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Article

Hepatocellular Carcinoma in Delta Hepatitis Versus HBV Monoinfection: Spot the Differences

by
Razvan Cerban
1,2,
Mirela Chitul
1,2,*,
Speranta Iacob
1,2,
Daria Gheorghe
2,
Diana Georgiana Stan
2 and
Liana Gheorghe
1,2
1
Department of Hepatology and Liver Transplantation, Fundeni Clinical Institute, 022328 Bucharest, Romania
2
Faculty of General Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
*
Author to whom correspondence should be addressed.
Livers 2025, 5(2), 23; https://doi.org/10.3390/livers5020023
Submission received: 7 February 2025 / Revised: 18 April 2025 / Accepted: 15 May 2025 / Published: 23 May 2025
(This article belongs to the Special Issue Clinical Management of Liver Cancers)
Review Reports Versions Notes

Abstract

:
Background: Hepatitis delta virus (HDV) was recently proven to be directly carcinogenic on hepatocytes via different mechanisms compared to hepatitis B virus (HBV). Our study evaluated the differences between hepatocellular carcinoma (HCC) behaviour in both cases. Methods: A retrospective tertiary care centre study was conducted and included all HBsAg-positive adult patients admitted from the 1st of January 2021 to the 31st of December 2022. IBM SPSS 29.0 was used for statistics. Patients were split into a control group, HBV + HCC, and a study group, HBV + HDV + HCC. Results: A total of 679 patients were included, with an estimated prevalence of HCC in the HDV population of 20.8% versus 9.1% in the control group, p < 0.001, with an OR = 2.263 and a CI 95% of (1.536–3.333), p = 0.001. Younger patients developed HCC in the HBV monoinfection group (mean ± SD, 50.65 ± 12.302 years vs. 51.4 ± 13.708, p = 0.457). Study group patients had smaller tumours (maximum diameter: 32.66 ± 23.181 mm vs. 56.75 ± 38.09 mm, p = 0.002), lower AFP values (177.24 ± 364.8 ng/mL vs. 183.07 ± 336.77 ng/mL, p = 0.941) and predominantly loco-regional treatment. BCLC classification (p = 0.001) and the AFP-Duvoux score (p = 0.001) showed more advanced HCC in HBV monoinfection, with access to mainly systemic therapies (p < 0.001). Conclusions: HCC is more frequent in HDV-infected patients, leading to a different HCC pattern, with smaller tumours, less advanced neoplasia and less access to curative treatment compared to HBV-monoinfection-associated HCC.

