirals against the Hepatitis C virus (HCV), the incidence of liver disease related to these viruses has significantly reduced.⁴ In a recent meta-analysis on the etiology of cirrhosis from India, alcohol was the most common cause of cirrhosis. When comparing the etiologies from studies published before 2005, from 2005 to 2015, and from 2015 to 2022, a reduction in the proportion of viral etiologies and an increase in the proportion of alcohol-related and NAFLD/cryptogenic-related cirrhosis were noted.⁵

Therefore, it is likely that the epidemiological profile of patients with HCC in India has also changed with respect to the underlying etiology of HCC. In this systematic review, we will discuss the etiological profile of patients with HCC in India, with special emphasis on recent changes.

Methods

The current meta-analysis was conducted as per the updated Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.⁶

Database Search

All relevant studies were searched from inception to July 2023 in MEDLINE, Embase, and Scopus using the following keywords: (Hepatocellular carcinoma OR HCC OR Liver cancer) AND (Alcohol OR HBV OR HCV OR NAFLD OR NASH OR BCS OR HVOTO OR AIH OR Autoimmune OR Wilson OR Cryptogenic) AND India. The title and abstract of the retrieved studies were screened by two independent reviewers, who then assessed the full texts for eligibility prior to inclusion. Additionally, the bibliographies of the included studies were screened for relevant studies. A third reviewer resolved any disagreement.

Study Inclusion

Both prospective and retrospective studies fulfilling the following criteria were included in the present systematic review: (a) Study population—Indian patients with HCC; (b) Outcome—proportion of various etiologies in patients with HCC. To avoid duplication, the study with a larger sample size was chosen if multiple studies from the same institution had overlapping study durations. Studies with sample sizes <20 (to reduce small study effect), conference abstracts, editorials, correspondences, and review articles were excluded. Studies with insufficient or irrelevant clinical data were also excluded.

Data Extraction and Quality Assessment

Two reviewers independently extracted the data, while a third reviewer arbitrated any conflicts. Each study's title, first author, year of publication, country, institution, study duration, number of patients, age and sex distribution, and etiology of HCC were collected. Using Joanna Briggs Institute critical appraisal tools,⁷ two independent reviewers evaluated the quality of the included studies. In the event of a disagreement, a third reviewer was contacted.

Data Analysis

Using a random-effects inverse-variance model, the pooled proportions were calculated. I² and the P value for heterogeneity were used to evaluate the studies' degree of heterogeneity. I² values of 25%, 50%, and 75% were considered the cutoffs for low, moderate, and considerable heterogeneity, respectively.⁸ A P value of less than 0.10 was considered statistically significant. For assessing publication bias, funnel plots were visually inspected. The sensitivity analysis utilized a leave-one-out meta-analysis, where one study is removed at each analysis, to analyze each research's impact on the overall effect-size estimate and find influential studies. Subgroup analysis was conducted using data on patient recruitment, study design, publication year (before or after 2014), and zone. STATA software (version 17, StataCorp., College Station, TX) was used for statistical analysis.

Results

Study Characteristics

A total of 3423 records were identified with the above search strategy, out of which 60 studies (n = 12,327) were included in the final analysis (Cohen's kappa coefficient: 0.637; substantial agreement).⁹^,¹⁰^,¹¹^,¹²^,¹³^,¹⁴^,¹⁵^,¹⁶^,¹⁷^,¹⁸^,¹⁹^,²⁰^,²¹^,²²^,²³^,²⁴^,²⁵^,²⁶^,²⁷^,²⁸^,²⁹^,³⁰^,³¹^,³²^,³³^,³⁴^,³⁵^,³⁶^,³⁷^,³⁸^,³⁹^,⁴⁰^,⁴¹^,⁴²^,⁴³^,⁴⁴^,⁴⁵^,⁴⁶^,⁴⁷^,⁴⁸^,⁴⁹^,⁵⁰^,⁵¹^,⁵²^,⁵³^,⁵⁴^,⁵⁵^,⁵⁶^,⁵⁷^,⁵⁸^,⁵⁹^,⁶⁰^,⁶¹^,⁶²^,⁶³^,⁶⁴^,⁶⁵^,⁶⁶^,⁶⁷^,⁶⁸ Figure 1 shows the PRISMA flowchart for the study selection and inclusion process. Table 1 and Supplementary Table 2 show the baseline characteristics of the studies included in the present analysis and the prevalence of various etiologies from individual studies. The pooled proportion of male patients was 86.8% (95% CI: 85.4–88.1; I² = 78.9%), and the pooled proportion of patients with cirrhosis was 92.6% (95% CI: 91.1–94.0; I² = 96.5%), with no significant change with respect to the publication year. Sixteen studies were from the South,⁹^,¹¹^,¹⁵^,¹⁸^,²⁵^,³⁰^,³¹^,³⁴^,⁴⁰^,⁴⁵^,⁵⁰^,⁵²^,⁵⁴^,⁵⁷^,⁶¹^,⁶³ 32 were from the North,¹²^,¹³^,¹⁴^,¹⁶^,¹⁹^,²⁰^,²¹^,²³^,²⁴^,²⁷^,²⁸^,²⁹^,³³^,³⁵^,³⁶^,³⁸^,³⁹^,⁴¹^,⁴²^,⁴³^,⁴⁴^,⁴⁶^,⁴⁸^,⁴⁹^,⁵¹^,⁵³^,⁵⁵^,⁵⁶^,⁶⁵^,⁶⁶^,⁶⁷^,⁶⁸ five were from the West,³²^,³⁷^,⁴⁷^,⁵⁹^,⁶¹ one was from the East,⁵⁸ and six were multicentric.¹⁰^,¹⁷^,²²^,²⁶^,⁶⁰^,⁶⁴

PRISMA flowchart for study identification, selection, and inclusion process.

Table 1.

Baseline Characteristics of the Studies Included in the Meta-analysis.

Author	Design	State or union territory	Zone	No. of patients	Mean age, in years	Males	Cirrhotics	Child-Pugh score, A/B/C	Study quality
Sundaram 1990⁹	Retrospective	Andhra Pradesh	South	58	–	–	50	–	7
Ramesh 1992¹⁰	Prospective	–	Multicentric	53	44.7	45	–	–	7
Joshi 2003¹¹	Retrospective	Telangana	South	40	–	33	30	6/11/13	6
Radhika 2004¹²	Prospective	Chandigarh	North	22	–	–	–	–	6
Saini 2006¹³	Prospective	Chandigarh	North	47	53.4	43	29	–	8
Kumar 2007¹⁴	Retrospective	New Delhi	North	213	50.4	177	161	–	9
Murugavel 2008¹⁵	Prospective	Tamil Nadu	South	142		123	–	–	9
Paul 2009¹⁶	Ambispective	New Delhi	North	324	52.4	284	316	165/110/49	8
Asim 2010¹⁷	Prospective	–	Multicentric	254	64.9	202	–	–	7
Devi 2010¹⁸	Prospective	Tamil Nadu	South	51	–	43	40	–	6
Sarma 2010¹⁹	Prospective	Chandigarh	North	101	58.9	–	101	38/47/16	9
Sharma 2010²⁰	Prospective	Chandigarh	North	70	58.84	62	49	–	7
Medhi 2012²¹	Prospective	New Delhi	North	267	–	–	–	–	7
Sarma 2012²²	Prospective	–	Multicentric	357	–	305	253	–	9
Arora 2013²³	Retrospective	New Delhi	North	142	60	130	126	43/63/36	9
Jain 2013²⁴	Retrospective	New Delhi	North	101	52.3	91	101	–	8
Pal 2013²⁵	Retrospective	Tamil Nadu	South	231	54.4	201	194	–	8
Kohli 2014²⁶	Retrospective	–	Multicentric	164	58	137	164	32/72/60	8
Sood 2014²⁷	Prospective	Punjab	North	128	49.8	106	127	–	9
Agarwal 2015²⁸	Prospective	New Delhi	North	53	63	48	47	31/21/0	6
Dhamija 2015²⁹	Retrospective	New Delhi	North	168	51.6	146	167	121/46/0	8
Srirambhatla 2015³⁰	Retrospective	Telangana	South	72	60	65	48	26/38/8	6
Lokesh 2017³¹	Retrospective	Karnataka	South	48	52	35	48	26/8/14	8
Ostwal 2017³²	Prospective	Maharashtra	West	39	58	36	39	35/4/0	6
Paul 2017³³	Prospective	New Delhi	North	50	53	41	50	44/6/0	6
Varghese 2017³⁴	Retrospective	Tamil Nadu	South	124	55.6	112	124	63/61/0	8
Bharali 2018³⁵	Prospective	New Delhi	North	50	56.55	–	–	–	8
Makol 2018³⁶	Retrospective	Chandigarh	North	70	58.21	61	70	A/(B + C): 33/37	7
Patkar 2019³⁷	Retrospective	Maharashtra	West	105	59	124	105	141/3/0	8
Paul 2019³⁸	Retrospective	New Delhi	North	126	52.8	101	126	94/32/0	8
Jamwal 2020³⁹	Prospective	New Delhi	North	56	–	37	–	–	7
Kedarisetty 2020⁴⁰	Prospective	Tamil Nadu	South	112	60.6	90	104	(A + B)/C: 112/0	7
Mukund 2020⁴¹	Retrospective	New Delhi	North	147	59.2	121	147	–	7
Paul 2020⁴²	Prospective	New Delhi	North	55	54.5	40	55	37/18/0	7
Soin 2020⁴³	Retrospective	Haryana	North	451	55	364	451	–	8
Chandra 2021⁴⁴	Retrospective	New Delhi	North	131	60	119	96	–	8
Dutta 2021⁴⁵	Prospective	Kerala	South	72	63	69	72	62/6/4	7
Ghosh 2021⁴⁶	Prospective	New Delhi	North	48	54.7	–	–	–	7
Jearth 2021⁴⁷	Retrospective	Maharashtra	West	508	58.3	444	398	–	8
Kumar 2021⁴⁸	Retrospective	New Delhi	North	29	56	24	29	28/1/0	6
Pamecha 2021⁴⁹	Retrospective	New Delhi	North	53	52	48	53	–	7
Patel 2021⁵⁰	Retrospective	Karnataka	South	55	63.9	52	55	36/19/0	7
Patidar 2021⁵¹	Retrospective	New Delhi	North	78	58	69	78	–	7
Rajkannu 2021⁵²	Retrospective	Tamil Nadu	South	28	53.5	24	28	–	6
Tohra 2021⁵³	Retrospective	Chandigarh	North	785	60	685	677	302/300/75	9
Anand 2022⁵⁴	Retrospective	Puducherry	South	50	58.12	36	50	33/17/0	7
Kumar 2022⁵⁵	Prospective	New Delhi	North	100	54	84	89	88/11/1	8
Mukund 2022⁵⁶	Prospective	New Delhi	North	26	61.38	24	26	17/9/0	6
Musunuri 2022⁵⁷	Retrospective	Karnataka	South	339	62.8	309	248	139/154/46	9
Richa 2022⁵⁸	Prospective	Bihar	East	68	57.5	–	–	–	8
Shukla 2022⁵⁹	Prospective	Maharashtra	West	672	57.4	561	657	361/223/73	9
Soni 2022⁶⁰	retrospective	–	Multicentric	59	60	–	15	17/26/16	7
Hui 2023⁶¹	Retrospective	Telangana	South	62	53	–	–	30/12/0	7
Jearth 2023⁶²	Retrospective	Maharashtra	West	508	54.5	444	398	199/142/57	8
Koshy 2023⁶³	Prospective	Kerala	South	1217	63	1110	1106	–	9
Kulkarni 2023⁶⁴	Retrospective	–	Multicentric	67	61	58	–	24/36/7	7
Mehra 2023⁶⁵	Ambispective	Haryana	North	31	59	25	–	–	6
Mukund 2023⁶⁶	Retrospective	New Delhi	North	151	63.46	141	–	75/76/0	7
Prabhakar 2023⁶⁷	Retrospective	New Delhi	North	2664	58.2	–	–	–	9
Sharma 2023⁶⁸	Retrospective	New Delhi	North	35	61	33	35	27/8/0	7

