One of the major challenges in the last few years is the possibility to transplant a HCV- positive kidney in a HCV-negative recipient with DAA treatment following transplantation. The positive consequences would be the increase of the organ supply, the shortening of the waiting period, and avoidance of long-term dialysis complications. On the other hand, there are concerns regarding the possibility of HCV fulminant hepatitis, rapid progression to cirrhosis, or failure of DAA treatment to cure the infection after transplantation. Some small studies (THINKER-1, EXPANDER-1) demonstrated encouraging results, but this approach needs to be explored further [4].

The field of HCV treatment in advanced CKD, including dialysis and KT patients, has continuously evolved. Preventive measures to reduce the risk of HCV transmission in the dialysis centers and the efficacy of DAA treatment made the elimination of virus C hepatitis in CKD patients possible.

#### **CONSENT FOR PUBLICATION**

Not applicable.

#### **CONFLICT OF INTEREST**

The author declares no conflict of interest, financial or otherwise.

### **ACKNOWLEDGEMENTS**

Declared none.

#### **REFERENCES**

#### **306** *What is New in Gastroenterology and Hepatology Mihai and Prelipcean*

1170-218. [http://dx.doi.org/10.1016/j.jhep.2020.08.018] [PMID: 32956768]

© 2022 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **CHAPTER 26**

# **Advances in Imaging Diagnosis of Hepatocellular Carcinoma - the Place of Contrast Enhanced Ultrasound (CEUS)**

#### **Mirela Dănilă1,\*** and **Ana Maria Ghiuchici1**

*1 Department of Gastroenterology and Hepatology, "Victor Babeș" University of Medicine and Pharmacy, 156, Liviu Rebreanu Bv, 300723, Timișoara, Romania*

**Abstract:** Hepatocellular carcinoma (HCC) is a primary malignant liver tumor that complicates advanced chronic liver disease, especially liver cirrhosis. Surveillance of this category of patients is mandatory for early detection of HCC and improved prognosis. Screening should be carried out by the abdominal US every 6 months with or without alpha-fetoprotein.

The diagnosis of HCC is confirmed by imaging methods that highlight the typical behavior of HCC: hyper-enhancement in the arterial phase and washout in the late phase. Imaging methods used for HCC diagnosis are Multi-detector computer tomography (MDCT), multi-phase nuclear magnetic resonance imaging (MRI), or contrast-enhanced ultrasound (CEUS).

LI-RADS algorithm is now one of the most used widely systems for the imaging diagnosis of HCC. It is a standardized system for technique, interpretation, reporting, and data collection for imaging (CT, MRI, and CEUS). The algorithm includes 8 categories with an increasing probability of HCC and malignancy with higher categories.

Studies that have attempted to validate this LI-RADS scheme for the diagnosis of HCC shown that LR-5 is highly predictive for HCC.

**Keywords:** Contrast-enhanced ultrasound, Diagnosis, Hepatocellular carcinoma, Liver cirrhosis, Liver Imaging Reporting and Data System, Magnetic resonance imaging, Multi-detector computer tomography.

**Ioan Sporea and Alina Popescu (Eds.) © 2022 The Author(s). Published by Bentham Science Publishers**

\* **Corresponding author Mirela Dănilă:** Department of Gastroenterology and Hepatology, "Victor Babeș" University of Medicine and Pharmacy, 156, Liviu Rebreanu Bv, 300723, Timișoara, Romania; Tel: +40256488003, Fax: +40256488003; E-mail<EMAIL_ADDRESS>
#### **INTRODUCTION**

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer, being the second most common cause of cancer death worldwide [1, 2]. The incidence of hepatocellular carcinoma (HCC) has been increasing in the last few years and is expected to increase until 2030 in some countries where the prevalence of nonalcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are raised [3].

Chronic liver diseases, especially liver cirrhosis, represent the major risk factor for hepatocellular carcinoma that accounts for 70% to 80% of the total liver cancer [4]. Most clinical practice guidelines recommend surveillance for early detection of HCC in this category of patients.

Hepatocarcinogenesis is a complex multistep process that includes the transition from regenerative nodules to hepatocellular carcinoma accompanied by changes in the blood supply of the nodules and malignant transformation consisting of gradually reducing the number of portal tracts while the number of unpaired arteries increases. In most cases, HCC is supplied mostly by the hepatic artery system, *via* abnormal unpaired arteries (a hypervascular tumor) [5].

This explains the characteristic enhancing pattern of HCC with hepatic arterial phase hyperenhancement and portal venous and/or delayed phases washout relative to the background liver on contrast enhanced imaging.

#### **Imaging Diagnosis of Hepatocellular Carcinoma**

Recent EASL guidelines recommend that the diagnosis of HCC in cirrhotic patients should be based on non-invasive criteria and/or pathology and in noncirrhotic patients, diagnosis of HCC should be confirmed by pathology [6].

In clinical practice, all patients with liver cirrhosis and chronic hepatitis with advanced fibrosis included in the category of risk for HCC must be followed for early detection of HCC. Screening should be carried out by the abdominal US every 6 months with or without alpha-fetoprotein (AFP) [6]. The ultrasound sensitivity as a surveillance test ranges from 58 to 89%, with specificity greater than 90% [7]. Because the US's performance in early detection of HCC is highly dependent on the expertise of the operator and the quality of the equipment, the guidelines recommend that surveillance be performed by experienced personnel [6].

After US screening, liver nodules found must be characterized using imaging methods: multi-detector computed tomography (MD-CT) or multi-phase nuclear magnetic resonance imaging (MRI), or contrast enhanced ultrasound (CEUS) [6].

# **Multi-detector Computer Tomography (MD-CT) and Multi-phase Nuclear Magnetic Resonance Imaging (MRI) in the HCC Diagnosis**

The noninvasive diagnosis of HCC using contrast enhanced imaging methods can be established only if the typical pattern is present. According to the European Association for the Study of Liver (EASL) guidelines, a single dynamic technique showing intense arterial uptake followed by a washout of contrast in the venousdelayed phases is valid to diagnose HCC [6]. Most guidelines recommend the diagnostic cut-off size of 1 cm.

These guidelines also recommend first-line imaging methods: multiphasic contrast-enhanced CT, multiphasic contrast-enhanced MRI, or gadoxeticenhanced MRI. If the imaging method used is not typical, then another method will be used, including contrast enhanced ultrasound (CEUS) [6].