1. Introduction

Hepatocellular carcinoma (HCC) represents the sixth most common type of neoplasia worldwide, with an incidence of 906,000 cases in 2020, ranking as the third cause for cancer-related deaths globally [1]. In terms of aetiology, until recently, viral hepatitis was the main cause of HCC. Currently, with the WHO initiative for viral hepatitis elimination by 2030, a changing trend towards advanced liver disease (ALD) in the context of alcohol-related liver disease (ArLD) and metabolic dysfunction-associated liver disease (MASLD) has been observed [2,3]. The current approach to tackling this healthcare challenge, namely HCC, is to increase screening in high-risk populations (abdominal ultrasound every six months ± alpha-fetoprotein (AFP)), leading to early-stage diagnoses and prompt access to curative therapy (resection, loco-regional therapy and liver transplantation) [4,5,6]. More recently, the GALAD score has been proposed for the screening of HCC, with good specificity and sensitivity, particularly useful in early-stage HCC [7]. This score uses five parameters, gender, age, AFP, lens culinaris agglutinin-reactive fraction of AFP (AFP-L3) and des gamma-carboxy prothrombin (DCP), which in addition to abdominal ultrasound (GALADUS score) leads to a higher detection of HCC [8,9].
The diagnosis of HCC, in the majority of cases, does not require liver biopsy for confirmation. In high-risk patients (cirrhotic patients according to EASL guidelines; cirrhosis, chronic HBV hepatitis and current or prior HCC history according to AASLD/LI-RADS; and cirrhosis, chronic HBV hepatitis and chronic HCV hepatitis according to APASL), typical imaging is enough for diagnosis. The classic HCC criteria on CT/MRI or contrast-enhanced ultrasound (the latter only in experienced centres) refers to the size of the neoplasia, non-rim arterial phase hyperenhancement (APHE) and non-peripheral washout [5,6,10]. However, when it comes to non-high-risk patients or an atypical appearance on imaging, liver biopsy remains the gold standard [11].
One of the major risk factors for developing HCC is advanced liver disease, irrespective of its etiology [12]. Once liver disease is suspected, the stage of the disease is established based on the level of fibrosis using non-invasive tests (NITs) such as the AST-to-platelet ratio index (APRI) or fibrosis-4 (FIB-4), but elastography, in addition to being non-invasive, has high specificity and sensitivity (>90%) [13]. The cut-offs recently recommended are >12.5 kPa for suspected ALD and >15 kPa for confirmed ALD [14,15]. Combining the level of fibrosis with the platelet level can detect the presence of portal hypertension [16]. Moreover, once cirrhosis is confirmed, the patients are investigated for decompensation of liver disease (jaundice, ascites, oesophageal varices and hepatic encephalopathy) and HCC [17]. In terms of disease severity and prognosis, the most-used scores in practice are Child Pugh Turcotte, MELD, MELD Na and UKELD. Recently, MELD 3.0 and the gender-equity model for liver allocation (GEMA) have been introduced in order to resolve gender disparities when it comes to liver transplantation [18].
HBV infection accounts for 50–80% of HCC cases. HBV is a known oncogenic virus, leading to HCC independently of the degree of liver fibrosis [19,20]. HDV, on the other hand, has not yet been recognized as a carcinogenic virus, but several studies have shown an up to three times higher risk for HCC in delta hepatitis compared to HBV monoinfection, and even six times higher if HIV coinfection is present [19,21]. The pattern of the tumour in HBV monoinfection described in several studies is multifocal, with a higher diameter and accompanied by higher AFP compared to delta infection. In the latter, lesions are often singular, of smaller size and with lower AFP, probably in the context of more frequent admissions for advanced liver disease in HDV infection [22,23,24,25]. Overall, HBV-associated HCC is more aggressive, with faster progression and vascular invasion compared to HCV, ALD and MASLD [26,27].
Abbas et al. analysed in their study the characteristics of 180 patients with HBV versus HDV-associated HCC. Patients with HDV infection had smaller livers, splenomegaly, large varices, a higher level of hepatocytolisis and lower albumin and lower platelet levels, in addition to a higher percentage of patients with Child Pugh class C, though not statistically significant. In contrast, when it comes to HCC, patients with HBV infection had multiple lesions, with similar diameters and incidence of portal vein thrombosis but higher AFP levels with more advanced TNM staging. However, there was no statistically significant difference in the BCLC stage or Okuda stage between the two groups [22].
The risk factors for developing HCC in HBV are male sex, older age, high viral load, genotype, degree of fibrosis and additional liver insults (HDV, HCV, HIV coinfection, alcohol, MASLD and aflatoxin exposure) [28]. Hence, a risk score called CAMD (cirrhosis, age, men, diabetes) has been proposed for HCC risk in HBV patients treated with nucleos(t)ide analogues (NAs). In delta hepatitis, the risk factors for developing liver neoplasia are younger age, high HDV RNA level, lower platelet level and large varices [29,30]. Another study from the USA identified the persistent high titre of HBsAg on NAs therapy as a potential risk factor for developing HCC [31]. This correlates well with the molecular pathways described in the pathophysiology of HCC [32].
The molecular pathways described in HBV and HDV are different, suggesting once more the independent oncogenic effect of HDV [29]. Three mechanisms have been described in the HCC pathogenesis: signalling pathway changes, reactive oxygen species (ROS) and inflammation [33]. HBV has a direct carcinogenic effect by infiltrating its DNA within the host genome, most frequently within the TERT promoter, leading to the modulation of telomerase length, inhibiting cell senescence and promoting cell growth [34]. Its indirect oncogenic effect happens via viral proteins (particulary HBx but also HBsAg, HBeAg and HBcAg) by interfering with different cell pathways (PI3K/Akt/mTOR, Wnt/FZD/β-catenin, IRS1/IGF and Ras/Raf/MAPK) [35,36]. Additionally, chronic inflammation due to the presence of the virus in the liver activates (NF)-kB and STAT3, leading to cell migration and decreased antitumoral response [37]. Moreover, TGF-β is secreted in high quantities by the tumour-induced macrophages, decreasing antineoplastic immunity [38].
On the other hand, HDV infection leads to HCC indirectly only via the activation of various cellular signalling pathways, epigenetic changes and oxidative stress induced by L-HDAg [29]. HDV inhibits apoptosis and promotes cell proliferation and growth by activating the following pathways: TGF-β, STAT3, NFκβ and Smad3 [39,40,41]. L-HDAg upregulates the activity of c-Jun, leading to higher quantities of TGF-β, which promotes oncogensis and liver fibrosis. Additionally, L-HDAg activates HBx, which further increases the level of TGF-β. The large antigen increases the expression of NADPH oxidase, leading to the release of reactive oxygen species (ROS), which further activate (NF)-kB and STAT3 [38]. SMAD3 pathway activation promotes fibrosis even more [42]. The epigenetic changes consist of long non-coding RNAs, which promote neoplasia, but the data are still scarce [43]. Nonetheless, it has been proven that HDV acts synergistically with HBV by further activating the STAT-3 and TGF-β pathways, explaining why the risk for HCC in HDV is approximately three times higher than in HBV alone [38]. In terms of the genes modulated by HDV, a recent study described seven genes that were upregulated by the presence of delta virus in HCC patients that were not modified in the HBV group [44].
Given the differences highlighted between HBV and delta-hepatitis-associated HCC, from the molecular level to clinical practice, our study aims to compare the prevalence and the clinical characteristics in the HDV HCC group versus HBV monoinfection HCC.