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Viral Etiology

A total of 54 studies (n = 11,806) reported the proportion of HCC cases with viral etiology.¹⁰^,12−16,¹⁹^,²⁰^,²¹^,²²^,²³^,²⁴^,²⁵^,²⁶^,²⁷^,²⁸^,²⁹^,³⁰^,³¹^,³²^,³³^,³⁴^,³⁶^,³⁷^,³⁸^,³⁹^,⁴⁰^,⁴¹^,⁴²^,⁴³^,⁴⁴^,⁴⁵^,⁴⁶^,⁴⁷^,⁴⁸^,⁴⁹^,⁵⁰^,⁵¹^,⁵²^,⁵³^,⁵⁴^,⁵⁵^,⁵⁶^,⁵⁷^,⁵⁹^,⁶⁰^,⁶¹^,⁶²^,⁶³^,⁶⁴^,⁶⁵^,⁶⁶^,⁶⁷^,⁶⁸ The pooled proportion of HCC cases with at least one positive viral marker was 56.0% (95% CI: 49.5–62.6; I² = 98.3%) (Table 2). There was a significant difference in the pooled proportion between studies that were published in or before 2014 (68.3%, 95% CI: 63.8–72.8) and studies published after 2014 (51.4%, 95% CI: 43.8–58.9) (P = 0.000), and between studies from the South zone (43.0%, 95% CI: 29.1–56.9) compared to those from the North zone (62.8%, 95% CI: 57.3–68.3) (P = 0.000). In the North zone, the pooled proportion from studies that were published in or before 2014 (70.1%, 95% CI: 66.1–74.1) was significantly higher than from studies published after 2014 (59.2%, 95% CI: 52.3–66.2) (P = 0.008).

Table 2.

Summary Table With Subgroup Analysis for Various Etiologies of Hepatocellular Carcinoma.

Etiology	Overall	Studies including consecutive cases	Prospective studies	Published before 2014	Published after 2014	Studies with ≥50 sample size	North zone	South zone	West zone
Viral	56.0% (49.5–62.6)	57.7% (47.9–67.4)	56.9% (43.1–70.7)	68.3% (63.8–72.8)	51.4% (43.8–58.9)	55.7% (48.6–62.9)	62.8% (57.3–68.3)	43.0% (29.1–56.9)	51.0% (41.5–60.5)
Hepatitis B virus	41.0% (35.8–46.1)	46.0% (39.2–52.8)	43.1% (32.5–53.6)	47.3% (40.3–54.3)	37.6% (32.0–43.1)	40.2% (34.7–45.7)	41.4% (36.0–46.8)	38.8% (26.6–51.0)	40.5% (31.6–49.3)
Hepatitis C virus	20.3% (17.0–23.6)	21.7% (27.3–26.1)	19.8% (14.8–24.7)	24.5% (17.5–31.6)	18.1% (14.4–21.9)	21.2% (17.5–24.8)	24.2% (20.2–28.2)	12.3% (8.4–16.2)	10.3% (9.0–11.7)
Nonviral	43.1% (36.5–49.8)	40.2% (30.3–50.1)	42.3% (28.1–56.5)	31.7% (27.2–36.2)	47.4% (39.7–55.1)	43.7% (36.5–51.0)	37.1% (31.5–42.6)	54.5% (39.3–69.7)	49.0% (39.5–58.5)
Alcohol	19.0% (15.6–22.4)	25.3% (19.6–31.1)	22.0% (13.2–30.8)	26.1% (16.0–36.3)	16.3% (12.9–19.7)	20.2% (16.5–23.9)	16.2% (13.1–19.3)	20.5% (11.6–29.5)	7.7% (4.9–10.4)
Nonalcoholic fatty liver disease	16.9% (12.1–21.7)	16.2% (10.5–21.9)	13.5% (6.8–20.1)	2.2% (0.1–4.4)	19.1% (14.0–24.2)	16.4% (11.2–21.6)	14.2% (8.3–20.2)	24.3% (0.0–72.9)	23.5% (19.2–27.8)
Multiple	7.9% (5.8–10.0)	10.8% (7.6–13.9)	9.3% (4.5–14.0)	13.2% (7.8–18.6)	4.6% (3.0–6.2)	8.2% (6.0–10.4)	7.0% (4.5–9.5)	2.4% (0.0–5.5)	5.5% (1.6–9.3)
Cryptogenic	8.7% (5.2–12.2)	13.3% (8.0–18.6)	7.9% (1.2–14.7)	13.7% (0.0–28.7)	7.6% (4.3–10.8)	8.9% (5.0–12.8)	8.3% (4.3–12.4)	8.9% (2.5–15.3)	14.3% (8.2–20.4)

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Hepatitis B Virus

Overall, 55 studies (n = 12,002) reported the proportion of HCC cases having at least one positive HBV marker.⁹^,¹⁰^,¹¹^,¹²^,¹³^,¹⁴^,¹⁵^,¹⁶^,¹⁷^,¹⁸^,¹⁹^,²⁰^,²¹^,²²^,²³^,²⁴^,²⁵^,²⁶^,²⁷^,²⁸^,²⁹^,³⁰^,³¹^,³²^,³³^,³⁴^,³⁵^,³⁶^,³⁷^,³⁸^,³⁹^,⁴⁰^,⁴¹^,⁴²^,⁴³^,⁴⁶^,⁴⁷^,⁴⁸^,⁴⁹^,⁵⁰^,⁵¹^,⁵³^,⁵⁴^,⁵⁵^,⁵⁶^,⁵⁷^,⁵⁸^,⁵⁹^,⁶¹^,⁶²^,⁶³^,⁶⁴^,⁶⁵^,⁶⁶^,⁶⁷ The pooled proportion of cases with HCC related to HBV was 41.0% (95% CI: 35.8–46.1; I² = 97.5%) (Table 2). There was a significant difference in the pooled proportion between studies that were published in or before 2014 (47.3%, 95% CI: 40.3–54.3) and studies published after 2014 (37.6%, 95% CI: 32.0–43.1) (P = 0.032). On analyzing studies from the South zone, those published in or before 2014 (52.0%, 95% CI: 38.3–65.7) had a higher proportion of patients with HBV than studies published after 2014 (31.4%, 95% CI: 19.7–43.2) (P = 0.025). However, studies from the North zone did not show a significant difference in the pooled proportion of patients with HBV among those published in or before 2014 (45.0%, 95% CI: 35.9–54.1) compared to those published after 2014 (39.5%, 95% CI: 33.5–45.6) (P = 0.325).

Hepatitis C Virus

A total of 51 studies (n = 11,775) reported the proportion of HCC cases having at least one positive HCV marker.¹⁰^,¹¹^,¹²^,¹³^,¹⁴^,¹⁵^,¹⁶^,¹⁷^,¹⁹^,²⁰^,²¹^,²²^,²³^,²⁴^,²⁵^,²⁶^,²⁷^,²⁸^,²⁹^,³⁰^,³¹^,³²^,³³^,³⁴^,³⁶^,³⁷^,³⁸^,³⁹^,⁴⁰^,⁴¹^,⁴²^,⁴³^,⁴⁶^,⁴⁷^,⁴⁸^,⁴⁹^,⁵⁰^,⁵¹^,⁵³^,⁵⁴^,⁵⁵^,⁵⁶^,⁵⁷^,⁵⁹^,⁶¹^,⁶²^,⁶³^,⁶⁴^,⁶⁵^,⁶⁶^,⁶⁷ The pooled proportion of cases with HCC related to HCV was 20.3% (95% CI: 17.0–23.6; I² = 96.2%) (Table 2). There was a significant difference in the pooled proportion between studies from the South zone (12.3%, 95% CI: 8.4–16.2) and the West zone (10.3%, 95% CI: 9.0–11.7) compared to those from the North zone (24.2%, 95% CI: 20.2–28.2) (P = 0.000). However, the pooled proportion between studies published in or before 2014 and those published after 2014 was comparable in the overall and subgroup analysis based on the zone.

Nonviral Etiology

A total of 54 studies (n = 11,806) reported the proportion of HCC cases with nonviral etiology.¹⁰^,¹²^,¹³^,¹⁴^,¹⁵^,¹⁶^,¹⁹^,²⁰^,²¹^,²²^,²³^,²⁴^,²⁵^,²⁶^,²⁷^,²⁸^,²⁹^,³⁰^,³¹^,³²^,³³^,³⁴^,³⁶^,³⁷^,³⁸^,³⁹^,⁴⁰^,⁴¹^,⁴²^,⁴³^,⁴⁴^,⁴⁵^,⁴⁶^,⁴⁷^,⁴⁸^,⁴⁹^,⁵⁰^,⁵¹^,⁵²^,⁵³^,⁵⁴^,⁵⁵^,⁵⁶^,⁵⁷^,⁵⁹^,⁶⁰^,⁶¹^,⁶²^,⁶³^,⁶⁴^,⁶⁵^,⁶⁶^,⁶⁷^,⁶⁸ The pooled proportion of HCC cases with no positive viral markers was 43.1% (95% CI: 36.5–49.8; I² = 98.4%) (Table 2). There was a significant difference in the pooled proportion between studies that were published in or before 2014 (31.7%, 95% CI: 27.2–36.2) and studies published after 2014 (47.4%, 95% CI: 39.7–55.1) (P = 0.000), and between studies from the South zone (54.5%, 95% CI: 39.3–69.7) compared to those from the North zone (37.1%, 95% CI: 31.5–42.6) (P = 0.000).