The MRI and CT sensitivity in HCC diagnosis was evaluated in a recent metaanalysis that included 19 studies [8]. This study showed a significant higher sensitivity for MRI with extracellular or with hepatospecific contrast over CT (82% *versus* 66%), but the specificity of MRI *versus* CT (91% *versus* 92%) was not different. For all imaging modalities, the results were better for HCC ≥2 cm, but not for HCC less than 2 cm in size. The study concludes that due to low to moderate quality of evidence and possible publication bias, the differences in pooled diagnostic performance are considered insufficient to definitively recommend MRI over CT.

In clinical practice, the choice between CT and MRI depends on patient safety preferences, local expertise, and possible contraindication, especially for MRI. Other MRI disadvantages are: higher cost, higher technical complexity, longer scan times, claustrophobia, increased tendency to the artifact. CT is more accessible, faster (has a short exposure time), but has the disadvantage of radiation exposure. For both diagnostic methods, renal insufficiency is the major limitation, because the kidneys eliminate most of the contrast agents used in CT and MRI.

# **LI-RADS Algorithm for CT and MRI**

In order to provide standardization for HCC imaging diagnosis, LI-RADS algorithm was developed. The first version of LI-RADS was released in 2011,

supported by the American College of Radiology (ACR), and the major LI-RADS updates followed in 2013, 2014, 2017, and 2018 [9, 10].

New imaging criteria for HCC diagnosis called CT/MRI LI-RADS v2018 (Liver Imaging Reporting and Data System) [10] include: *major imaging features*: nonrim arterial phase enhancement, tumor/observation size, nonperipheral washout, *additional major feature* enhancing capsule and threshold growth (≥50% increase in the size of a mass in ≤6 months); and also *ancillary features* [10].

CT/MRI LI-RADS algorithm defines eight diagnostic categories based on imaging. These categories are from LR-1-definitely benign lesions to LR- -definitely HCC, LR-NC, LR-TIV, and LR-M [10].

LI-RADS v2018 algorithm changes the LI-RADS v2017 definition for LR5: a liver observation 10-19 mm in size with nonrim APHE and nonperipheral washout in patients at risk for HCC must be classified LR5. Using these new criteria for LR5 result in up-categorized of 40% of the nodules classified as LR4 by LI-RADSv2017 [11]. This study also showed that with the numerical increase of LI-RADS categories, the percentage of HCC in each category also increases, but no HCC or other malignancy was reported in the LR-1 category [11].

Other studies had demonstrated improved sensitivity and accuracy of the v2018 LR-5 category as compared with v2017 for the diagnosis of HCC [12 - 14].

After the HCC diagnosis, the disease's staging is essential to determine the outcome and planning of optimal therapy and include assessing tumor extension. For this purpose, CE-MRI or helical CT is also used. CT of the chest, abdomen, and pelvis is recommended to rule out an extrahepatic spread. Also, AFP level, liver function, portal pressure, and clinical performance status are mandatory to provide the best treatment management.

The new version of LI-RADS is now integrated into the AASLD 2018 HCC clinical practice guidance [15]. This algorithm also defines categories for assessing treatment response after loco-regional therapy for HCC.

### **Contrast Enhanced Ultrasound (CEUS) in the Diagnosis of Hepatocellular Carcinoma**

US is the most widely used imaging technique for HCC surveillance in patients at risk, but US has no role in HCC characterization. The development of second generation ultrasound contrast media accompanied by dedicated software has

improved the diagnosis of ultrasound in the characterization of focal hepatic lesions.

Several second-generation contrast agents are available for CEUS examination. The most commonly used are: SonoVue/Lumason (Bracco Suisse SA, Geneva, Switzerland), Definity/Luminity (Lantheus Medical Imaging, Inc., North Billerica, MA, USA), Optison (GE Healthcare AS, Oslo, Norway), Sonazoid (GE Healthcare AS, Oslo, Norway).

CEUS permits real-time visualization of contrast-enhancement patterns of lesions during all three vascular phases (arterial, portal-venous, and late). The arterial phase starts 10 to 20 seconds after the contrast agent injection and lasts for 25 to 35 seconds approximately, following by the portal-venous phase that lasts for two minutes after contrast agent injection. The portal-venous phase is followed by the late phase, which lasts for 5 minutes (until the bubbles are cleared from the circulation). For HCC in the cirrhotic liver, the key feature is APHE, followed by washout with late-onset and mild degree [16].

The use of CEUS in clinical practice is supported by multiple studies highlighting both its performance in FLL characterization and malignant/benign differentiation. A large meta-analysis published by Friedrich-Rust, which included 8,147 FLLs, CEUS showed good performance in malignant *versus* benign differentiation (93% Se and 90% Sp) [17].

The large DEGUM study also shows that CEUS has high sensitivity, specificity, positive predictive value, and negative predictive value (95.8, 83.1, 95.4, and 95.9%, respectively) for differentiating benign *versus* malignant lesions. CEUS has been proved to be a sensitive method for the diagnosis of HCCs [18].

The first European Federation of Societies in Ultrasound in Medicine and Biology EFSUMB guidelines concerning the use of CEUS were published in 2004 [19], updated in 2008 [20], 2012 [21], and the last version in 2020 [22].

The EFSUMB guidelines formulated indications regarding the use of CEUS in the cirrhotic liver [19, 20]:

● to characterize all nodules found on routine US surveillance and to establish a diagnosis of HCC,

The guidelines recommend that before starting the CEUS examination is mandatory to review the patient's clinical history, laboratory data, and any prior imaging findings. Also, a systematic liver examination must be performed using B-mode and Doppler US.

Most hepatocellular HCCs exhibit a short hyper-enhancement in the arterial phase, but not all HCCs exhibit contrast washout in the portal or/and late phase, and this latter feature limits the sensitivity of CEUS in the diagnosis of HCC. More recent studies suggest that washout in HCC is of mild intensity and often occurs in the late phase (after 4–6 minutes) [23], and some well-differentiated HCC may show no washout at all [24].

Despite the good performance reported in the HCC evaluation, CEUS was dropped from the previous EASL and AASL guidelines based on CEUS' inability to differentiate between HCC and CCC [25].

### **CEUS LI-RADS in the Diagnosis of Hepatocellular Carcinoma (HCC)**

CEUS LI-RADS algorithm was created to harmonize the interpretation of CEUS with that of CT and MRI and reduce diagnostic errors and inter-observer variability in patients at risk for developing hepatocellular carcinoma.

The first version of CEUS LI-RADS was released in 2016 by the ACR and then revised in 2017, and just as CT/MRI, LI-RADS is a standardized system for technique, interpretation, reporting, and data collection for contrast enhanced ultrasound exams in patients at risk for developing hepatocellular carcinoma [26, 27].