2. Materials and Methods

A retrospective observational study was conducted in a hepatology tertiary care centre between the 1st of January 2021 and the 31st of December 2022. All adult HBsAg-positive patients were included and evaluated for HCC via abdominal ultrasound and AFP then confirmed in our Radiology Department with CT scan/MRI (the typical HCC aspect of APHE and non-peripheral washout if atypical liver biopsy was performed for confirmation).
Patients aged younger than 18 years old with negative HBsAg (seroconversion) or lost to follow-up were excluded. All patients signed an informed consent. Our study was approved by the local ethical committee. Patients were searched via the intrahospital electronic system (Hipocrate) using the ICD 10 codes (namely C22.0 for HCC and B18.1/B18.0 for HBV or HDV infection).
Patients were divided in two groups: HBV-associated HCC (control group) and HDV-associated HCC (study group). Data regarding demographics (age and gender), disease characteristics (disease stage and disease severity: MELD, MELD Na and MELD3.0), routine blood tests (FBC, U&Es, transaminases, alkaline phospatase and GGT and AFP) and viral markers were collected (HBsAg titre, HDV antibodies, HBe antigen and antibodies status and HBV DNA and HDV RNA levels). Disease stage, namely chronic hepatitis, compensated cirrhosis and decompensated cirrhosis, was established based on liver stiffness measurement (using Fibroscan) using the 12.5 kPa cut-off for cirrhosis. Cirrhotic patients were further evaluated for decompensation: jaundice, ascites, oesophageal varices and hepatic encephalopathy. In terms of disease severity, the cut-off for severe disease was 15 for MELD, MELD Na and MELD 3.0. For determining HBsAg titre and anti-HDV, enzyme-linked immunosorbent assays were used (kit from Dia.Pro Diagnostic Probes, Milan, Italy). The HBV DNA level was measured via PCR chain reaction using a RoboGene HBV DNA Quantification Kit 2.0 Roboscreen GmbH, Leipzig, Germany. HDV RNA was determined via PCR chain reaction with a RoboGene HDV RNA Quantification Kit 2.0 from Roboscreen GmbH, Leipzig, Germany. For detecting HCC, a Hitachi Arietta V70 ultrasound system was used, in addition to serum AFP determined with an enzyme-linked immunosorbent assay (kit from Siemens Healthineers, Erlangen, Germany).
SPSS IBM 29.0 (BM Corporation, Armonk, NY, USA) was used for statistics. For continuous data, an independent-sample T test was performed, whereas for non-normal distribution, the Mann–Whitney nonparametrical test was carried out. For qualitative data, we used the Chi square test, but for smaller groups, the Fisher exact test was performed. In terms of correlation, Pearson correlation was the choice for continuous data, whereas the Spearman correlation coefficient was determined for discrete variables. Logistic regression was performed for the risk of HCC in both groups. The confidence interval was set at 95%, and a p value less than 0.05 was considered statistically significant.

3. Results

3.1. Epidemiology

A total of 679 HBsAg-positive patients were included in our study, and 307 had HDV-positive antibodies. A total of 98 patients had liver lesions confirmed as HCC, equivalent to a prevalence of 14.43% of HCC within the HBsAg-positive population. A total of 65.3% of the HCC patients were antiHDV+, and only 34.7% were diagnosed with HBV infection alone. Hence, the prevalence of HCC in the HDV population was 20.8%, versus only 9.1% in the HBV monoinfection population, p < 0.001. The OR for developing HCC in delta hepatitis was 2.263 with a CI of (95%, 1.536–3.333), p = 0.001, compared to HBV monoinfection.
A total of 14 patients had HCC and a non-cirrhotic liver and needed liver biopsy for confirmation of diagnosis, equivalent to 14.28% of the HCC cases. Nine patients had chronic hepatitis B and five had chronic hepatitis D; hence, 9.18% of the patients developed non-cirrhotic HCC in the setting of chronic HBV infection and only 5.1% due to chronic delta hepatitis.

3.2. Demographics and Liver Disease Characteristics

No significant difference in gender was seen between the two groups, but a male predominance was observed in both cases (71.9% in HDV vs. 79.5%, p = 0.807). Younger age was noticed in the HDV chronic infection patients compared to HBV monoinfection (mean ± SD, 59 ± 8.727 years vs. 63 ± 11.28 years, p = 0.027). In terms of disease stage, advanced liver disease was seen in patients with delta hepatitis (chronic hepatitis 12.5% vs. 29.4% in the control group; compensated cirrhosis 50% vs. 44.1%; decompensated cirrhosis 37.5% vs. 26.5%, p < 0.001). Accordingly, MELD, MELD Na and MELD 3.0 were higher in the delta population compared to HBV infection (mean ± SD, 13.21 ± 6.31 vs. 11.14 ± 5.869, p < 0.001; 15.44 ± 7.36 vs. 12.53 ± 6.382, p < 0.001; 14.86 ± 7.828 vs. 11.75 ± 6.884, p = 0.002), (Table 1).
Additionally, patients with delta hepatitis had lower leucocyte and neutrophil levels (5.500 ± 2.17 × 103 U/L vs. 7.31 ± 3.01 × 103 U/L, p = 0.001; 3.583 ± 1.99 × 103 U/L vs. 5.01 ± 2.98 × 103 U/L, p = 0.025), lower platelets and PLR (125.52 ± 7.23 × 103 U/L vs. 182.24 ± 10.11 × 103 U/L, p = 0.01; 108.3 ± 57.6 vs. 136.1 ± 71.96, p = 0.05) and higher liver transaminase (ALT: 71.3 ± 61.6 U/L vs. 36.9 ± 28.4 U/L, p = 0.01; AST: 95.75 ± 88.18 U/L vs. 51.3 ± 41.54 U/L, p = 0.00). Lower HBV DNA and a higher HBsAg titre was seen in delta hepatitis patients compared HBV chronic infection but without statistical significance (HBV DNA 34059 ± 232325 UI/mL vs. 215310 ± 1299333 UI/mL, p = 0.082, HBsAg 161917 ± 202517 S/CO vs. 1622 ± 1832 S/CO, p = 0.288) (Table 1).
In terms of treatment, 38.3% of patients were taking NAs when admitted in our unit: 67.6% with HBV monoinfection and the remaining 32.4% with delta chronic infection.