Alcohol-Related

Overall, data from 46 studies (n = 11,164)¹¹^,¹⁴^,¹⁶^,¹⁷^,¹⁸^,¹⁹^,²²^,²³^,²⁴^,²⁵^,²⁶^,²⁷^,²⁹^,³⁰^,³¹^,³²^,³³^,³⁴^,³⁶^,³⁷^,³⁸^,³⁹^,⁴¹^,⁴²^,⁴³^,⁴⁵^,⁴⁶^,⁴⁷^,⁴⁸^,⁴⁹^,⁵¹^,⁵²^,⁵³^,⁵⁴^,⁵⁵^,⁵⁶^,⁵⁷^,⁵⁹^,⁶⁰^,⁶¹^,⁶²^,⁶³^,⁶⁴^,⁶⁵^,⁶⁶^,⁶⁷ showed that the pooled proportion of cases with HCC with significant alcohol intake was 19.0% (95% CI: 15.6–22.4; I² = 96.3%), with no difference between studies published in or before 2014 (26.1%, 95% CI: 16.0–36.3) and studies published after 2014 (16.3%, 95% CI: 12.9–19.7) (P = 0.072) (Table 2). There was no difference in the proportion of patients with significant alcohol intake between North and South (16.2%, 95% CI: 13.1–19.3 vs. 20.5%, 95% CI: 11.6–29.5) but between South and West (20.5%, 95% CI: 11.6–29.5 vs. 7.7%, 95% CI: 4.9–10.4) (P = 0.007) and between North and West (16.2%, 95% CI: 13.1–19.3 vs. 7.7%, 95% CI: 4.9–10.4) (P = 0.000).

Nonalcoholic Fatty Liver Disease

A total of 28 studies (n = 7600) reported the proportion of HCC cases with NAFLD as an etiology.²⁴^,²⁵^,²⁶^,²⁷^,²⁹^,³³^,³⁶^,³⁷^,³⁸^,³⁹^,⁴¹^,⁴²^,⁴³^,⁴⁶^,⁴⁷^,⁴⁸^,⁴⁹^,⁵¹^,⁵²^,⁵³^,⁵⁵^,⁵⁶^,⁵⁹^,⁶²^,⁶⁴^,⁶⁵^,⁶⁶^,⁶⁷ The pooled proportion of cases with HCC related to NAFLD was 16.9% (95% CI: 12.1–21.7; I² = 98.6%) (Table 2). There was a significant difference in the pooled proportion between studies that were published in or before 2014 (2.2%, 95% CI: 0.1–4.4) and studies published after 2014 (19.1%, 95% CI: 14.0–24.2) (P = 0.000). There was a significant difference in the proportion of patients with NAFLD between North and West (14.2%, 95% CI: 8.–19.3 vs. 23.5%, 95% CI: 19.2–27.8) (P = 0.013).

Multiple Factors

Multiple etiologies were defined as cases where patients had more than one etiology for HCC. Overall, data from 22 studies (n = 6934)¹⁴^,¹⁵^,¹⁶^,¹⁹^,²²^,²³^,²⁴^,²⁵^,²⁶^,²⁷^,²⁹^,³⁰^,³²^,³³^,⁴¹^,⁴²^,⁴⁶^,⁴⁷^,⁵⁵^,⁵⁹^,⁶²^,⁶⁷ showed that the pooled proportion of HCC cases with multiple etiologies was 7.9% (95% CI: 5.8–10.0; I² = 94.4%) (Table 2). The most common mixed etiology was a combination of viral (HBV > HCV) with alcohol. There was a significant difference in the pooled proportion between studies that were published in or before 2014 (13.2%, 95% CI: 7.8–18.6) and studies published after 2014 (4.6%, 95% CI: 3.0–6.2) (P = 0.000).

Cryptogenic

A total of 16 studies (n = 2709) reported data on HCC with unknown etiologies.¹⁴^,¹⁶^,²⁴^,²⁹^,³¹^,³³^,³⁸^,³⁹^,⁴¹^,⁴⁶^,⁴⁷^,⁴⁹^,⁵²^,⁵⁵^,⁵⁹^,⁶⁴ The pooled proportion of cryptogenic HCC cases was 8.7% (95% CI: 5.2–12.2; I² = 92.0%) (Table 2). Figure 2 summarizes the findings of the present analysis in terms of etiology and their changing pattern with time.

Chart diagram showing the pooled proportions of various etiologies of hepatocellular carcinoma in India with their 95% confidence intervals (error bars). NAFLD, nonalcoholic fatty liver disease.

Publication Bias, Sensitivity Analysis, and Meta-regression Analysis

Funnel plot inspection showed significant publication bias for all the etiologies (Supplementary Figure 1), while a small-study effect was present for HCV, alcohol, NAFLD, and multiple etiologies (Supplementary Table 2). The small-study effect persisted even after the exclusion of studies with <50 patients. Sensitivity analysis based on study design, sample size, and leave-one-out analysis did not show a significant difference from the overall effect size. Meta-regression analysis showed that publication year (Figure 3) and mean age (Figure 4) were significant contributors to heterogeneity (Table 3).

Bubbleplot for the contribution of publication year towards the heterogeneity in effect size with respect to HCC related to (A) viral, (B) Hepatitis B, (C) Hepatitis C, (D) nonviral, (E) alcohol, (F) nonalcoholic fatty liver disease.

Bubbleplot for the contribution of mean age of the population towards the heterogeneity in effect size with respect to HCC related to (A) viral, (B) Hepatitis B, (C) Hepatitis C, (D) nonviral, (E) alcohol, (F) nonalcoholic fatty liver disease.

Table 3.

P Value for Meta-regression Analysis for Significant Covariates Contributing to Heterogeneity Concerning Various Etiologies.

Etiology	No. of patients	Year of publication	Mean age	Proportion of male patients	Proportion of patients with cirrhosis
Viral	0.2194	0.0014	0.0000	0.0085	0.4627
Hepatitis B virus	0.0685	0.0006	0.0049	0.1260	0.2767
Hepatitis C virus	0.7290	0.7977	0.2576	0.3849	0.1221
Nonviral	0.1762	0.0010	0.0000	0.0185	0.7923
Alcohol	0.8747	0.3413	0.0108	0.9415	0.1537
NAFLD	0.2068	0.0004	0.0013	0.0903	0.7535
Multiple	0.7387	0.3060	0.3836	0.4197	0.7753
Cryptogenic	0.0042	0.1123	0.7673	0.9553	0.2436

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Bold indicates a significant P value.

NAFLD, nonalcoholic fatty liver disease.

Discussion

There is considerable heterogeneity in reporting the prevalence of etiologies of HCC in India. While in the West, there are data suggesting that NAFLD will overtake viral hepatitis as the most common etiology of HCC in the very near future,⁶⁹ Indian data in this regard are sketchy. The current meta-analysis shows that, overall, the most common etiology of HCC in India is viral-related. While, of late, a few studies in India have shown that NAFLD has overtaken viral hepatitis as the etiology of HCC,⁵⁷^,⁶⁷ the current meta-analysis suggests that, as of now, viral hepatitis remains the most common etiology of HCC in India.

There is a significant difference in the proportion of patients diagnosed with viral etiology before and after 2014. This trend applies more to patients from the North zone. The decreasing trend in the prevalence of viral-related HCC post-2014 could be attributed to the increased use of effective antivirals. A recent meta-analysis from India reported the pooled prevalence of HBV in pregnant women as 1.6%,⁷⁰ compared to the previously reported prevalence of 2.4% in the general population.⁷¹ This shift was not, however, evident in the case of HCV-related HCC. It is plausible that since HCV drugs have been made available only recently, the effect will be seen most likely after a few years. In addition, the proportion of patients with viral etiology is significantly greater in the North zone compared to the South. The primary reason for this dichotomy could be the higher prevalence of HBV and HCV in the community in North India compared to that in the South.⁷² The prevalence of co-infection of HBV and HCV in the community also seems to be higher in the North zone compared to the South zone.⁷²^,⁷³

There is a significant difference between the proportion of HCC patients with nonviral etiology before 2014 and after 2014, with a higher proportion after 2014. Over the years, there has been a reduction in viral and an increase in nonviral etiologies. The increase in the prevalence of nonviral etiologies of HCC could be due to multiple factors—the development of effective treatment regimens to combat viral hepatitis, increased awareness regarding Hepatitis B and Hepatitis C, the emergence of lifestyle diseases including obesity and diabetes, increasing incidence of NAFLD and the associated spectrum of liver diseases and the greater use of investigative modalities for etiological diagnosis of HCC.⁷⁴ The major nonviral etiologies of HCC, apart from alcohol and NAFLD, include iron overload syndromes, use of oral contraceptives, aflatoxin, exposure to pesticides, betel quid chewing, Wilson disease, α-₁ antitrypsin deficiency, and autoimmune hepatitis.⁷⁴

The current meta-analysis also shows that a significantly higher proportion of patients were diagnosed with NAFLD after 2014. It is possible that previously, NAFLD-related HCC patients were being labeled ‘cryptogenic.’ The increasing awareness among hepatologists and physicians regarding NAFLD in recent years could have resulted in greater proportions of patients being labeled ‘NAFLD-related HCC.’⁷⁵ However, the converse could also be equally true. Obesity and certain components of the metabolic syndrome are frequently associated with NAFLD patients. Therefore, HCC patients of nonviral etiology in whom no other etiology could be elucidated might run the risk of being labeled ‘NAFLD-related’ based on the presence of ‘metabolic dysfunction’ as per the Metabolic (dysfunction) associated Fatty Liver Disease (MAFLD) or Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) criteria. It would be pertinent to mention here that in a prospective cohort of more than 900,000 adults followed up for 16 years in the United States, the presence of obesity was found to be significantly associated with an increased risk of death from HCC.⁷⁶ In another longitudinal cohort study, which included 578,700 individuals, both obesity and metabolic syndrome could predict HCC development over a mean follow-up of 12 years.⁷⁷ These studies were, however, conducted prior to 2014, and whether the association of obesity and metabolic syndrome is independent of NAFLD or NASH needs to be examined.

This meta-analysis also throws interesting data on the presence of multiple causative factors in the etiological work-up of HCC. Around 10% of HCC patients can have multiple etiologies. It is important, therefore, from the management perspective not to miss those. It is all the more essential to investigate, as far as rationally and judiciously possible, HCC patients who are more likely to be labeled ‘cryptogenic’ or ‘NAFLD-related.’ Around 10% of HCC patients can have cryptogenic etiology. These patients need to be investigated thoroughly to rule out known causes of liver disease and liver cancer.

This meta-analysis was limited by the fact that a majority of the studies prior to 2014 did not report the prevalence of NAFLD-related HCC since many of these patients were labeled ‘cryptogenic.’ This could potentially lead to underreporting of NAFLD-related HCC cases prior to 2014. Also, we could not analyze the contributory effect of various risk factors like tobacco smoking and metabolic risk factors towards HCC. Second, the majority of the studies were retrospective, with predominant hospital-based reporting of observational data leading to selection bias. Third, studies have shown that HBV DNA can still be positive in patients with HCC in the absence of HBsAg, indicating the presence of occult HBV infection.⁷⁸ Occult HBV infection has been found to be strongly associated with the odds of developing HCC.⁷⁹ However, not all the included studies in this meta-analysis look for the presence of HBV DNA. Fourth, patients of different zones may migrate to other areas while seeking better medical care. While most centers would record the etiology treated, they would not record the area of origin of the patients, leading to potential misclassification based on zone. There was a paucity of studies from the Eastern part of India, which includes the states of Bihar, Orissa, Jharkhand, West Bengal, and the Northeastern regions, and is home to a significant proportion of the Indian population. In the absence of data from this zone, the true prevalence of various etiologies of HCC in India remains unknown. Lastly, there is a lack of data on the difference in outcomes and staging of disease based on the etiology.