LI-RADS algorithm must be applied only for pure blood-pool agents —such as Lumason® (in the USA)/SonoVue® (outside the USA) and Definity® (in the USA, Canada)/ Luminity® (outside the USA, Canada), in patients at high risk for HCC with lesions visible at the precontrast ultrasound examination.

**CEUS LI-RADS** *diagnostic categories* are the same as in MRI and CT: CEUS LR**-**1 to LR5, CEUS LR-NC, CEUS LR-M, CEUS TIV [26, 27].

The major features that are used for categorization are:

lesion and the appearance in the portal/late phase).

After CEUS examination and characterization of liver observation in the arterial, portal and late phase, in the next step, *ancillary features* can be applied to downgrade or upgrade the category. *Ancillary features favoring malignancy* (for HCC) are: nodule-in-nodule architecture, mosaic architecture, and other malignancy-definite growth. *Ancillary features favoring benignity* are: size stability ≥ 2 years and size reduction [26 - 28].

After the final characterization of liver observation/nodule, we can include the lesion in one of the following CEUS LI-RADS diagnostic categories [27, 28]:

**Fig. (1).** CEUS LR-1 A. Cyst - an unenhanced area in all phases; B. fat sparing – isoenhancening in all phases.

#### **314** *What is New in Gastroenterology and Hepatology Dănilă and Ghiuchici*

**Fig. (2).** CEUS LR-4 Baseline US image shows a slightly hypoechoic lesion sized 1.9 cm in segment VIII. At CEUS, the nodule is highly hypervascular during the arterial phase and with no washout in the late phase.

**Fig. (3).** CEUS LR-5 a nodule with arterial phase hyperenhancement and late and mild washout.

Even if they share the same algorithm, there are still differences between CEUS LI-RADS and CT/MRI LI-RADS [29]. The advantages of CEUS are:

● CEUS is a real-time imaging method and is more sensitive than CT or MRI for detecting APHE- the most important imaging feature for diagnosing HCC. In liver nodules categorized LR-3 and LR-4 at CT and MRI, CEUS is an excellent alternative imaging option to demonstrate APHE;

● vascular pseudo-lesions are rarely seen in CEUS examination. In liver cirrhosis, arterio-portal shunts are frequent, and these appear- in CT and MRI with APHE. These pseudo-lesions may be mistaken for true lesions on CT or MR;

● contrast agents used in CEUS examination are safe in patients with renal failure; multiple injections of microbubble contrast agents are allowed in the same examination if necessary for a more complete characterization of a lesion or to assess additional observations;

● CEUS does not use ionizing radiation as does CT. CEUS and is cheaper than CT or MRI;

● CEUS also has some potential limitations: CEUS is usually not suitable for the staging of hepatocellular carcinoma and is more operator-dependent than CT or MRI.

Several studies have attempted to validate this LI-RADS scheme for the diagnosis of HCC. In Terzy *et al*. [30] study, about 1000 liver nodules from 848 patients with chronic liver disease at risk of HCC were evaluated. The LR-5 category was 98.5% predictive of HCC with no risk of misdiagnosis for pure cholangiocarcinoma. Regarding the major concern that CEUS may misdiagnose ICC, the study shows that none of 519 LR-5 were pure ICC.

A recent prospective multicenter study funded by the DEGUM assessed the diagnostic accuracy of standardized contrast-enhanced ultrasound (CEUS) for the noninvasive diagnosis of HCC in high-risk patients. The authors compared standardized CEUS at the time of the examination (CEUS on-site) and two CEUS algorithms ESCULAP (Erlanger Synopsis for Contrast-enhanced Ultrasound for Liver lesion Assessment in Patients at risk) and CEUS LI-RADS. The sensitivity for the diagnosis of HCC was 94.2% (CEUS algorithm ESCULAP), 90.9% (CEUS on-site), and 64% CEUS LI-RADS algorithm (p < 0.001). All three modalities had high positive predictive values – around 90%. The study results showed that CEUS on-site diagnosis by an experienced examiner achieved an almost equal diagnostic accuracy compared to CEUS-based diagnostic algorithms [31].

In liver lesions found in cirrhotic patients, with inconclusive imaging findings, a biopsy with pathological examination can be performed for a definite diagnosis, depending on the size of the lesion, the intended treatment, and the stage of the disease.

#### **316** *What is New in Gastroenterology and Hepatology Dănilă and Ghiuchici*

Since radiological diagnosis is crucial for HCC, imaging studies must be performed in expert centers.

#### **CONCLUSIONS**

Contrast enhanced ultrasound for the diagnosis of HCC can help for a quick diagnosis, with some advantages over CT/MRI. CEUS LI-RADS diagnostic categories are useful for a better diagnosis.

#### **CONSENT FOR PUBLICATION**

Not applicable.

### **CONFLICT OF INTEREST**

The authors confirm that this chapter contents have no conflict of interest.

#### **ACKNOWLEDGEMENTS**

Declared none.

### **REFERENCES**

[http://dx.doi.org/10.1002/lt.25614] [PMID: 31344753]

[http://dx.doi.org/10.1111/liv.12115] [PMID: 23432804]

#### **318** *What is New in Gastroenterology and Hepatology Dănilă and Ghiuchici*

[PMID: 29734449]

[http://dx.doi.org/10.1016/j.jhep.2017.11.007] [PMID: 29133247]

[31] Schellhaas B, Bernatik T, Bohle W, *et al.* Contrast-enhanced ultrasound algorithms (CEUS-LIRADS/ESCULAP) for the noninvasive diagnosis of hepatocellular carcinoma - a prospective multicenter DEGUM study. Ultraschall Med 2020 Jul 14. English. [http://dx.doi.org/10.1055/a-1198-4874]

© 2022 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **Treatment of Intermediate Stage Hepatocellular Carcinoma – from Guidelines and Beyond**

#### **Zeno Spârchez1,\*** and **Iuliana Nenu1**

*1 Institute for Gastroenterology and Hepatology "O.Fodor", University of Medicine and Pharmacy "Iuliu Hatieganu", Cluj-Napoca, Romania*

**Abstract:** Hepatocellular carcinoma (HCC) BCLC-B class is characterized by an extensive heterogeneity due to the wide range of liver function (Child Pugh A or B cirrhosis) and variable lesion number and size. With this regard, hepatologists must develop a better stratification of this HCC stage for patients to benefit from a better treatment allocation.