3.3. HCC Demographics, Characteristics and Correlations

In terms of HCC demographics, the patients’ ages and genders were different compared to the chronic infection setting. Women tended to develop HCC more frequently in both the control and study group, and younger age was noticed in the control group. The HCC associated with delta hepatitis patients had a trend towards intraMilan tumours compared to control group but without statistical significance (intraMilan: 56.2% vs. 41.2%; extraMilan: 43.8% vs. 58.8%; p = 0.097). Patients with HBV-associated HCC presented portal vein thrombosis more frequently than patients with delta hepatitis (57.1% vs. 42.9%, p = 0.016). Patients with delta hepatitis had smaller tumours, with lower AFP on HCC diagnosis (tumour maximum diameter: 32.66 ± 23.181 mm vs. 56.75 ± 38.09 mm, p = 0.002; AFP: 177.24 ± 364.8 ng/mL vs. 183.07 ± 336.77 ng/mL, p = 0.941). A similar distribution of tumours within the liver segments was observed (p = 0.397), with segment VII being the most frequently involved in the study group (34.4% vs. 20.6%) followed by segment VIII (12.5% vs. 20.6%) and segment V (14.1% vs. 14.7%), with the rest of the segments being less involved (Table 2).
BCLC classification showed less advanced tumours in the study group (BCLC A: 71.6% vs. 44.8%; BCLC B: 25.3% vs. 21.5%; BCLC C: 1.4% vs. 13.2%; BCLC D: 1.7% vs. 13.2%, p = 0.001). Similar results were obtained when the AFP-Duvoux score was compared between groups. In delta hepatitis patients, 0 points were obtained in 49.1% vs. only 40.6% in the control group, followed by 2 points (16.4% in delta hepatitis vs. 3.1%), whereas in the control group, 21.9% scored 6 points compared to only 1.8% in the study group, p = 0.013. These results are also reflected in the type of treatment patients received for HCC, with predominantly TACE in the study group (31.2% vs. 29.4%), followed by combined loco-regional therapies (6.2% vs. 2.9%) and resection (4.7% vs. 5.9%), whereas in the control group, systemic therapy occupied an important place (32.4% vs. 1.6%), p < 0.001. The rest of the patients from both groups (56.3% in the study group and 29.4% in the control group) were either referred for liver transplantation as the first line of treatment or for best supportive care. A total of 60.9% of the patients with HDV-associated HCC were included on the waiting list as part of the treatment plan for HCC versus only 11.4% in the control group, p = 0.001. A total of 65.7% of the patients from the study group included on the waiting list were already transplanted by the end of the study (Table 2).
Additionally, when it comes to NA treatment and HCC, 38.2% had this medication previously prescribed: 48.7% were from study group and 51.3% from the control group (HBV only). When looking at the whole study population, the percentage of patients with HCC and receiving NAs (15.2%, n = 39) was similar to the percentage of HCC patients not receiving NAs (14.2%, n = 59), p = 0.723. Logistic regression showed no significant correlation between HCC and NAs both in HBV monoinfection (exp (B) 1.671, p = 0.160) and HDV infection (exp(B) 1.156, p = 0.639); hence, treatment with NAs was not considered as a confounding factor for developing HCC in both groups.
The presence of HCC was strongly correlated with delta hepatitis (p = 0.001) and higher severity scores: MELD (p = 0.001), MELD Na (p = 0.001) and MELD 3.0 (p = 0.001). Moreover, a higher titre of HBsAg was associated with the diagnosis of HCC in both groups (p = 0.027). The delta-hepatitis-associated HCC had a statistically significant correlation with higher MELD (p = 0.001), MELD Na (p = 0.001) and MELD 3.0 (p = 0.001), lower HBV DNA titre (p = 0.001) and higher HBsAg titre (p = 0.001). The latter two were also observed when calculating the mean ± SD for both groups (study group vs. control: HBV DNA 4880 ± 7292 UI/mL vs. 677565.44 ± 1918192 UI/mL, p = 0.33, HBsAg 12363.47 ± 5935.93 S/CO vs. 1199.74 ± 1386.75 S/CO, p = 0.31) but without statistical significance. Additionally, an obvious trend of lower HDV RNA was noticed in the case of HCC associated with HDV infection compared to chronic delta hepatitis patients without HCC (mean ± SD: 74845.6 ± 406850.8 UI/mL vs. 771294.6 ± 7398030 UI/mL, p = 0.352). However, no statistically significant correlation was observed between HCC occurrence and HDV RNA titre, p =0.352.