To conclude, viral hepatitis, predominantly HBV, is the most common etiology of HCC in India. Over the past 3 decades, the proportion of cases with HCC due to HBV has been on a declining trend, and those related to NAFLD are increasing. However, the proportion of HCC cases related to HCV and alcohol has remained constant. Future health policies should be focused on creating awareness and control of the emerging epidemic of NAFLD.

Credit authorship contribution statement

Conceptualization: AC, ApS; Data curation: SG, AnS, AV, SH, PA, SK; Formal analysis: SG, DLP, AnS; Funding acquisition: N/A; Investigation: SG, DLP, AnS; Methodology: SG, AC, ApS; Project administration: SG, AC, ApS; Resources: SG, AnS, AV, SH, PA, SK; Software: SG; Supervision; AC, ApS; Validation: SG, AC, ApS; Visualization: SG; Roles/Writing - original draft: SG, DLP, AnS, PA; Writing - review & editing: SG, AC, DLP, AnS, AV, SH, PA, SK, ApS.

Conflicts of interest

The authors have none to declare.

Funding

None.

Footnotes

Supplementary data to this article can be found online at https://doi.org/10.1016/j.jceh.2024.101391.

Appendix A. Supplementary data

The following is the supplementary data to this article:

Multimedia component 1

mmc1.docx^{(303.9KB, docx)}

References

1.Acharya S.K. Epidemiology of hepatocellular carcinoma in India. J Clin Exp Hepatol. 2014;4:S27–S33. doi: 10.1016/j.jceh.2014.05.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
2.Factsheet - National Cancer Registry Programme (ICMR-NCDIR), Bengaluru, India. https://ncdirindia.org/All_Reports/Report_2020/Factsheet/Fact_Sheet_2020.pdf
3.Shalimar, Elhence A., Bansal B., et al. Prevalence of non-alcoholic fatty liver disease in India: a systematic review and meta-analysis. J Clin Exp Hepatol. 2022;12:818–829. doi: 10.1016/j.jceh.2021.11.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
4.Mondal D., Das K., Chowdhury A. Epidemiology of liver diseases in India. Clin Liver Dis (Hoboken). 2022;19:114–117. doi: 10.1002/cld.1177. [DOI] [PMC free article] [PubMed] [Google Scholar]
5.Swaroop S., Vaishnav M., Arora U., et al. Etiological spectrum of cirrhosis in India: a systematic review and meta-analysis. J Clin Exp Hepatol. 2023 doi: 10.1016/j.jceh.2023.10.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
6.Page M.J., McKenzie J.E., Bossuyt P.M., et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. doi: 10.1136/bmj.n71. [DOI] [PMC free article] [PubMed] [Google Scholar]
7.Munn Z., Barker T.H., Moola S., et al. Methodological quality of case series studies: an introduction to the JBI critical appraisal tool. JBI Evid Synth. 2020;18:2127–2133. doi: 10.11124/JBISRIR-D-19-00099. [DOI] [PubMed] [Google Scholar]
8.Higgins J.P., Thompson S.G., Deeks J.J., Altman D.G. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–560. doi: 10.1136/bmj.327.7414.557. [DOI] [PMC free article] [PubMed] [Google Scholar]
9.Sundaram C., Reddy C.R., Ramana G.V., et al. Hepatitis B surface antigen, hepatocellular carcinoma and cirrhosis in south India--an autopsy study. Indian J Pathol Microbiol. 1990 Oct;33:334–338. PMID: 1966741. [PubMed] [Google Scholar]
10.Ramesh R., Munshi A., Panda S.K. Prevalence of hepatitis C virus antibodies in chronic liver disease and hepatocellular carcinoma patients in India. J Gastroenterol Hepatol. 1992 Jul-Aug;7:393–395. doi: 10.1111/j.1440-1746.1992.tb01006.x. PMID: 1325197. [DOI] [PubMed] [Google Scholar]
11.Joshi N., Kumar A., Rani M.S., Chandra N., Ramanjaneyulu E.R. Clinical and aetiological profile of hepatoma at a tertiary care centre. Trop Gastroenterol. 2003 Apr-Jun;24:73–75. PMID: 14603825. [PubMed] [Google Scholar]
12.Radhika N.S., Duseja A., Rajwanshi A., et al. Clinico-cytopathological spectrum of hepatocellular carcinoma, its correlation with serum alpha-fetoprotein level, and hepatitis B and C viral markers. Trop Gastroenterol. 2004 Jul-Sep;25:116–120. PMID: 15682657. [PubMed] [Google Scholar]
13.Saini N., Bhagat A., Sharma S., Duseja A., Chawla Y. Evaluation of clinical and biochemical parameters in hepatocellular carcinoma: experience from an Indian center. Clin Chim Acta. 2006 Sep;371:183–186. doi: 10.1016/j.cca.2006.02.038. Epub 2006 May 2. Erratum in: Clin Chim Acta. 2007 Feb;377(1-2):289. PMID: 16647699. [DOI] [PubMed] [Google Scholar]
14.Kumar M., Kumar R., Hissar S.S., et al. Risk factors analysis for hepatocellular carcinoma in patients with and without cirrhosis: a case-control study of 213 hepatocellular carcinoma patients from India. J Gastroenterol Hepatol. 2007 Jul;22:1104–1111. doi: 10.1111/j.1440-1746.2007.04908.x. Epub 2007 Jun 7. PMID: 17559381. [DOI] [PubMed] [Google Scholar]
15.Murugavel K.G., Mathews S., Jayanthi V., et al. Alpha-fetoprotein as a tumor marker in hepatocellular carcinoma: investigations in south Indian subjects with hepatotropic virus and aflatoxin etiologies. Int J Infect Dis. 2008 Nov;12:e71–e76. doi: 10.1016/j.ijid.2008.04.010. Epub 2008 Jul 26. PMID: 18658001. [DOI] [PubMed] [Google Scholar]
16.Paul S.B., Chalamalasetty S.B., Vishnubhatla S., et al. Clinical profile, etiology and therapeutic outcome in 324 hepatocellular carcinoma patients at a tertiary care center in India. Oncology. 2009;77:162–171. doi: 10.1159/000231886. Epub 2009 Jul 28. PMID: 19641335. [DOI] [PubMed] [Google Scholar]
17.Asim M., Khan L.A., Husain S.A., et al. Genetic polymorphism of glutathione S transferases M1 and T1 in Indian patients with hepatocellular carcinoma. Dis Markers. 2010;28:369–376. doi: 10.3233/DMA-2010-0717. PMID: 20683151; PMCID: PMC3833703. [DOI] [PMC free article] [PubMed] [Google Scholar]
18.Mohana Devi S., Balachandar V., Murugan P.V., Sasikala K., Manikantan P., Venkatakrishnan L.K. Identification of chromosomal aberrations by using trypsin G-banding in hepatocellular carcinoma patients (HCC) in Tamil Nadu, India. Trop Life Sci Res. 2010 Aug;21:31–46. PMID: 24575188; PMCID: PMC3819068. [PMC free article] [PubMed] [Google Scholar]
19.Sarma S., Sharma B., Chawla Y.K., et al. Comparison of 7 staging systems in north Indian cohort of hepatocellular carcinoma. Trop Gastroenterol. 2010 Oct-Dec;31:271–278. PMID: 21568142. [PubMed] [Google Scholar]
20.Sharma B., Srinivasan R., Chawla Y.K., et al. Clinical utility of prothrombin induced by vitamin K absence in the detection of hepatocellular carcinoma in Indian population. Hepatol Int. 2010 Jul 13;4:569–576. doi: 10.1007/s12072-010-9186-2. PMID: 21063479; PMCID: PMC2940002. [DOI] [PMC free article] [PubMed] [Google Scholar]
21.Medhi S., Sarma M.P., Asim M., Kar P. Genetic variants of heat shock protein A1L2437 and A1B1267 as possible risk factors for hepatocellular carcinoma in India. J Viral Hepat. 2013 Apr;20:e141–e147. doi: 10.1111/jvh.12021. Epub 2012 Nov 20. PMID: 23490384. [DOI] [PubMed] [Google Scholar]
22.Sarma M.P., Asim M., Medhi S., Bharathi T., Diwan R., Kar P. Viral genotypes and associated risk factors of hepatocellular carcinoma in India. Cancer Biol Med. 2012 Sep;9:172–181. doi: 10.7497/j.issn.2095-3941.2012.03.004. PMID: 23691475; PMCID: PMC3643662. [DOI] [PMC free article] [PubMed] [Google Scholar]
23.Arora A., Sharma P., Tyagi P., et al. Hepatitis B virus infection can cause hepatocellular carcinoma in less advanced liver cirrhosis: a comparative study of 142 patients from North India. J Clin Exp Hepatol. 2013 Dec;3:288–295. doi: 10.1016/j.jceh.2013.08.007. Epub 2013 Sep 20. PMID: 25755516; PMCID: PMC3940433. [DOI] [PMC free article] [PubMed] [Google Scholar]
24.Jain D., Nayak N.C., Kumaran V., Saigal S. Steatohepatitic hepatocellular carcinoma, a morphologic indicator of associated metabolic risk factors: a study from India. Arch Pathol Lab Med. 2013 Jul;137:961–966. doi: 10.5858/arpa.2012-0048-OA. PMID: 23808468. [DOI] [PubMed] [Google Scholar]
25.Pal S., Ramachandran J., Kurien R.T., et al. Hepatocellular carcinoma continues to be diagnosed in the advanced stage: profile of hepatocellular carcinoma in a tertiary care hospital in South India. Trop Doct. 2013 Jan;43:25–26. doi: 10.1177/0049475512473600. Epub 2013 Feb 26. PMID: 23443626. [DOI] [PubMed] [Google Scholar]
26.Kohli A., Murphy A.A., Agarwal C., et al. HCC surveillance results in earlier HCC detection: results from an Indian cohort. Springerplus. 2014 Oct 17;3:610. doi: 10.1186/2193-1801-3-610. PMID: 25392781; PMCID: PMC4209002. [DOI] [PMC free article] [PubMed] [Google Scholar]
27.Sood A., Midha V., Goyal O., Goyal P., Sood N., Sharma S.K. Profile of hepatocellular carcinoma in a tertiary care hospital in Punjab in northern India. Indian J Gastroenterol. 2014 Jan;33:35–40. doi: 10.1007/s12664-013-0373-7. Epub 2013 Sep 6. PMID: 24222369. [DOI] [PubMed] [Google Scholar]
28.Agarwal A., Yadav A.K., Kumar A., et al. Transarterial chemoembolization in unresectable hepatocellular carcinoma--assessing the factors affecting the survival: an audit from a tertiary care center in northern India. Indian J Gastroenterol. 2015;34:117–126. doi: 10.1007/s12664-015-0544-9. [DOI] [PubMed] [Google Scholar]
29.Dhamija E., Paul S.B., Gamanagatti S.R., Acharya S.K. Biliary complications of arterial chemoembolization of hepatocellular carcinoma. Diagn Interv Imaging. 2015;96:1169–1175. doi: 10.1016/j.diii.2015.06.017. [DOI] [PubMed] [Google Scholar]
30.Srirambhatla J., Linga V.G., Kalpathi K.M., et al. Current profile of hepatocellular carcinoma from a tertiary care center in Andhra Pradesh. Indian J Gastroenterol. 2015;34:335–336. doi: 10.1007/s12664-015-0590-3. [DOI] [PubMed] [Google Scholar]
31.Lokesh K.N., Chaudhuri T., Lakshmaiah K.C., et al. Advanced hepatocellular carcinoma: a regional cancer center experience of 48 cases. Indian J Cancer. 2017;54:526–529. doi: 10.4103/ijc.IJC_373_17. [DOI] [PubMed] [Google Scholar]
32.Ostwal V., Gupta T., Chopra S., et al. Tolerance and adverse event profile with sorafenib in Indian patients with advanced hepatocellular carcinoma. South Asian J Cancer. 2017;6:144–146. doi: 10.4103/sajc.sajc_44_17. [DOI] [PMC free article] [PubMed] [Google Scholar]
33.Paul S.B., Dhamija E., Gamanagatti S.R., et al. Evaluation of tumor response to intra-arterial chemoembolization of hepatocellular carcinoma: comparison of contrast-enhanced ultrasound with multiphase computed tomography. Diagn Interv Imaging. 2017;98:253–260. doi: 10.1016/j.diii.2016.09.002. [DOI] [PubMed] [Google Scholar]
34.Varghese J., Kedarisetty C., Venkataraman J., et al. Combination of TACE and sorafenib improves outcomes in BCLC stages B/C of hepatocellular carcinoma: a single centre experience. Ann Hepatol. 2017;16:247–254. doi: 10.5604/16652681.1231583. [DOI] [PubMed] [Google Scholar]
35.Bharali D., Banerjee B.D., Bharadwaj M., Husain S.A., Kar P. Expression analysis of apolipoproteins AI & AIV in hepatocellular carcinoma: a protein-based hepatocellular carcinoma-associated study. Indian J Med Res. 2018;147:361–368. doi: 10.4103/ijmr.IJMR_1358_16. [DOI] [PMC free article] [PubMed] [Google Scholar]
36.Makol A., Kanthaje S., Dhiman R.K., Kalra N., Chawla Y.K., Chakraborti A. Association of liver cirrhosis severity with type 2 diabetes mellitus in hepatocellular carcinoma. Exp Biol Med (Maywood) 2018;243:323–326. doi: 10.1177/1535370217744511. [DOI] [PMC free article] [PubMed] [Google Scholar]
37.Patkar S., Parray A., Mahendra B., Kurunkar S., Goel M. Performance of Hong Kong Liver Cancer staging system in patients of hepatocellular carcinoma treated with surgical resection: an Indian validation study. J Surg Oncol. 2019;120:1119–1125. doi: 10.1002/jso.25704. [DOI] [PubMed] [Google Scholar]