Trans-arterial chemo-embolization (TACE) procedure is the most widely used therapeutic option for intermediate stage HCC. One therapy is not beneficial unless clinicians might predict its outcome. Along these lines, several predictive factors for the TACE success have emerged such as mRECIST criteria, HAP and mHAP, Munich and CHIP score. The overall survival (OS) after the TACE procedure is around 16 months and in rigorous selected candidates, might increase the survival up to 3 years. Nevertheless, in some BCLC B patients, other therapies have proved their benefit compared to TACE. Resection and liver transplantation when technically possible is associated with an increased OS *versus* TACE. Moreover, astounding results have arisen from the combination of TACE with radiofrequency ablation. However, the literature fails to support the use of multi-kinase inhibitors in combination with TACE. Selective internal radiation therapy (SIRT) also known as radioembolization (TARE) induces fewer side effects and maintains a better tumoral control than TACE, but it is less available worldwide and is less cost-efficient.

In conclusion, navigating through all these treatment options, we believe that intermediate stage HCC has to be managed in a personalized way for each patient in order to have the best outcome.

**Keywords:** Hepatocellular carcinoma, Intermediate stage BCLC B, TACE.

\* **Corresponding author Zeno Spârchez:** Institute for Gastroenterology and Hepatology "O.Fodor", University of Medicine and Pharmacy "Iuliu Hatieganu", Cluj-Napoca, Romania; Tel: 0040 745185153, Fax: 0040 264 433427; Email<EMAIL_ADDRESS>
> **Ioan Sporea and Alina Popescu (Eds.) © 2022 The Author(s). Published by Bentham Science Publishers**

# **INTRODUCTION**

## **BCLC B Subgroup and Beyond**

The Barcelona Clinic Liver Cancer (BCLC) system grading was first presented more than 20 years ago, along its way has incorporated changes according to the clinical setting and treatment options and nowadays it still represents the cornerstone of hepatocellular carcinoma (HCC) classification [1, 2]. Since its original publication, it is acknowledged that BCLC-B class is defined by a subset of patients categorized as intermediate-stage HCC with multifocal disease confined to the preserved liver function, without vascular invasion and good performance status.

In theory, patients with BCLC-B stage are ineligible for curative treatment, but can benefit from trans-arterial chemo-embolization (TACE) as a standard of care [2]. According to the European Association for the Study of the Liver (EASL) the median survival for untreated patients at an intermediate-stage [BCLC-B – multinodular disease, good performance status (PS), without vascular invasion or extrahepatic spread] is around 16 months and in rigorous selected candidates, TACE can increase the survival up to 3 years [3].

On this subject, hepatologists and oncologists have agreed that BCLC-B class is characterized by an extensive heterogeneity due to the wide range of liver function (Child Pugh A or B cirrhosis) and variable lesion number and range. In order to limit the variability of TACE results worldwide, a sub-classification of intermediate stage HCC has been proposed by Bolondi (Table **1**) and later by Kudo (Table **2**) [4, 5]. Taking into account these subclassifications patients might benefit from a better treatment allocation as given below.

**Table 2. Kinki score.**

Clinicians have to bear in mind that a solitary nodule of HCC beyond 5 cm without vascular invasion and metastasis and without cancer-related symptoms might benefit from surgical resection if technically feasible and thus should be reclassified as BCLC-A [6]. Moreover, a poor outcome of treatment might be defined by an impaired performance status, refractory ascites, and events such as spontaneous bacterial peritonitis, hyponatremia or recurrent encephalopathy. In the absence of liver transplantation which is the only possible treatment, dismally the patient must be restaged as BCLC-D [7].

# **TACE Treatment Point of View**

As a result of an exclusively arterial vascularization of HCC tumors and comprising the fact that the normal surrounding liver parenchyma is vascularized from branches of the portal vein, TACE and other image-guided transcatheter treatments were born in order to destruct arterial tumoral vessels and hence inducing tumor necrosis [8].

TACE procedure is based on intra-arterial infusion of a chemotherapy agent such as doxorubicin or cisplatin, frequently embedded in lipiodol as a vehicle to increase vulnerability to the drug. Furthermore, the tumoral blood vessels will be embolized with different agents such as gelatin sponge particles, metallic coils, polyvinyl alcohol, starch microspheres and autologous blood clots leading to an increased tumoricidal and ischemic effect [9, 10]. The five most common adverse effects reported are liver enzyme abnormalities (18.1%), fever (17.2%), hematological/bone marrow toxicity (13.5%), pain (11%), and vomiting (6%), which are related to the occurrence of postembolization syndrome. The overall mortality rate was reported less than 1% and is due to acute liver insufficiency [11].

Nevertheless, TACE therapy has its vicissitudes, the contraindications ruled out by Raoul *et al.* being listed in Fig. (**1**) [12].

**Fig. (1).** List of contraindications to TACE treatment.

Drug-eluting beads (DEBs) have the potential to actively sequester a drug and subsequently release it slowly, in a controlled manner, after implantation within the tumor vessels. Along these lines, DEB-TACE hypothetically might augment the intensity and duration of ischemia in the target lesion with enhanced drug delivery and without significant side effects [13]. Nonetheless a meta-analysis that comprehended studies has brought to light that DEB-TACE is not superior compared to conventional TACE regarding OS. Although this technique is not available in many centers, might represent a paramount alternative if the beads will contain multikinase inhibitors or maybe immunotherapeutic agents.

As mentioned previously in the chapter, although TACE is the most widely used therapeutic option for intermediate stage HCC, a wide hiatus stands between guidelines and clinical practice. Clinicians have reported using downstaging therapies such as ablation, radioembolization, combination treatments with systemic therapies or even radical resection [14, 15]. Although TACE results might be distinctive across centers due to intermediate stage heterogeneity, it seems that liver function, nodule size, selectivity of embolization, emulsifying agents, and degree of treatment delivery play an important role in the treatment success [16]. Two randomized controlled trials and quite a few meta-analyses outlined the survival benefits of TACE compared to BSC [17, 18]. Although conventional TACE remains a palliative treatment method, it prolongs the survival up to 40 months. Likewise, a systematic review on more than 10.000

patients concedes that overall survival (OS) was 70.3% at one year, 51.8% at two years, 40.4% at three years, and 32.4% at five years with a median OS of 19.4 months (95% CI 16.2–22.6) [11]. Nonetheless, ten years ago, was published an intriguing meta-analysis questioning the performance of TACE, but the results were abandoned due to the bias of selection of numerous heterogeneous studies [19].

The success of the procedure is measured radiologically, by contrast, enhanced Computer Tomography (CE-CT) according to modified Response Evaluation Criteria in Solid Tumors (mRECIST). Radiologists characterize some important points to mention: response to therapy – either complete or partial, if the disease is stable or progressive under treatment, the potential appearance of new lesions, pleural effusions or ascites, lymph nodes in the porta hepatis vein and malignant portal vein thrombosis [18]. However, there is an uncertainty due to operator variability and the fact that the extent of necrosis sometimes might be overestimated when using mRECIST criteria. Unfortunately, some patients classified as having a complete response by these criteria have evidence of residual disease on pathological examination of surgical tissues after subsequent resection or transplantation [20, 21]. Nevertheless, studies favor assessing survival outcomes after loco-regional treatments and systemic therapies according to mRECIST response criteria [22]. One meta-analysis encompassing seven clinical trials brought to light what seems to be obvious, that a patient with a complete or a partial response has a better survival compared to those with stable or progressive disease [23].