4. Discussions

4.1. Epidemiology

The prevalence of HCC within the HBsAg population was 14.43%, comparable with the Eurohep group, with an HCC occurrence of 13.5% within this population [45]. Our study highlighted a higher prevalence of HCC in the study group, 20.8% vs. 9.1% in the control group. A similar trend has been observed in various studies, such as a Japanese study showing a 9% HCC occurrence in HDV infection compared to only 3% in the case of HBV monoinfection [46,47]. Hence, an OR of 2.26 was seen for developing HCC in delta hepatitis in our population, similar to the OR of 3.2 in the Eurohep group study and 2.87 seen in the Japanese cohort, 2.12 in a Swedish meta-analysis and 2.08 in a Chinese cohort [45,46,48,49]. However, contrasting studies have also been published, showing a similar risk of HCC in HBV/HBV + HDV coinfection [50,51]. In contrast, a study performed by Wranke et al. showed that patients with HBV and cirrhosis have a higher risk for HCC than patients with HDV cirrhosis [52].

4.2. Demographics and Liver Disease Characteristics

Patients with chronic delta hepatitis are younger than patients with HBV infection alone, a trend captured in other studies as well [53,54]. The male gender predominance seen in both monoinfection and coinfection has also been described in other studies, with a percentage around 71% in many of them, similar to the 71.9% we obtained in the HDV patients [19,55]. When it comes to disease stage, patients with HDV infection are more prone to having advanced liver disease upon diagnosis, with higher percentages with cirrhosis (87.5% vs. 70.6%) compared with HBV monoinfection, findings comparable with data published previously that suggest a 30–70% prevalence of cirrhosis in HDV patients at diagnosis [19,56]. Another meta-analysis on this topic showed a prevalence of cirrhosis in HDV infection around 38.85% vs. only 14.36% in HBV monoinfection [57]. Moreover, the stage of the disease is supported by the severity scores as well, with MELD, MELD Na and MELD 3.0 higher in the HBV + HDV-infected patients.
Furthermore, the higher severity of liver disease in delta hepatitis was also suggested by the higher level of transaminases, lower platelet level and lower PLR. This suggests a higher portal hypertension, as demonstrated previously in the HDV-HCC population [22,58]. Moreover, patients with delta hepatitis have lower leucocyte and neutrophil levela, probably in the context of advanced liver disease, being more susceptible to infections. Lower HBV DNA and higher HBsAg were observed within the delta hepatitis patients. Diaz et al. showed that HBV viremia is decreased in chronic delta hepatitis and particularly in the case of HCC [59].