38.Paul S.B., Sahu P., Sreenivas V., et al. Prognostic role of serial alpha-fetoprotein levels in hepatocellular carcinoma treated with locoregional therapy. Scand J Gastroenterol. 2019;54:1132–1137. doi: 10.1080/00365521.2019.1660403. [DOI] [PubMed] [Google Scholar]
39.Jamwal R., Krishnan V., Kushwaha D.S., Khurana R. Hepatocellular carcinoma in non-cirrhotic versus cirrhotic liver: a clinico-radiological comparative analysis. Abdom Radiol (NY) 2020;45:2378–2387. doi: 10.1007/s00261-020-02561-z. [DOI] [PubMed] [Google Scholar]
40.Kedarisetty C.K., Bal S., Parida S., et al. Role of N-acetyl cysteine in post-transarterial chemoembolization transaminitis in hepatocellular carcinoma: a single-center experience. J Clin Exp Hepatol. 2021;11:299–304. doi: 10.1016/j.jceh.2020.10.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
41.Mukund A., Vats P., Jindal A., Patidar Y., Sarin S.K. Early hepatocellular carcinoma treated by radiofrequency ablation-mid- and long-term outcomes. J Clin Exp Hepatol. 2020;10:563–573. doi: 10.1016/j.jceh.2020.04.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
42.Paul S.B., Acharya S.K., Gamanagatti S.R., Sreenivas V., Shalimar S., Gulati M.S. Acetic acid versus radiofrequency ablation for the treatment of hepatocellular carcinoma: a randomized controlled trial. Diagn Interv Imaging. 2020;101:101–110. doi: 10.1016/j.diii.2019.06.011. [DOI] [PubMed] [Google Scholar]
43.Soin A.S., Bhangui P., Kataria T., et al. Experience with LDLT in patients with hepatocellular carcinoma and portal vein tumor thrombosis postdownstaging. Transplantation. 2020;104:2334–2345. doi: 10.1097/TP.0000000000003162. [DOI] [PubMed] [Google Scholar]
44.Chandra K.B., Singhal A. Predictors of macrovascular invasion and extrahepatic metastasis in treatment naive hepatocellular carcinoma: when is [18F] FDG PET/CT relevant? Nucl Med Mol Imaging. 2021;55:293–301. doi: 10.1007/s13139-021-00714-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
45.Dutta D., Tatineni T., Yarlagadda S., et al. Hepatocellular carcinoma patients with portal vein thrombosis treated with robotic radiosurgery: interim results of a prospective study. Indian J Gastroenterol. 2021;40:389–401. doi: 10.1007/s12664-021-01172-w. [DOI] [PubMed] [Google Scholar]
46.Ghosh A., Yadav R., Shalimar, Gamanagatti S. Respiratory triggered diffusion-weighted imaging with a single diffusion sensitising gradient to reduce image acquisition time - a feasibility study in the workup of hepatocellular carcinoma. Eur J Radiol. 2021 Aug;141 doi: 10.1016/j.ejrad.2021.109807. Epub 2021 Jun 3. PMID: 34146912. [DOI] [PubMed] [Google Scholar]
47.Jearth V., Patil P.S., Mehta S., et al. Correlation of clinicopathological profile, prognostic factors, and survival outcomes with baseline alfa-fetoprotein levels in patients with hepatocellular carcinoma: a biomarker that is bruised but not broken. J Clin Exp Hepatol. 2022;12:841–852. doi: 10.1016/j.jceh.2021.11.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
48.Kumar R., Yadav H.P., Thaper D., Kamal R., Gupta A., Kirti S. Efficacy and toxicity of SBRT in advanced hepatocellular carcinoma with portal vein tumor thrombosis - a retrospective study. Rep Pract Oncol Radiother. 2021;26:573–581. doi: 10.5603/RPOR.a2021.0048. [DOI] [PMC free article] [PubMed] [Google Scholar]
49.Pamecha V., Sinha P.K., Rajendran V., et al. Living donor liver transplantation for hepatocellular carcinoma in Indian patients- Is the scenario different? Indian J Gastroenterol. 2021;40:295–302. doi: 10.1007/s12664-020-01138-4. [DOI] [PubMed] [Google Scholar]
50.Patel A., Subbanna I., Bhargavi V., Swamy S., Kallur K.G., Patil S. Transarterial radioembolization (TARE) with 131 iodine-lipiodol for unresectable primary hepatocellular carcinoma: experience from a tertiary care center in India. South Asian J Cancer. 2021;10:81–86. doi: 10.1055/s-0041-1731600. [DOI] [PMC free article] [PubMed] [Google Scholar]
51.Patidar Y., Chandel K., Condati N.K., Srinivasan S.V., Mukund A., Sarin S.K. Transarterial chemoembolization (TACE) combined with sorafenib versus TACE in patients with BCLC stage C hepatocellular carcinoma - a retrospective study. J Clin Exp Hepatol. 2022;12:745–754. doi: 10.1016/j.jceh.2021.12.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
52.Rajakannu M., Vij M., Shaikh T.M.A., Rammohan A., Reddy M.S., Rela M. Prognostic impact of incidentally detected hepatocellular carcinoma in explanted livers after living donor liver transplantation. Indian J Gastroenterol. 2021;40:30–34. doi: 10.1007/s12664-020-01127-7. [DOI] [PubMed] [Google Scholar]
53.Tohra S., Duseja A., Taneja S., et al. Experience with changing etiology and nontransplant curative treatment modalities for hepatocellular carcinoma in a real-life setting-a retrospective descriptive analysis. J Clin Exp Hepatol. 2021;11:682–690. doi: 10.1016/j.jceh.2021.02.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
54.Anand S., Pottakkat B., Raja K., Chandrasekar S., Satheesh S. Transarterial chemoembolization in patients with hepatocellular carcinoma beyond Barcelona-Clinic Liver Cancer- B and portal vein tumor thrombosis: experience from a tertiary care center. Indian J Cancer. 2022;59:325–329. doi: 10.4103/ijc.IJC_769_19. [DOI] [PubMed] [Google Scholar]
55.Kumar S., Nadda N., Paul S., et al. Evaluation of the cell-free DNA integrity index as a liquid biopsy marker to differentiate hepatocellular carcinoma from chronic liver disease. Front Mol Biosci. 2022;9 doi: 10.3389/fmolb.2022.1024193. [DOI] [PMC free article] [PubMed] [Google Scholar]
56.Mukund A., Bansal A., Patidar Y., Thapar S., Sharma M.K., Sarin S.K. Role of contrast-enhanced ultrasound with Perfluorobutane in lesion detection, guidance for microwave ablation, and response assessment of hepatocellular carcinoma. Abdom Radiol (NY) 2022;47:3459–3467. doi: 10.1007/s00261-022-03609-y. [DOI] [PubMed] [Google Scholar]
57.Musunuri B., Shetty S., Bhat G., Udupa K., Pai A. Profile of patients with hepatocellular carcinoma: an experience from a tertiary care center in India. Indian J Gastroenterol. 2022;41:127–134. doi: 10.1007/s12664-021-01209-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
58.Surit R., Shekhar R., Sinha D.K., Singh S.K., Kumar U., Prasad N. Hepatitis B in hepatocellular carcinoma patients and its correlation with alpha-fetoprotein and liver enzymes. J Cancer Res Ther. 2022;18:903–906. doi: 10.4103/jcrt.JCRT_239_19. [DOI] [PubMed] [Google Scholar]
59.Shukla A., Patkar S., Sundaram S., et al. Clinical profile, patterns of care & adherence to guidelines in patients with hepatocellular carcinoma: prospective multi-center study. J Clin Exp Hepatol. 2022;12:1463–1473. doi: 10.1016/j.jceh.2022.05.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
60.Soni S., Pareek P., Narayan S., Rakesh A., Abhilasha A. Hepatocellular carcinoma (HCC) in North-Western India: a retrospective study focusing on epidemiology, risk factors, and survival. J Gastrointest Cancer. 2022;53:921–929. doi: 10.1007/s12029-021-00712-z. [DOI] [PubMed] [Google Scholar]
61.Hui M., Uppin S.G., Uppin M.S., et al. Hepatocellular carcinoma: a clinicopathological and immunohistochemical study of 116 cases from a tertiary care hospital in Southern India. Indian J Cancer. 2023;60:191–198. doi: 10.4103/ijc.IJC_1004_19. [DOI] [PubMed] [Google Scholar]
62.Jearth V., Patil P.S., Mehta S., et al. A study of the clinical profile, predictors, prognostic features, and survival of patients with hepatocellular carcinoma having macroscopic portal vein tumor thrombosis. Indian J Gastroenterol. 2022;41:533–543. doi: 10.1007/s12664-022-01289-6. [DOI] [PubMed] [Google Scholar]
63.Koshy A., Devadas K., Panackel C., et al. Multi-center prospective survey of hepatocellular carcinoma in Kerala: more than 1,200 cases. Indian J Gastroenterol. 2023;42:233–240. doi: 10.1007/s12664-022-01314-8. [DOI] [PubMed] [Google Scholar]
64.Kulkarni A.V., Krishna V., Kumar K., et al. Safety and efficacy of atezolizumab-bevacizumab in real world: the first Indian experience. J Clin Exp Hepatol. 2023;13:618–623. doi: 10.1016/j.jceh.2023.02.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
65.Mehra P., Kataria T., Gupta D., Krishan S. An observational study on tumour response of portal vein tumour thrombus in hepatocellular carcinoma. J Radiosurg SBRT. 2022;8:257–264. [PMC free article] [PubMed] [Google Scholar]
66.Mukund A., Tripathy T.P., Patel R.K., et al. Percutaneous ablative therapies for hepatocellular carcinoma in the caudate lobe of the liver: efficacy and outcome. Br J Radiol. 2023;96 doi: 10.1259/bjr.20220086. [DOI] [PMC free article] [PubMed] [Google Scholar]
67.Prabhakar T., Kaushal K., Prasad M., et al. Etiologic fractions in patients of hepatocellular carcinoma in India with and without a background of cirrhosis: a multi-centric study. Hepatol Int. 2023;17:745–752. doi: 10.1007/s12072-023-10498-w. [DOI] [PubMed] [Google Scholar]
68.Sharma D., Thaper D., Kamal R., Yadav H.P. Role of palliative SBRT in Barcelona clinic liver cancer-stage C hepatocellular carcinoma patients. Strahlenther Onkol. 2023;199:838–846. doi: 10.1007/s00066-023-02065-x. [DOI] [PubMed] [Google Scholar]
69.Llovet J.M., Kelley R.K., Villanueva A., et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7:6. doi: 10.1038/s41572-020-00240-3. [DOI] [PubMed] [Google Scholar]
70.Giri S., Sahoo S., Angadi S., Afzalpurkar S., Sundaram S., Bhrugumalla S. Seroprevalence of hepatitis B virus among pregnant women in India: a systematic review and meta-analysis. J Clin Exp Hepatol. 2022;12:1408–1419. doi: 10.1016/j.jceh.2022.08.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
71.Batham A., Narula D., Toteja T., Sreenivas V., Puliyel J.M. Systematic review and meta-analysis of prevalence of hepatitis B in India. Indian Pediatr. 2007;44:663–674. [PubMed] [Google Scholar]
72.Kumar D., Peter R.M., Joseph A., Kosalram K., Kaur H. Prevalence of viral hepatitis infection in India: a systematic review and meta-analysis. J Educ Health Promot. 2023;12:103. doi: 10.4103/jehp.jehp_1005_22. [DOI] [PMC free article] [PubMed] [Google Scholar]
73.Shanmugam R.P., Balakrishnan S., Varadhan H., Shanmugam V. Prevalence of hepatitis B and hepatitis C infection from a population-based study in Southern India. Eur J Gastroenterol Hepatol. 2018;30:1344–1351. doi: 10.1097/MEG.0000000000001180. [DOI] [PubMed] [Google Scholar]
74.Hamed M.A., Ali S.A. Non-viral factors contributing to hepatocellular carcinoma. World J Hepatol. 2013;5:311–322. doi: 10.4254/wjh.v5.i6.311. [DOI] [PMC free article] [PubMed] [Google Scholar]
75.Younossi Z.M., Henry L. Epidemiology of non-alcoholic fatty liver disease and hepatocellular carcinoma. JHEP Rep. 2021;3 doi: 10.1016/j.jhepr.2021.100305. [DOI] [PMC free article] [PubMed] [Google Scholar]
76.Calle E.E., Rodriguez C., Walker-Thurmond K., Thun M.J. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348:1625–1638. doi: 10.1056/NEJMoa021423. [DOI] [PubMed] [Google Scholar]
77.Borena W., Strohmaier S., Lukanova A., et al. Metabolic risk factors and primary liver cancer in a prospective study of 578,700 adults. Int J Cancer. 2012;131:193–200. doi: 10.1002/ijc.26338. [DOI] [PubMed] [Google Scholar]
78.Mak L.Y., Wong D.K.H., Pollicino T., Raimondo G., Hollinger F.B., Yuen M.F. Occult hepatitis B infection and hepatocellular carcinoma: epidemiology, virology, hepatocarcinogenesis and clinical significance. J Hepatol. 2020;73:952–964. doi: 10.1016/j.jhep.2020.05.042. [DOI] [PubMed] [Google Scholar]
79.Huang X., Hollinger F.B. Occult hepatitis B virus infection and hepatocellular carcinoma: a systematic review. J Viral Hepat. 2014;21:153–162. doi: 10.1111/jvh.12222. [DOI] [PubMed] [Google Scholar]