One therapy is not beneficial unless clinicians might predict its outcome. Along these lines, several predictive factors for TACE success are listed and related to tumor burden (performance status, number, size, vascular invasion, and serum AFP levels), liver function (Child-Pugh score, serum bilirubin levels, and ascites) and associated comorbidities. Taking these clinical and serological factors into consideration, the HAP score was the first designed score to guide TACE treatment and it is based on bilirubin, albumin, AFP and tumor size as seen in (Table **3**) [24]. Patients with HAP C or D values might not benefit from an adequate TACE treatment.

**Table 3. HAP score and modified HAP score. 4 stages comprise the HAP scale as the following scoring for each parameter. HAP A =0 points; HAP B =1 point; HAP C =2 points; HAP D >2 points. mHAP-II A =0 points; mHAP-II B =1 point; mHAP-II C =2 points; mHAP-II D=3-5 points. Alb- albumin; AFPalphafeto protein; Bt - total bilirubin; tu- tumor.**

**324** *What is New in Gastroenterology and Hepatology Spârchez and Nenu*

However, Park *et al*. proposed a modified HAP score eliminating bilirubin and adding portal vein involvement and mRECIST criteria response [25]. Unfortunately, the new score did not show any superiority compared to the HAP score in the clinical setting. However, Cappelli *et al.* also modified the HAP score (Table **4**) integrating tumor number, where a single tumor receives 0 points while two or more lesions receive 1 point and therefore having a better performance comparing to the other scores [26].

**Table 4. HAP score and modified HAP score. 4 stages comprise the HAP scale as the following scoring for each parameter. HAP A =0 points; HAP B =1 point; HAP C =2 points; HAP D >2 points. mHAP-II A =0 points; mHAP-II B =1 point; mHAP-II C =2 points; mHAP-II D=3-5 points. Alb- albumin; AFPalphafeto protein; Bt - total bilirubin; tu- tumor.**

Another evaluation score comes from Germany, known as the Munich TACE score and depicts AFP, serum bilirubin, prothrombin concentration, creatinine, CRP, and tumor extension (Table **5**) [27]. The group evaluated their proposed score revealing an AUROC of 0.71 which was superior to the aforementioned scores [28].

**Table 5. Munich-transarterial chemo-embolization (TACE) score. Alb- albumin; AFP- alphafeto protein; Bt - total bilirubin; CRP- C reactive protein; crea- creatinine.**

Ogasawara *et al.* have determined that patients carrying hepatitis C virus might represent a beneficial factor for receiving direct-acting antivirals against hepatitis C virus and slowing tumor development [29]. It is known as CHIP score – (Table **6**). However, given the fact that the design also encompasses Child-Pugh score makes it unreliable to clinicians. However, we must highlight the puzzle that encompasses whether to administer DAA to patients with HCV and intermediate HCC. Our group has tented some remarks according to Bolondi's subclassification [4]. Hence, for B1 patients DAA treatment should be initiated after TACE if the procedure is successful considering that these patients have the best OS [30]. For B2 patients we believe that the decision to start DAA therapy should be based on tumor response to TACE: treatment with DAA for those with complete response to TACE or reTACE, after adequate tumor control is documented. And last, for B3 and B4 patients probably DAA therapy might be initiated in the context of clinical trials [30].

#### **326** *What is New in Gastroenterology and Hepatology Spârchez and Nenu*

Because the uncertainty of prognostic scores is not enough, a new dilemma has been brought to light. Under what circumstances the procedure has to be repeated and for how many times if tumor recurrence is present? Indubitably, major progression, extrahepatic metastasis or vascular invasion counteract the procedure. Moreover, impaired liver function and altered PS will hinder reTACE procedure. Last but not least, clinicians should bear in mind that doxorubicin is a potential cardiotoxic and should monitor cardiac activity when repeating TACE [31].

Forner and collaborators proposed a logic treatment algorithm illustrated below in Fig. (**2**) [32]. It seems that there is an unsteady balance between the advantages and disadvantages of retreatment. Clinicians must accept the given fact that the TACE procedure itself imbalances liver function and sometimes shortens the OS compared to patients that shifted to sorafenib treatment. In addition, it seems that sorafenib after procedure relapse is also superior in patients who have received one unsuccessful TACE compared to those who had three or more successive procedures [33]. Moreover, it must be kept in mind that the novel and in vogue immunotherapy agents might be superior to a reTACE treatment. If the philosophical dilemma is "to reTACE or not to reTACE" the answer stands in a personalized case-by-case manner.

**Fig. (2).** TACE treatment follow-up algorithm (adapted from Forner 2014). CR- complete response; PRpartial response; PS- performance status.

### **Thinking Outside the Tace Box**

Is there any room for *surgery within intermediate stage HCC?* is another dilemma that was long debated in the hepatology community. As stated before in the chapter, if technically feasible, it is recommended to perform surgery for solitary nodules larger than 5 cm. However, when possible, it is endorsed to measure hepatic venous portal gradient to select candidates without clinically

#### *Treatment HCC What is New in Gastroenterology and Hepatology* **327**

significant portal hypertension to prevent postoperatively liver failure. Studies concluded that surgery when technically possible is associated with an increased OS compared to TACE, 51.5% 3-year survival rate *vs* 18.1%; 43% 5-year survival *vs* 15%, p<0.001). The same assumptions are available for patients who underwent *liver transplantation* outside Milan criteria and inside up-to-7 score. Encouraging results were published by Kamo *et al.* on 56 patients with intermediate stage HCC who were transplanted and experienced a 5-year overall survival and recurrence rates of 88%/64%/58% and 22%/34%/44%, respectively [34]. Certainly, more advertising campaigns and more social entrepreneurship skills are necessary to raise awareness of organ donation to the general population.

Analogous to surgery, *percutaneous ablation techniques* have been proposed for intermediate stage HCC with impressive results regarding OS. Moreover, astounding results have arisen from the combination of TACE with radiofrequency ablation (RFA) [35]. A meta-analysis that included eleven studies and compared the impact of combined TACE plus RFA *versus* TACE only regimen in patients with intermediate stage HCC with diameter >5 cm, reported that the combined regimen had a higher survival rate *versus* TACE alone [36]. Although the published results so far are very encouraging, surgery, transplantation and percutaneous ablation seem to be available in the clinical trials or isolated cases. Hence, it is paramount to develop a better stratification of intermediate stage HCC for patients to benefit from the appropriate treatment.