4.3. HCC Demographics, Characteristics and Correlations

In terms of demographics, we noticed that women develop HCC at a higher percentage compared to the chronic viral infection setting, as demonstrated in other HBV + HDV + HCC studies [23]. Moreover, patients with HBV-associated HCC tend to be younger compared to the HDV-HCC group, in contrast with other studies that show younger age in both HDV chronic infection and in the HDV + HCC setting [22,23]. When it comes to neoplasia characteristics, we highlighted in our study that patients with HBV-associated HCC have larger tumours, with higher AFP and predominantly with extraMilan criteria. Furthermore, they present with more advanced BCLC and AFP-Duvoux scores compared to HDV-associated HCC, consistent with the findings published by Abbas et al. Additionally, the latter mentioned study described a similar rate of portal vein thrombosis in both groups, in contrast with our results that showed a higher percentage of this thrombotic event in the HBV + HCC group [22]. Hence, our delta-hepatitis-associated HCC patients had access to curative treatment at a higher percentage, with loco-regional therapy and liver transplantation options compared to the HBV + HCC case, where systemic therapy was more frequent overall, as shown also by Huo et al. as well [50].
HCC was correlated with advanced liver disease, showed by the MELD, MELD Na and MELD 3.0 scores, emphasizing once more the importance of liver fibrosis in HCC occurrence [60]. Additionally, a direct connection has been observed between a higher HBsAg titre and HCC development in both groups, a correlation described by Jung et al. as well, who showed a decreased risk of HCC when the HBsAg titre is reduced by at least 50% after NA treatment, but also in a review published by Zheng et al. highlighting a typically higher HBsAg titre in patients with HCC [31,61]. Particularly in the case of delta hepatitis, HCC was associated with more advanced liver disease (using severity scores MELD, MELD Na and MELD 3.0) but also with a lower HBV titre and higher HBsAg titre, as shown in the study published by Diaz et al., emphasizing that the HBV DNA levels both in the serum and within the tumour are very low in HDV + HCC cases [59]. However, Farci et al. mentioned in a review published in 2021 that data regarding HBV DNA in HCC associated with delta hepatitis are scarce.
Some studies in the field showed lower HDV viremia in the case of HCC (also confirmed in our study), particularly in the case of cirrhosis, but demonstrated a direct correlation between persistently high HDV viremia and non-cirrhotic HCC [60]. Other articles also showed that persistent replication of HDV RNA is a risk factor for non-cirrhotic HCC [43,62]. Interestingly, it has been published that in liver biopsies, the level of HDV RNA within the tumour is markedly decreased compared to the surrounding non-tumoral area [59].
Hence, HDV RNA did not correlate with HCC occurrence in our study, as shown by other studies as well, which demonstrated that the level of HDV viremia correlates poorly with HCC once extensive fibrosis exists [30,63]. As a result, HDV viremia correlates well with HCC occurrence only in the non-cirrhotic patients.
The less aggressive pattern of HDV-associated HCC can be attributed to two major differences compared to HBV monoinfection HCC: the different molecular signature of the virus in inducing neoplasia and the more frequent screening in HDV patients [22,38]. The molecular mechanisms for HDV carcinogenesis are not fully understood yet, but the hepatocytes’ mutations induced by delta infection and the epigenetic changes are completely different than those from HBV-monoinfection-induced HCC [34]. However, the differences noted in the tumour behaviour can also be explained by the frequency in screening of HDV patients. Our study took place in a tertiary care centre; hence, a high percentage of the HDV patients were referred to us from the whole country for liver transplantation. Patients evaluated for the waiting list for liver transplantation have frequent admissions; hence, they are prone to be more frequently screened for HCC with AFP and ultrasound. Similarly, a recent study highlighted that HDV-HCC patients are usually diagnosed in specialized centres as part of surveillance programs, whereas HBV monoinfection HCC patients tend to be diagnosed when symptoms have already developed [64]. This is further supported by another study, which showed that screening in HBV monoinfection patients leads to lower mortality due to HCC [65].
The individualized screening programs represent a major solution to increase the early-stage diagnosis of HCC and the chance for curative treatment, as shown for HCV patients who were risk stratified, and those with high risk had screening performed every 2–3 months [66]. A recent published article emphasized the new approaches in improving screening (patient information, primary care referral for screening of high-risk populations, identification of the high-risk population, risk scores, people outreach and more sensitive screening tests), which would improve the monitoring for HCC [67]. Additionally, a study from the UK highlighted the importance of the route to diagnosis in predicting the outcome of HCC, showing that patients in surveillance programs (outpatients) were diagnosed in early stages compared to those diagnosed in EDs (emergency patients) [68].
Our study showed that HCC is associated with severe liver disease and a higher titre of HBsAg; hence, screening can be intensified in chronic hepatitis B and delta with the latter features to at least 4–6 months instead of 6 months. In Romania, HDV cirrhosis/HCC represent the main indication for liver transplantation (36.7%), showing once more the need for early-stage diagnosis of HCC and new therapies to prevent HDV complications, including HCC, particularly in the context of the shortage of organs [69]. HBV monoinfection patients tend to be diagnosed later, when the tumour is more aggressive, thus having lower access to liver transplantation. Enhancing monitoring in these patients leads to early-stage diagnosis (lower BCLC class) and access to liver transplantation/loco-regional treatment.
A key limitation in interpreting our findings on tumour aggressiveness is the absence of data regarding whether patients were diagnosed with HCC under standard ultrasound surveillance. Surveillance enables the early detection of HCC and is directly associated with smaller tumour size, earlier BCLC stage and greater access to curative treatment. Without knowing which patients were under surveillance, it is difficult to determine whether the observed differences in tumour size and staging between the HBV and HBV/HDV groups are due to biological differences or simply reflect disparities in monitoring intensity. This lack of data limits the strength of our conclusions regarding the true aggressiveness of tumours in each group and should be considered when interpreting the results.

5. Conclusions

In conclusion, HCC is more frequent in delta hepatitis patients, leading to a different HCC pattern with smaller tumours, less advanced treatment and less access to curative treatment compared to HBV-monoinfection-associated HCC. HCC is associated with more advanced liver disease and a higher HBsAg titre in both HBV and HBV-HDV infections. Delta-hepatitis-associated HCC occurs in patients with advanced liver disease (higher MELD, MELD Na and MELD 3.0), a higher HBsAg titre and a lower HBV DNA titre. As a result, patients with the previously mentioned features should have their screening individualized in order to diagnose HCC in the early stage and ensure access to curative treatment.

6. Limitations

This study is a retrospective study, which did not ensure matching for potential confounders such as age, gender, cirrhosis, alcohol use and MASLD, which can all impact HCC prognosis. Additionally, our study did not have a healthy control group (our control group was composed of patients with HBV monoinfection + HCC). Additionally, our study did not collect information on whether HCC was diagnosed through routine surveillance or symptomatic presentation. This missing variable represents a significant confounder, as surveillance status strongly influences tumour stage at diagnosis. Consequently, the strength of our findings related to tumour aggressiveness and stage between groups is attenuated by this limitation.

7. Future Research Directions

The need for prospective studies looking into the differences between HBV and HBV + HDV HCC is of paramount importance, in addition to matching for potential confounders, which would clearly evaluate the cause of the different HCC patterns in the two groups. Is it the molecular footprint of the virus or the different monitoring between these patients (patients with HDV are more frequently admitted given the indication for liver transplant once advanced liver disease exists)? Moreover, there is an urgent need for studies that present risk scores for HCC in HBV and HDV in order to tailor surveillance based on them. Another direction of the study would be the clinical utility of the novel biomarkers involved in HBV and HDV-associated HCC [70].