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[bib1] 1.Acharya S.K. Epidemiology of hepatocellular carcinoma in India. J Clin Exp Hepatol. 2014;4:S27–S33. doi: 10.1016/j.jceh.2014.05.013. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib2] 2.Factsheet - National Cancer Registry Programme (ICMR-NCDIR), Bengaluru, India. https://ncdirindia.org/All_Reports/Report_2020/Factsheet/Fact_Sheet_2020.pdf

[bib3] 3.Shalimar, Elhence A., Bansal B., et al. Prevalence of non-alcoholic fatty liver disease in India: a systematic review and meta-analysis. J Clin Exp Hepatol. 2022;12:818–829. doi: 10.1016/j.jceh.2021.11.010. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib4] 4.Mondal D., Das K., Chowdhury A. Epidemiology of liver diseases in India. Clin Liver Dis (Hoboken). 2022;19:114–117. doi: 10.1002/cld.1177. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib5] 5.Swaroop S., Vaishnav M., Arora U., et al. Etiological spectrum of cirrhosis in India: a systematic review and meta-analysis. J Clin Exp Hepatol. 2023 doi: 10.1016/j.jceh.2023.10.002. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib6] 6.Page M.J., McKenzie J.E., Bossuyt P.M., et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. doi: 10.1136/bmj.n71. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib7] 7.Munn Z., Barker T.H., Moola S., et al. Methodological quality of case series studies: an introduction to the JBI critical appraisal tool. JBI Evid Synth. 2020;18:2127–2133. doi: 10.11124/JBISRIR-D-19-00099. [DOI] [PubMed] [Google Scholar]

[bib8] 8.Higgins J.P., Thompson S.G., Deeks J.J., Altman D.G. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–560. doi: 10.1136/bmj.327.7414.557. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib9] 9.Sundaram C., Reddy C.R., Ramana G.V., et al. Hepatitis B surface antigen, hepatocellular carcinoma and cirrhosis in south India--an autopsy study. Indian J Pathol Microbiol. 1990 Oct;33:334–338. PMID: 1966741. [PubMed] [Google Scholar]

[bib10] 10.Ramesh R., Munshi A., Panda S.K. Prevalence of hepatitis C virus antibodies in chronic liver disease and hepatocellular carcinoma patients in India. J Gastroenterol Hepatol. 1992 Jul-Aug;7:393–395. doi: 10.1111/j.1440-1746.1992.tb01006.x. PMID: 1325197. [DOI] [PubMed] [Google Scholar]

[bib11] 11.Joshi N., Kumar A., Rani M.S., Chandra N., Ramanjaneyulu E.R. Clinical and aetiological profile of hepatoma at a tertiary care centre. Trop Gastroenterol. 2003 Apr-Jun;24:73–75. PMID: 14603825. [PubMed] [Google Scholar]

[bib12] 12.Radhika N.S., Duseja A., Rajwanshi A., et al. Clinico-cytopathological spectrum of hepatocellular carcinoma, its correlation with serum alpha-fetoprotein level, and hepatitis B and C viral markers. Trop Gastroenterol. 2004 Jul-Sep;25:116–120. PMID: 15682657. [PubMed] [Google Scholar]

[bib13] 13.Saini N., Bhagat A., Sharma S., Duseja A., Chawla Y. Evaluation of clinical and biochemical parameters in hepatocellular carcinoma: experience from an Indian center. Clin Chim Acta. 2006 Sep;371:183–186. doi: 10.1016/j.cca.2006.02.038. Epub 2006 May 2. Erratum in: Clin Chim Acta. 2007 Feb;377(1-2):289. PMID: 16647699. [DOI] [PubMed] [Google Scholar]

[bib14] 14.Kumar M., Kumar R., Hissar S.S., et al. Risk factors analysis for hepatocellular carcinoma in patients with and without cirrhosis: a case-control study of 213 hepatocellular carcinoma patients from India. J Gastroenterol Hepatol. 2007 Jul;22:1104–1111. doi: 10.1111/j.1440-1746.2007.04908.x. Epub 2007 Jun 7. PMID: 17559381. [DOI] [PubMed] [Google Scholar]

[bib15] 15.Murugavel K.G., Mathews S., Jayanthi V., et al. Alpha-fetoprotein as a tumor marker in hepatocellular carcinoma: investigations in south Indian subjects with hepatotropic virus and aflatoxin etiologies. Int J Infect Dis. 2008 Nov;12:e71–e76. doi: 10.1016/j.ijid.2008.04.010. Epub 2008 Jul 26. PMID: 18658001. [DOI] [PubMed] [Google Scholar]

[bib16] 16.Paul S.B., Chalamalasetty S.B., Vishnubhatla S., et al. Clinical profile, etiology and therapeutic outcome in 324 hepatocellular carcinoma patients at a tertiary care center in India. Oncology. 2009;77:162–171. doi: 10.1159/000231886. Epub 2009 Jul 28. PMID: 19641335. [DOI] [PubMed] [Google Scholar]