Last but not least our attention was also focused on **combination treatments** between the combination of TACE and other treatment options. Probably the most debated combination in the hepatology community is between *TACE and sorafenib*. A meta-analysis has reported intriguing results that the combination regimen was better than TACE alone in terms of time to disease progression, but in terms of OS it seems that there was no significant difference. While the combination has been proved its efficacy in Asian cohorts, it seems that for European ones does not bring any improvement [37, 38]. One explanation stands probably in the etiology of the cirrhosis, while in the East predominate viral hepatitis, in the West alcohol and obesity are the core of cirrhosis.

*Selective Internal Radiation Therapy* (SIRT) also known as *radioembolization* (TARE) is based on the intra-arterial injection of small microspheres (25–35 mm) loaded with the radionuclide yttrium- 90 (90Y) which emit high-energy, low penetration radiation that further induces tumor necrosis and thus is indicated for patients with locally advanced HCC [39]. Several reports concede encouraging results revealing a median survival time of 17.2 months for patients at intermediate stages and 10 months to 12 months for patients at advanced stages with portal vein invasion [40, 41]. Compared to TACE, SIRT induces fewer side effects and maintains a better tumoral control. However, it is less available worldwide, more difficult to assess and the selection of patients is more rigorous. Instead, two RCTs compared SIRT with sorafenib and surprisingly revealed no significant difference in terms of OS [42, 43]. Although, SIRT was similar to sorafenib concerning OS with better quality of life it seems that is more advantageous than sorafenib in portal vein thrombosis [44].

The good news in the management of liver cancer is the fact that HCC is a radiosensitive tumor. Thus, external beam radiation therapy, including *stereotactic ablative body radiotherapy* (SABR), has been more and more used with success [45]. A meta-analysis published in 2018 by Rim *et al.* analyzed the data from 32 studies including 1950 patients with HCC and portal vein thrombosis, treated by SABR had an overall response rate of 70%, significantly better than the one achieved with SIRT. Almost half of the patients survived for at least 1 year. The most common clinically significant toxicity reported was platelet abnormality in 15% of the patients [46]. In 2018, Yoon published randomized data on 90 patients who received either Sorafenib or TACE-RT. 78% of the patients had multiple lesions, and the median tumor size was quite large (9.7cm). TACE-RT was associated with a significantly longer time to progression than sorafenib (31 *vs*. 11.7 weeks) and significantly better overall survival [47].

*Immune Check-point Inhibitors* bursted in many clinical trials with very encouraging results for advanced HCC [48]. Using own immune system to fight against tumoral cells was one of the most ingenious ideas in oncology and revolutionized patient care. If locoregional treatments such as TACE, SIRT and ablation induce a powerful immune response and release into the circulation huge amounts of tumor-associated antigens, why not combine them with immunotherapeutic agents [49]? Although it is at its beginning of these combined regimens, tremelimumab in combination with TACE for intermediate stage HCC revealed as expected a better OS and might be a ray of hope for the hepatology and oncology community [50].

### **HOW TO NAVIGATE THROUGH ALL OPTIONS**

We find it helpful to add a short summation of the therapies used in intermediate HCC as following:

*Treatment HCC What is New in Gastroenterology and Hepatology* **329**

Certainly, the not-so-distant future will bring to both patients and clinicians more, unique and brighter ways of treating hepatocellular carcinoma. Only by simple searching on https://www.clinicaltrials.gov/ and filling with the term "intermediate HCC" can be found 22 trials based on numerous novel approaches that are currently ongoing or have just finished enrolling patients.

We believe that the treatment of intermediate stage HCC needs a personal touch from a tumor board made by hepatologists, oncologists, surgeons and interventional radiologists.

# **CONSENT FOR PUBLICATION**

Not applicable.

# **CONFLICT OF INTEREST**

The author declares no conflict of interest, financial or otherwise.

### **ACKNOWLEDGEMENTS**

Declared none.

### **REFERENCES**

[1] Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003; 362(9399): 1907-17. [http://dx.doi.org/10.1016/S0140-6736(03)14964-1] [PMID: 14667750]

#### **330** *What is New in Gastroenterology and Hepatology Spârchez and Nenu*

[http://dx.doi.org/10.1159/000367768] [PMID: 27386427]

[http://dx.doi.org/10.1159/000485471] [PMID: 29662837]

#### **332** *What is New in Gastroenterology and Hepatology Spârchez and Nenu*

[http://dx.doi.org/10.1200/JCO.2017.76.0892] [PMID: 29498924]

© 2022 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **Direct-acting Oral Anticoagulants in Liver Cirrhosis: What is the Current Status?**

#### **Anca Trifan1,\*** and **Irina Gîrleanu1**

*1 "Grigore T. Popa" University of Medicine and Pharmacy Iaşi, Institute of Gastroenterology and Hepatology, Iasi, Romania*

**Abstract:** In the last few years, the coagulation abnormalities associated with liver cirrhosis were better characterized, concluding that the patients with liver cirrhosis are predisposed to thrombotic or bleeding complications. Portal vein thrombosis is the most frequent thrombotic event, associated with liver cirrhosis. Atrial fibrillation is also a frequent comorbidity in patients with liver cirrhosis associated with higher risks of embolic complications, needing an anticoagulant prophylactic treatment. Direct-acting oral anticoagulants (DOACs), warfarin, unfractionated heparin or low weight molecular heparin are not always efficient in liver cirrhosis. According to recent studies, DOACs are relatively safe in Child-Pugh class A or B liver cirrhosis for the treatment of acute portal vein thrombosis or prevention of embolic events in patients associating atrial fibrillation. All DOACs are contraindicated in patients with Child-Pugh class C liver cirrhosis.

**Keywords:** Anticoagulation, Atrial fibrillation, Direct-acting oral anticoagulants, Liver cirrhosis, Portal vein thrombosis, Thrombosis.

#### **INTRODUCTION**

The role of anticoagulant (AC) treatment in patients with liver cirrhosis (LC) is still a debated subject. Patients with cirrhosis were considered to be naturally anticoagulated due to the decreased production of pro-coagulant proteins and platelets, combined with an increased international normalized ratio (INR). New data have shown that patients diagnosed with LC are at a concomitant risk of hemorrhagic and thrombotic events due to increased platelet aggregation, decreased fibrinolysis, and decreased synthesis of natural anticoagulants as protein C, protein S and antithrombin III (AT III) [1] (Fig. **1**).