8. Possible Applications of the Research

In order to increase early HCC detection and ensure prompt access to treatment, the screening for dysplastic nodules can be individualized and increased in frequency in patients with advanced liver disease and a high AgHbs titre, as suggested in our study. In HDV patients, an additional risk factor can be taken into account, namely a low HBV DNA titre.

Author Contributions

Conceptualization, L.G., S.I. and R.C.; methodology, R.C. and M.C.; formal analysis, R.C. and M.C.; data curation, M.C., D.G.S. and D.G.; supervision and project administration, L.G. and S.I. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Ethic Committee Name: Fundeni Clinical Institute Ethics Committee; Approval Code: 5342; Approval Date: 22 February 2016.

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

Data available upon request from corresponding author.

Acknowledgments

This article is a revised and expanded version of a paper entitled “Delta hepatitis versus HBV monoinfection associated hepatocellular carcinoma: spot the difference”, which was presented at the EASL Liver Cancer Summit, Paris, on the 21st of February 2025, with the support of the “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania, as part of Mirela Chitul’s PhD programme.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

AFPAlpha-fetoprotein
AFP-DuvouxAFP-Duvoux score
AFP-L3Lens culinaris agglutinin-reactive fraction of AFP
ALDAdvanced liver disease
ArLDAlcohol-related liver disease
AASLDAmerican Association for the Study of Liver Diseases
ALTAlanine aminotransferase
APASLAsian Pacific Association for the Study of the Liver
APHEArterial phase hyperenhancement
APRIAST-to-platelet ratio index
ASTAspartate aminotransferase
BCLCBarcelona Clinic Liver Cancer
CAMDCirrhosis, age, men, diabetes
CIConfidence interval
CTComputed Tomography
DCPDes gamma-carboxy prothrombin
EASLEuropean Association for the Study of the Liver
FBCFull Blood Count
FIB-4Fibrosis-4
GALADGender, age, AFP, AFP-L3 and desgamma-carboxy prothrombin
GEMAGender-equity model for liver allocation
GGTGamma-Glutamyl Transferase
HBeAgHepatitis B e Antigen
HBcAgHepatitis B Core Antigen
HBsAgHepatitis B Surface Antigen
HBVHepatitis B Virus
HBV DNAHepatitis B Virus DNA
HCCHepatocellular carcinoma
HDVHepatitis delta virus
HDV RNAHepatitis delta virus RNA
HIVHuman immunodeficiency virus
IGFInsulin-Like Growth Factor
IRS1Insulin Receptor Substrate 1
J HepatolJournal of Hepatology
L-HDAgLarge hepatitis D antigen
LI-RADSLiver imaging reporting and data system
MELDModel for end-stage liver disease
MELD 3.0Updated model for end-stage liver disease score
MELD NaModel for end-stage liver disease sodium score
MAPKMitogen-Activated Protein Kinase
MASLDMetabolic dysfunction-Associated liver disease
mTORMammalian Target of Rapamycin
NAsNucleos(t)ide analogues
NADPH oxidaseNicotinamide adenine dinucleotide phosphate oxidase
NITsNon-invasive tests
NFκBNuclear Factor Kappa B
OROdds Ratio
PCRPolymerase chain reaction
PI3KPhosphoinositide 3-Kinase
PLRPlatelet-to-lymphocyte ratio
PVPortal vein
RafRapidly Accelerated Fibrosarcoma
RasA family of related proteins regulating cell signalling
RNARibonucleic Acid
ROSReactive oxygen species
SDStandard Deviation
Smad3SMAD Family Member 3
SPSSStatistical Package for the Social Sciences
STAT3Signal Transducer and Activator of Transcription 3
TACETransarterial Chemoembolization
TERTTelomerase reverse transcriptase
TGF-βTransforming Growth Factor Beta
TNF-αTumour Necrosis Factor Alpha
TNMTumour, Node, Metastasis Classification System
TxTreatment
U&EsUrea and Electrolytes
UKELDUnited Kingdom Model for End-Stage Liver Disease
WCCWhite cell count
WHOWorld Health Organization
WL for LTWaiting List for Liver Transplant
WntWingless/Integrated Signalling Pathway