[bib17] 17.Asim M., Khan L.A., Husain S.A., et al. Genetic polymorphism of glutathione S transferases M1 and T1 in Indian patients with hepatocellular carcinoma. Dis Markers. 2010;28:369–376. doi: 10.3233/DMA-2010-0717. PMID: 20683151; PMCID: PMC3833703. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib18] 18.Mohana Devi S., Balachandar V., Murugan P.V., Sasikala K., Manikantan P., Venkatakrishnan L.K. Identification of chromosomal aberrations by using trypsin G-banding in hepatocellular carcinoma patients (HCC) in Tamil Nadu, India. Trop Life Sci Res. 2010 Aug;21:31–46. PMID: 24575188; PMCID: PMC3819068. [PMC free article] [PubMed] [Google Scholar]

[bib19] 19.Sarma S., Sharma B., Chawla Y.K., et al. Comparison of 7 staging systems in north Indian cohort of hepatocellular carcinoma. Trop Gastroenterol. 2010 Oct-Dec;31:271–278. PMID: 21568142. [PubMed] [Google Scholar]

[bib20] 20.Sharma B., Srinivasan R., Chawla Y.K., et al. Clinical utility of prothrombin induced by vitamin K absence in the detection of hepatocellular carcinoma in Indian population. Hepatol Int. 2010 Jul 13;4:569–576. doi: 10.1007/s12072-010-9186-2. PMID: 21063479; PMCID: PMC2940002. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib21] 21.Medhi S., Sarma M.P., Asim M., Kar P. Genetic variants of heat shock protein A1L2437 and A1B1267 as possible risk factors for hepatocellular carcinoma in India. J Viral Hepat. 2013 Apr;20:e141–e147. doi: 10.1111/jvh.12021. Epub 2012 Nov 20. PMID: 23490384. [DOI] [PubMed] [Google Scholar]

[bib22] 22.Sarma M.P., Asim M., Medhi S., Bharathi T., Diwan R., Kar P. Viral genotypes and associated risk factors of hepatocellular carcinoma in India. Cancer Biol Med. 2012 Sep;9:172–181. doi: 10.7497/j.issn.2095-3941.2012.03.004. PMID: 23691475; PMCID: PMC3643662. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib23] 23.Arora A., Sharma P., Tyagi P., et al. Hepatitis B virus infection can cause hepatocellular carcinoma in less advanced liver cirrhosis: a comparative study of 142 patients from North India. J Clin Exp Hepatol. 2013 Dec;3:288–295. doi: 10.1016/j.jceh.2013.08.007. Epub 2013 Sep 20. PMID: 25755516; PMCID: PMC3940433. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib24] 24.Jain D., Nayak N.C., Kumaran V., Saigal S. Steatohepatitic hepatocellular carcinoma, a morphologic indicator of associated metabolic risk factors: a study from India. Arch Pathol Lab Med. 2013 Jul;137:961–966. doi: 10.5858/arpa.2012-0048-OA. PMID: 23808468. [DOI] [PubMed] [Google Scholar]

[bib25] 25.Pal S., Ramachandran J., Kurien R.T., et al. Hepatocellular carcinoma continues to be diagnosed in the advanced stage: profile of hepatocellular carcinoma in a tertiary care hospital in South India. Trop Doct. 2013 Jan;43:25–26. doi: 10.1177/0049475512473600. Epub 2013 Feb 26. PMID: 23443626. [DOI] [PubMed] [Google Scholar]

[bib26] 26.Kohli A., Murphy A.A., Agarwal C., et al. HCC surveillance results in earlier HCC detection: results from an Indian cohort. Springerplus. 2014 Oct 17;3:610. doi: 10.1186/2193-1801-3-610. PMID: 25392781; PMCID: PMC4209002. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib27] 27.Sood A., Midha V., Goyal O., Goyal P., Sood N., Sharma S.K. Profile of hepatocellular carcinoma in a tertiary care hospital in Punjab in northern India. Indian J Gastroenterol. 2014 Jan;33:35–40. doi: 10.1007/s12664-013-0373-7. Epub 2013 Sep 6. PMID: 24222369. [DOI] [PubMed] [Google Scholar]

[bib28] 28.Agarwal A., Yadav A.K., Kumar A., et al. Transarterial chemoembolization in unresectable hepatocellular carcinoma--assessing the factors affecting the survival: an audit from a tertiary care center in northern India. Indian J Gastroenterol. 2015;34:117–126. doi: 10.1007/s12664-015-0544-9. [DOI] [PubMed] [Google Scholar]

[bib29] 29.Dhamija E., Paul S.B., Gamanagatti S.R., Acharya S.K. Biliary complications of arterial chemoembolization of hepatocellular carcinoma. Diagn Interv Imaging. 2015;96:1169–1175. doi: 10.1016/j.diii.2015.06.017. [DOI] [PubMed] [Google Scholar]

[bib30] 30.Srirambhatla J., Linga V.G., Kalpathi K.M., et al. Current profile of hepatocellular carcinoma from a tertiary care center in Andhra Pradesh. Indian J Gastroenterol. 2015;34:335–336. doi: 10.1007/s12664-015-0590-3. [DOI] [PubMed] [Google Scholar]

[bib31] 31.Lokesh K.N., Chaudhuri T., Lakshmaiah K.C., et al. Advanced hepatocellular carcinoma: a regional cancer center experience of 48 cases. Indian J Cancer. 2017;54:526–529. doi: 10.4103/ijc.IJC_373_17. [DOI] [PubMed] [Google Scholar]

[bib32] 32.Ostwal V., Gupta T., Chopra S., et al. Tolerance and adverse event profile with sorafenib in Indian patients with advanced hepatocellular carcinoma. South Asian J Cancer. 2017;6:144–146. doi: 10.4103/sajc.sajc_44_17. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib33] 33.Paul S.B., Dhamija E., Gamanagatti S.R., et al. Evaluation of tumor response to intra-arterial chemoembolization of hepatocellular carcinoma: comparison of contrast-enhanced ultrasound with multiphase computed tomography. Diagn Interv Imaging. 2017;98:253–260. doi: 10.1016/j.diii.2016.09.002. [DOI] [PubMed] [Google Scholar]

[bib34] 34.Varghese J., Kedarisetty C., Venkataraman J., et al. Combination of TACE and sorafenib improves outcomes in BCLC stages B/C of hepatocellular carcinoma: a single centre experience. Ann Hepatol. 2017;16:247–254. doi: 10.5604/16652681.1231583. [DOI] [PubMed] [Google Scholar]

[bib35] 35.Bharali D., Banerjee B.D., Bharadwaj M., Husain S.A., Kar P. Expression analysis of apolipoproteins AI & AIV in hepatocellular carcinoma: a protein-based hepatocellular carcinoma-associated study. Indian J Med Res. 2018;147:361–368. doi: 10.4103/ijmr.IJMR_1358_16. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib36] 36.Makol A., Kanthaje S., Dhiman R.K., Kalra N., Chawla Y.K., Chakraborti A. Association of liver cirrhosis severity with type 2 diabetes mellitus in hepatocellular carcinoma. Exp Biol Med (Maywood) 2018;243:323–326. doi: 10.1177/1535370217744511. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib37] 37.Patkar S., Parray A., Mahendra B., Kurunkar S., Goel M. Performance of Hong Kong Liver Cancer staging system in patients of hepatocellular carcinoma treated with surgical resection: an Indian validation study. J Surg Oncol. 2019;120:1119–1125. doi: 10.1002/jso.25704. [DOI] [PubMed] [Google Scholar]

[bib38] 38.Paul S.B., Sahu P., Sreenivas V., et al. Prognostic role of serial alpha-fetoprotein levels in hepatocellular carcinoma treated with locoregional therapy. Scand J Gastroenterol. 2019;54:1132–1137. doi: 10.1080/00365521.2019.1660403. [DOI] [PubMed] [Google Scholar]

[bib39] 39.Jamwal R., Krishnan V., Kushwaha D.S., Khurana R. Hepatocellular carcinoma in non-cirrhotic versus cirrhotic liver: a clinico-radiological comparative analysis. Abdom Radiol (NY) 2020;45:2378–2387. doi: 10.1007/s00261-020-02561-z. [DOI] [PubMed] [Google Scholar]

[bib40] 40.Kedarisetty C.K., Bal S., Parida S., et al. Role of N-acetyl cysteine in post-transarterial chemoembolization transaminitis in hepatocellular carcinoma: a single-center experience. J Clin Exp Hepatol. 2021;11:299–304. doi: 10.1016/j.jceh.2020.10.007. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib41] 41.Mukund A., Vats P., Jindal A., Patidar Y., Sarin S.K. Early hepatocellular carcinoma treated by radiofrequency ablation-mid- and long-term outcomes. J Clin Exp Hepatol. 2020;10:563–573. doi: 10.1016/j.jceh.2020.04.016. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib42] 42.Paul S.B., Acharya S.K., Gamanagatti S.R., Sreenivas V., Shalimar S., Gulati M.S. Acetic acid versus radiofrequency ablation for the treatment of hepatocellular carcinoma: a randomized controlled trial. Diagn Interv Imaging. 2020;101:101–110. doi: 10.1016/j.diii.2019.06.011. [DOI] [PubMed] [Google Scholar]

[bib43] 43.Soin A.S., Bhangui P., Kataria T., et al. Experience with LDLT in patients with hepatocellular carcinoma and portal vein tumor thrombosis postdownstaging. Transplantation. 2020;104:2334–2345. doi: 10.1097/TP.0000000000003162. [DOI] [PubMed] [Google Scholar]

[bib44] 44.Chandra K.B., Singhal A. Predictors of macrovascular invasion and extrahepatic metastasis in treatment naive hepatocellular carcinoma: when is [18F] FDG PET/CT relevant? Nucl Med Mol Imaging. 2021;55:293–301. doi: 10.1007/s13139-021-00714-6. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib45] 45.Dutta D., Tatineni T., Yarlagadda S., et al. Hepatocellular carcinoma patients with portal vein thrombosis treated with robotic radiosurgery: interim results of a prospective study. Indian J Gastroenterol. 2021;40:389–401. doi: 10.1007/s12664-021-01172-w. [DOI] [PubMed] [Google Scholar]

[bib46] 46.Ghosh A., Yadav R., Shalimar, Gamanagatti S. Respiratory triggered diffusion-weighted imaging with a single diffusion sensitising gradient to reduce image acquisition time - a feasibility study in the workup of hepatocellular carcinoma. Eur J Radiol. 2021 Aug;141 doi: 10.1016/j.ejrad.2021.109807. Epub 2021 Jun 3. PMID: 34146912. [DOI] [PubMed] [Google Scholar]

[bib47] 47.Jearth V., Patil P.S., Mehta S., et al. Correlation of clinicopathological profile, prognostic factors, and survival outcomes with baseline alfa-fetoprotein levels in patients with hepatocellular carcinoma: a biomarker that is bruised but not broken. J Clin Exp Hepatol. 2022;12:841–852. doi: 10.1016/j.jceh.2021.11.006. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib48] 48.Kumar R., Yadav H.P., Thaper D., Kamal R., Gupta A., Kirti S. Efficacy and toxicity of SBRT in advanced hepatocellular carcinoma with portal vein tumor thrombosis - a retrospective study. Rep Pract Oncol Radiother. 2021;26:573–581. doi: 10.5603/RPOR.a2021.0048. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib49] 49.Pamecha V., Sinha P.K., Rajendran V., et al. Living donor liver transplantation for hepatocellular carcinoma in Indian patients- Is the scenario different? Indian J Gastroenterol. 2021;40:295–302. doi: 10.1007/s12664-020-01138-4. [DOI] [PubMed] [Google Scholar]