\* **Corresponding author Anca Trifan:** "Grigore T. Popa" University of Medicine and Pharmacy Iaşi, Institute of Gastroenterology and Hepatology, Iasi, Romania; Tel +40 722306020, Fax +40 232246611; E-mail<EMAIL_ADDRESS>
> **Ioan Sporea and Alina Popescu (Eds.) © 2022 The Author(s). Published by Bentham Science Publishers**

*Direct-acting Oral Anticoagulants What is New in Gastroenterology and Hepatology* **335**

**Fig. (1).** Coagulation balance in patients with liver cirrhosis.

Multiple beneficial effects were attributed to AC in LC including decreasing decompensation rate or liver fibrosis [2]. A recent meta-analysis that evaluated survival rate and the antifibrotic effects of AC in animal models of liver cirrhosis concluded that the AC treatment could influence liver fibrosis, portal pressure and liver inflammation, with no impact on survival [3].

#### **Direct Oral Anticoagulants in Liver Cirrhosis-real World Evidence**

During the last decades, several indications of anticoagulation in patients with liver cirrhosis arise, starting with acute non-malignant portal vein thrombosis (PVT), preventing deep vein thrombosis (DVT) or thrombotic complications in non-valvular atrial fibrillation (AF) patients, to even prevent LC decompensation [4]. Many AC regimens were proposed and the studies were very inhomogeneous regarding this aspect [5]. There are four main direct-acting oral anticoagulants (DOACs) used frequently in our daily practice: rivaroxaban, apixaban or edoxaban (inhibitors of activated factor X) and dabigatran (inhibitor of thrombin). These anticoagulants are indicated in stroke prevention in non-valvular AF, venous thromboembolism (VTE) prophylaxis in patients after orthopaedic surgery, and the treatment of acute thromboembolic diseases [6]. The possibility of oral administration with no need of laboratory monitoring, and the mechanism of action not evolving the AT III make, in theory, the almost perfect anticoagulant

treatment for patients with LC, although we have to consider that both rivaroxaban and apixaban are in majority metabolized in the liver (67%) with half-lives between 5 hours and 12 hours [7]. Also, their concentration is depending on the plasma total protein level. Half of the total quantity of edoxaban is metabolized in the hepatocytes and has half-live of 10-15 hours [7]. Dabigatran is the DOACs with very low hepatic metabolism and his half-live [12-14 hours] is not influenced by the plasmatic proteins [7]. Also, dabigatran has a potent antidote – Idarucizumab (a monoclonal inhibitor antibody). Adexan *et al*fa is a recombinant modified human factor Xa protein and represents the antidote for the factor Xa inhibitors [8]. Idarucizumab has an intravenous administration, in a single dose with maximum effect [9]. Ciraparantag directly interacts with factor Xa inhibitors [10], but also with dabigatran, LMWH, and unfractionated heparin and at the moment there are ongoing studies evaluating its effect as an antidote for all the above anticoagulants. Also, gastric lavage soon after ingestion and hemodialysis in very severe cases could represent emergency therapeutic measures in dabigatran overdose.

Until now the ideal anticoagulant was not yet developed. In patients with cirrhosis, the efficacy of LMWH is decreased due to decreased levels of AT III, protein synthesized by the liver. The International Normalized Ratio (INR) is not correctly representing the real coagulation status in patients with LC and the INR could not be used to monitor the anticoagulant treatment (warfarin oracenocoumarol) [1]. DOACs would have theoretical advantages over antivitamin K antagonists (VKAs) or LMWH in cirrhosis and PVT [5].

DOACs have several advantages over VKA therapy, including oral administration, no need for frequent laboratory monitoring and low drug-drug interaction or food interactions. DOACs pharmacokinetics is represented in Table **1** [7, 11].

DOACs are indicated in non-cirrhotic patients for prevention or treatment of venous embolism, excepting patients with mechanical heart valves or those with antiphospholipid syndrome. Compared to VKA, DOACs do not need a dose adjustment and frequent laboratory testing and, most important, DOACs do not reduce protein C and S levels.

**Table 1. DOACs hepatic metabolism and pharmacokinetics.**

*Direct-acting Oral Anticoagulants What is New in Gastroenterology and Hepatology* **337**

Abbreviation: CP- Child-Pugh class; DOACs- direct-acting oral anticoagulants; INR-International normalized ratio; NR- not reported.

#### **Anticoagulant Treatment in Liver Cirrhosis: Indications**

Including the recent data regarding the safety of the AC in patients with LC, this treatment is now indicated in patients with LC diagnosed with acute nonmalignant PVT on the liver transplant awaiting list, cirrhotic patients with AF as a prophylactic treatment and the treatment and prophylaxis of DVT. The severe COVID-19 infection could represent an emergent indication of AC in patients with LC.

#### **Non-malignant PVT Treatment**

The early reports on the use of the DOACs in LC contained few case reports [12]. Intagliata *et al.* [13] was the first who evaluated the safety and the efficacy of DOACS in LC. He retrospectively described 20 patients with LC treated with apixaban or rivaroxaban for PVT, DVT or AF. The patients received 20 mg rivaroxaban or 10 mg apixaban (15 patients), and in 5 patients there was prescribed half of the initial recommended dose. The Child-Pugh (CP) class C patients were excluded from the study. Five percent of the patients treated with DOACs developed major bleeding complications with no fatal outcome. In this cohort, there were no drug induced liver injury, although considering the bleeding rate, larger prospective studies should confirm the safety of this treatment.

The Baveno VI consensus and some guidelines recommend anticoagulation primarily for PVT in patients on the liver transplant awaiting list and acute symptomatic PVT [14, 15]. The European Association for the Study of the Liver (EASL) clinical guidelines extended the indication for anticoagulation to all patients with LC and acute PVT [16].

Until now there are no clear data on the natural history of PVT and this fact raises doubts on the efficacy of the AC treatment. The studies that evaluated the efficacy of the AC reported a very low rate of spontaneous recanalization [17, 18].

Francoz *et al.* [19] reported no recanalization in the absence of AC, while more than 40% achieved total recanalization during AC. Senzolo *et al.* [20] described

#### **338** *What is New in Gastroenterology and Hepatology Trifan and Gîrleanu*

thrombus progression in three quarters of patients that did not receive AC, compared to only 15% from the treated cohort. At the moment there are a few studies reporting the use of AC in patients with LC. Almost half of the patients achieved total recanalization after AC, while partial recanalization was observed in 15% – 35% of patients [19 - 22]. The small number of patients is one of the most important problems that needs to be soon overcome. The bleeding complications- gastrointestinal [variceal bleeding, post ligation ulcer, peptic ulcers], intracerebral hemorrhages, epistaxis and hematuria were the most frequent hemorrhagic complications [19, 20, 22]. Considering all these data, the DOACs appeared to be a more simple and safer alternative to anticoagulation in cirrhosis patients. The studies including DOACs treatment in patients with LC and PVT are summarized in Table **2**.