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Table 1. Demographics and disease characteristics. This table illustrates the demographic and disease characteristics of the whole HBV and HDV population included in the study. Bold-used to highlight the statistical significant findings. Abbreviations used in the table: HBV—hepatitis B virus; HDV—hepatitis D virus; MELD—model for end-stage liver disease score; MELD Na—model for end-stage liver disease sodium score; MELD 3.0—updated model for end-stage liver disease score; WCC—white cell count; NEUT—neutrophils; PLT—platelets; PLR—platelet-to-lymphocyte ratio; AST—aspartate aminotransferase; ALT—alanine aminotransferase; HBsAg—HBs antigen.
Table 1. Demographics and disease characteristics. This table illustrates the demographic and disease characteristics of the whole HBV and HDV population included in the study. Bold-used to highlight the statistical significant findings. Abbreviations used in the table: HBV—hepatitis B virus; HDV—hepatitis D virus; MELD—model for end-stage liver disease score; MELD Na—model for end-stage liver disease sodium score; MELD 3.0—updated model for end-stage liver disease score; WCC—white cell count; NEUT—neutrophils; PLT—platelets; PLR—platelet-to-lymphocyte ratio; AST—aspartate aminotransferase; ALT—alanine aminotransferase; HBsAg—HBs antigen.
HBV MonoinfectionHBV + HDVp Value
Age (years)63 ± 11.2859 ± 8.727p = 0.027
Gender (male)79.5%71.9%p = 0.807
MELD11.4 ± 5.86913.21 ± 6.31p < 0.001
MELD Na12.53 ± 6.38215.44 ± 7.36p < 0.001
MELD 3.011.75 ± 6.88414.86 ± 7.828p = 0.002
WCC7.31 ± 3.01 × 103 U/L5.5 ± 2.17 × 103 U/Lp = 0.001
NEUT5.01 ± 2.98 × 103 U/L3.583 ± 1.99 × 103 U/Lp = 0.025
PLT182.2 ± 10.11 × 103 U/L125.52 ± 7.23 × 103 U/Lp = 0.01
PLR136.1 ± 71.96108.3 ± 57.6p = 0.05
AST36.9 ± 28.4 U/L71.3 ± 61.6 U/Lp = 0.01
ALT51.3 ± 41.54 U/L95.75 ± 88.18 U/Lp = 0.00
HBsAg titre (S/CO)1622 ± 183216,191.7 ± 20,251.7p = 0.288
HBV DNA (UI/mL)21,531 ± 12,993.3334,059 ± 23,232.5p = 0.082
Table 2. Demographics and HCC characteristics. The difference in demographics and HCC characteristics between the control group (HCC + HBV) and study group (HCC + HBV + HDV). Bold-used to highlight the statistical significant findings. Abbreviations used in the table: HCC—hepatocellular carcinoma; HBV—hepatitis B virus; HDV–hepatitis D virus; PV—portal vein; AFP–alpha-fetoprotein; BCLC—Barcelona clinic liver cancer; Tx—treatment; WL—waiting list; LT—liver transplantation.
Table 2. Demographics and HCC characteristics. The difference in demographics and HCC characteristics between the control group (HCC + HBV) and study group (HCC + HBV + HDV). Bold-used to highlight the statistical significant findings. Abbreviations used in the table: HCC—hepatocellular carcinoma; HBV—hepatitis B virus; HDV–hepatitis D virus; PV—portal vein; AFP–alpha-fetoprotein; BCLC—Barcelona clinic liver cancer; Tx—treatment; WL—waiting list; LT—liver transplantation.
HCC + HBVHCC + HBV + HDVp Value
Age (years)50.65 ± 12.30251.4 ± 13.708p = 0.457
Gender (females)53.1%54%p = 0.817
extraMilan58.8%43.8%p = 0.097
PV thrombosis57.1%42.9%p = 0.016
HCC size (mm)56.75 ± 38.0932.66 ± 23.181p = 0.002
AFP (ng/mL)183.07 ± 336.77177.24 ± 364.8p = 0.941
BCLC A44.8%71.6%p = 0.001
BCLC B21.5%25.3%p = 0.001
BCLC C13.2%1.4%p = 0.001
BCLC D13.2%1.7%p = 0.001
AFP-DUVOUX 040.6%49.1%p = 0.013
AFP-DUVOUX 23.1%16.4%p = 0.013
AFP-DUVOUX 621.9%1.8%p = 0.013
Loco-regional Tx38. 2%42.1%p < 0.001
Systemic Tx32.4%1.6%p < 0.001
WL for LT11.4%60.9%p = 0.001
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MDPI and ACS Style

Cerban, R.; Chitul, M.; Iacob, S.; Gheorghe, D.; Stan, D.G.; Gheorghe, L. Hepatocellular Carcinoma in Delta Hepatitis Versus HBV Monoinfection: Spot the Differences. Livers 2025, 5, 23. https://doi.org/10.3390/livers5020023

AMA Style

Cerban R, Chitul M, Iacob S, Gheorghe D, Stan DG, Gheorghe L. Hepatocellular Carcinoma in Delta Hepatitis Versus HBV Monoinfection: Spot the Differences. Livers. 2025; 5(2):23. https://doi.org/10.3390/livers5020023

Chicago/Turabian Style

Cerban, Razvan, Mirela Chitul, Speranta Iacob, Daria Gheorghe, Diana Georgiana Stan, and Liana Gheorghe. 2025. "Hepatocellular Carcinoma in Delta Hepatitis Versus HBV Monoinfection: Spot the Differences" Livers 5, no. 2: 23. https://doi.org/10.3390/livers5020023

APA Style

Cerban, R., Chitul, M., Iacob, S., Gheorghe, D., Stan, D. G., & Gheorghe, L. (2025). Hepatocellular Carcinoma in Delta Hepatitis Versus HBV Monoinfection: Spot the Differences. Livers, 5(2), 23. https://doi.org/10.3390/livers5020023

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