[bib50] 50.Patel A., Subbanna I., Bhargavi V., Swamy S., Kallur K.G., Patil S. Transarterial radioembolization (TARE) with 131 iodine-lipiodol for unresectable primary hepatocellular carcinoma: experience from a tertiary care center in India. South Asian J Cancer. 2021;10:81–86. doi: 10.1055/s-0041-1731600. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib51] 51.Patidar Y., Chandel K., Condati N.K., Srinivasan S.V., Mukund A., Sarin S.K. Transarterial chemoembolization (TACE) combined with sorafenib versus TACE in patients with BCLC stage C hepatocellular carcinoma - a retrospective study. J Clin Exp Hepatol. 2022;12:745–754. doi: 10.1016/j.jceh.2021.12.009. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib52] 52.Rajakannu M., Vij M., Shaikh T.M.A., Rammohan A., Reddy M.S., Rela M. Prognostic impact of incidentally detected hepatocellular carcinoma in explanted livers after living donor liver transplantation. Indian J Gastroenterol. 2021;40:30–34. doi: 10.1007/s12664-020-01127-7. [DOI] [PubMed] [Google Scholar]

[bib53] 53.Tohra S., Duseja A., Taneja S., et al. Experience with changing etiology and nontransplant curative treatment modalities for hepatocellular carcinoma in a real-life setting-a retrospective descriptive analysis. J Clin Exp Hepatol. 2021;11:682–690. doi: 10.1016/j.jceh.2021.02.002. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib54] 54.Anand S., Pottakkat B., Raja K., Chandrasekar S., Satheesh S. Transarterial chemoembolization in patients with hepatocellular carcinoma beyond Barcelona-Clinic Liver Cancer- B and portal vein tumor thrombosis: experience from a tertiary care center. Indian J Cancer. 2022;59:325–329. doi: 10.4103/ijc.IJC_769_19. [DOI] [PubMed] [Google Scholar]

[bib55] 55.Kumar S., Nadda N., Paul S., et al. Evaluation of the cell-free DNA integrity index as a liquid biopsy marker to differentiate hepatocellular carcinoma from chronic liver disease. Front Mol Biosci. 2022;9 doi: 10.3389/fmolb.2022.1024193. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib56] 56.Mukund A., Bansal A., Patidar Y., Thapar S., Sharma M.K., Sarin S.K. Role of contrast-enhanced ultrasound with Perfluorobutane in lesion detection, guidance for microwave ablation, and response assessment of hepatocellular carcinoma. Abdom Radiol (NY) 2022;47:3459–3467. doi: 10.1007/s00261-022-03609-y. [DOI] [PubMed] [Google Scholar]

[bib57] 57.Musunuri B., Shetty S., Bhat G., Udupa K., Pai A. Profile of patients with hepatocellular carcinoma: an experience from a tertiary care center in India. Indian J Gastroenterol. 2022;41:127–134. doi: 10.1007/s12664-021-01209-0. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib58] 58.Surit R., Shekhar R., Sinha D.K., Singh S.K., Kumar U., Prasad N. Hepatitis B in hepatocellular carcinoma patients and its correlation with alpha-fetoprotein and liver enzymes. J Cancer Res Ther. 2022;18:903–906. doi: 10.4103/jcrt.JCRT_239_19. [DOI] [PubMed] [Google Scholar]

[bib59] 59.Shukla A., Patkar S., Sundaram S., et al. Clinical profile, patterns of care & adherence to guidelines in patients with hepatocellular carcinoma: prospective multi-center study. J Clin Exp Hepatol. 2022;12:1463–1473. doi: 10.1016/j.jceh.2022.05.006. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib60] 60.Soni S., Pareek P., Narayan S., Rakesh A., Abhilasha A. Hepatocellular carcinoma (HCC) in North-Western India: a retrospective study focusing on epidemiology, risk factors, and survival. J Gastrointest Cancer. 2022;53:921–929. doi: 10.1007/s12029-021-00712-z. [DOI] [PubMed] [Google Scholar]

[bib61] 61.Hui M., Uppin S.G., Uppin M.S., et al. Hepatocellular carcinoma: a clinicopathological and immunohistochemical study of 116 cases from a tertiary care hospital in Southern India. Indian J Cancer. 2023;60:191–198. doi: 10.4103/ijc.IJC_1004_19. [DOI] [PubMed] [Google Scholar]

[bib62] 62.Jearth V., Patil P.S., Mehta S., et al. A study of the clinical profile, predictors, prognostic features, and survival of patients with hepatocellular carcinoma having macroscopic portal vein tumor thrombosis. Indian J Gastroenterol. 2022;41:533–543. doi: 10.1007/s12664-022-01289-6. [DOI] [PubMed] [Google Scholar]

[bib63] 63.Koshy A., Devadas K., Panackel C., et al. Multi-center prospective survey of hepatocellular carcinoma in Kerala: more than 1,200 cases. Indian J Gastroenterol. 2023;42:233–240. doi: 10.1007/s12664-022-01314-8. [DOI] [PubMed] [Google Scholar]

[bib64] 64.Kulkarni A.V., Krishna V., Kumar K., et al. Safety and efficacy of atezolizumab-bevacizumab in real world: the first Indian experience. J Clin Exp Hepatol. 2023;13:618–623. doi: 10.1016/j.jceh.2023.02.003. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib65] 65.Mehra P., Kataria T., Gupta D., Krishan S. An observational study on tumour response of portal vein tumour thrombus in hepatocellular carcinoma. J Radiosurg SBRT. 2022;8:257–264. [PMC free article] [PubMed] [Google Scholar]

[bib66] 66.Mukund A., Tripathy T.P., Patel R.K., et al. Percutaneous ablative therapies for hepatocellular carcinoma in the caudate lobe of the liver: efficacy and outcome. Br J Radiol. 2023;96 doi: 10.1259/bjr.20220086. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib67] 67.Prabhakar T., Kaushal K., Prasad M., et al. Etiologic fractions in patients of hepatocellular carcinoma in India with and without a background of cirrhosis: a multi-centric study. Hepatol Int. 2023;17:745–752. doi: 10.1007/s12072-023-10498-w. [DOI] [PubMed] [Google Scholar]

[bib68] 68.Sharma D., Thaper D., Kamal R., Yadav H.P. Role of palliative SBRT in Barcelona clinic liver cancer-stage C hepatocellular carcinoma patients. Strahlenther Onkol. 2023;199:838–846. doi: 10.1007/s00066-023-02065-x. [DOI] [PubMed] [Google Scholar]

[bib69] 69.Llovet J.M., Kelley R.K., Villanueva A., et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7:6. doi: 10.1038/s41572-020-00240-3. [DOI] [PubMed] [Google Scholar]

[bib70] 70.Giri S., Sahoo S., Angadi S., Afzalpurkar S., Sundaram S., Bhrugumalla S. Seroprevalence of hepatitis B virus among pregnant women in India: a systematic review and meta-analysis. J Clin Exp Hepatol. 2022;12:1408–1419. doi: 10.1016/j.jceh.2022.08.005. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib71] 71.Batham A., Narula D., Toteja T., Sreenivas V., Puliyel J.M. Systematic review and meta-analysis of prevalence of hepatitis B in India. Indian Pediatr. 2007;44:663–674. [PubMed] [Google Scholar]

[bib72] 72.Kumar D., Peter R.M., Joseph A., Kosalram K., Kaur H. Prevalence of viral hepatitis infection in India: a systematic review and meta-analysis. J Educ Health Promot. 2023;12:103. doi: 10.4103/jehp.jehp_1005_22. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib73] 73.Shanmugam R.P., Balakrishnan S., Varadhan H., Shanmugam V. Prevalence of hepatitis B and hepatitis C infection from a population-based study in Southern India. Eur J Gastroenterol Hepatol. 2018;30:1344–1351. doi: 10.1097/MEG.0000000000001180. [DOI] [PubMed] [Google Scholar]

[bib74] 74.Hamed M.A., Ali S.A. Non-viral factors contributing to hepatocellular carcinoma. World J Hepatol. 2013;5:311–322. doi: 10.4254/wjh.v5.i6.311. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib75] 75.Younossi Z.M., Henry L. Epidemiology of non-alcoholic fatty liver disease and hepatocellular carcinoma. JHEP Rep. 2021;3 doi: 10.1016/j.jhepr.2021.100305. [DOI] [PMC free article] [PubMed] [Google Scholar]

[bib76] 76.Calle E.E., Rodriguez C., Walker-Thurmond K., Thun M.J. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348:1625–1638. doi: 10.1056/NEJMoa021423. [DOI] [PubMed] [Google Scholar]

[bib77] 77.Borena W., Strohmaier S., Lukanova A., et al. Metabolic risk factors and primary liver cancer in a prospective study of 578,700 adults. Int J Cancer. 2012;131:193–200. doi: 10.1002/ijc.26338. [DOI] [PubMed] [Google Scholar]

[bib78] 78.Mak L.Y., Wong D.K.H., Pollicino T., Raimondo G., Hollinger F.B., Yuen M.F. Occult hepatitis B infection and hepatocellular carcinoma: epidemiology, virology, hepatocarcinogenesis and clinical significance. J Hepatol. 2020;73:952–964. doi: 10.1016/j.jhep.2020.05.042. [DOI] [PubMed] [Google Scholar]

[bib79] 79.Huang X., Hollinger F.B. Occult hepatitis B virus infection and hepatocellular carcinoma: a systematic review. J Viral Hepat. 2014;21:153–162. doi: 10.1111/jvh.12222. [DOI] [PubMed] [Google Scholar]

PERMALINK

Changing Etiological Spectrum of Hepatocellular Carcinoma in India—A Systematic Review and Meta-analysis

Suprabhat Giri

Ashok Choudhury

Dibya L Praharaj

Ankita Singh

Arun Vaidya

Sidharth Harindranath

Prajna Anirvan

Shivam Kalia

Akash Shukla

Abstract

Background

Methods

Results

Conclusion

Graphical abstract

Methods

Database Search

Study Inclusion

Data Extraction and Quality Assessment

Data Analysis

Results

Study Characteristics

Figure 1.

Table 1.

Viral Etiology

Table 2.

Hepatitis B Virus

Hepatitis C Virus

Nonviral Etiology

Alcohol-Related

Nonalcoholic Fatty Liver Disease

Multiple Factors

Cryptogenic

Figure 2.

Publication Bias, Sensitivity Analysis, and Meta-regression Analysis

Figure 3.

Figure 4.

Table 3.

Discussion

Credit authorship contribution statement

Conflicts of interest

Funding

Footnotes

Appendix A. Supplementary data

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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