#### *Direct-acting Oral Anticoagulants What is New in Gastroenterology and Hepatology* **339**

In the VALDIG study, major bleedings with DOACs discontinuation were seen in only 0.71% of patients without cirrhosis and 2.7% of patients with LC [29]. Intagliata *et al.* [13] demonstrated that two thirds of the CP class A or B LC patients received DOACs for PVT treatment, although they did not report the recanalization rate. They also described the PVT recurrence during the AC treatment, considering that other mechanisms of thrombosis could be involved in this special population. Considering the efficacy of VKAs, Hanafy *et al* [27] compared in a clinical trial rivaroxaban with warfarin in 80 patients with virus C compensated LC. The recanalization rate was 85%, significantly higher compared to 45% in patients treated with warfarin. Also, the DOACs patients had a higher survival rate and lower gastrointestinal hemorrhages. Edoxaban and warfarin were compared in LC patients with PVT by Nagaoki *et al.* [28], concluding that edoxaban is an effective AC treatment, although the majority of the gastrointestinal bleeding events were associated with the edoxaban treatment (15% *vs* 7%).

Recently, Mohan *et al.* demonstrated that the rate of treatment response with AC was 66.7% and compared with the control group of only 26%. The subgroup analysis, the treatment response rate was higher in patients receiving DOACs (76.7% compared to 60.7% for LMWH and 66% for VKAs) [30]. These results indicate that AC treatment for PVT in patients with LC has more benefits than no treatment.

A recent meta-analysis that aimed to investigate the safety and efficacy of AC in patients with LC and PVT [31], concluded that early AC treatment should be supported in patients with LC and acute non-malignant PVT. According to the subgroup analysis regarding the type of AC regimes, the recanalization rates were higher in DOACs alone compared to VKAs, fondaparinux, and LMWH alone. Another single center study reported a higher rate of PVT recanalization after DOACs treatment [32].

Both, European Medicines Agency (EMA) and Food and Drug Administration (FDA) recommend Child-Pugh class as a method to evaluate LC severity and to guide the DOACs treatment. FDA [33] and EMA [34] do not recommend DOACs in patients with Child-Pugh class C LC. Rivaroxaban is contraindicated in Child-Pugh class B LC. Apixaban, dabigatran and edoxaban can be used in patients with Child-Pugh class A or B LC with adjusted doses. Acute renal insufficiency, chronic kidney disease, drug-drug interactions and history of bleeding events should be thoroughly evaluated before DOACs treatment initiation. In patients with long-term AC the ratio between risks and benefits should be periodically and continuously evaluated.

#### **Atrial Fibrillation and Liver Cirrhosis**

Atrial fibrillation is one of the most frequent clinical arrhythmias. The long-term DOACs treatment is recommended in AF patients according to the thrombotic risk in order to prevent ischemic events. Impaired liver function secondary to LC represents one of the most significant risk factors for bleeding in AF patients treated with AC [35]. Considering all this data, the experience of AC treatment in cirrhotic patients with AF is limited. Moreover the guidelines make no clear statement regarding the AC for embolic events prevention in cirrhotic patients with AF [35]. The appropriate dose of DOACs in patients with AF and LC remains to be demonstrated. The pieces of evidence for the efficacy of DOACs in preventing ischemic events in patients with AF and LC are scanty as most of the randomized controlled trials excluded the patients with LC.

A recent retrospective cohort study, confirmed that DOACs could be safely administrated in Child-Pugh class A or B cirrhotic patients diagnosed with nonvalvular AF or DVT. They also demonstrated that the prophylaxis with DOACs in LC has the same efficacy as warfarin prophylaxis [25]. Furthermore, DOACs were associated with a reduction in the overall mortality (pooled HR 0.77, 95% CI 0.61-0.96).

In a meta-analysis recently published, DOACs were associated with a lower risk of hemorrhagic complications, intracerebral hemorrhage and ischemic stroke, with no reduction in the risk of gastrointestinal bleeding in cirrhotic patients compared with warfarin. The results were not influenced by the DOACs dosage. More over, in the LC group the bleeding risk and also the ischemic risk was lower in patients receiving DOACs compared with warfarin. Of all DOACs, dabigatran and apixaban reduce the risk of hemorrhagic complications, including gastrointestinal bleeding. At present, two studies that evaluated the safety of DOACs compared to warfarin in AF and LC were published [36, 37].

Until now, the dose of DOACs for preventing ischemic events in patients with LC and AF is not determined. The VALDIG consortium demonstrated that reduceddose DOACs therapy has the same rates of bleeding complication compared to regular-dose in patients with LC [29]. Moreover, a recent meta-analysis, including patients with LC and AF, demonstrated the same efficacy for the reduced-dose of DOACs compared with the regular-dose [30]. There are limited data regarding the efficacy of the reduced-dose compared to regular-dose of DOACs in patients with LC. The data reported until now suggests that lower doses of DOACs may be safer and with the same efficacy in patients with LC and short term treatment.

All four DOACs are contraindicated in patients with Child-Pugh class C LC, and these data are according to the US FDA recommendation for DOACs [33]. Even if DOACs significantly reduce the risk of major hemorrhagic events, ischemic stroke, and intracerebral hemorrhage with no statistically significant effect on the risk of digestive tract bleeding compared to warfarin, the dabigatran or apixaban seems to be safer regarding bleeding complications in AF patients with mild to moderate LC. Low-dose DOACs, dabigatran or apixaban could represent a safer alternative for long-term AC in AF patients and LC.

## **DVT in Patients with Liver Cirrhosis**

The incidence of DVT in patients with LC is not lower compared to those without LC [38, 39]. Moreover, the reports including large population cohorts demonstrated that patients with LC had an increased risk of developing VTE [40, 41]. The data were confirmed by a meta-analysis that demonstrated a higher risk of DVT in patients with LC compared to controls [42]. Despite this risk, prophylactic AC for DVT in hospitalized patients with LC is not routinely used [43]. No studies demonstrated, until now, that the prophylactic AC in patients with risk factors for DVT is more harmful in the context of LC and all the cirrhotic patients should receive at least mechanical DVT prophylaxis during hospitalization [44].

Recently, Naqvi *et al* [45] demonstrated that there is no major difference in bleeding rates between DOACs and warfarin groups in patients with LC that received AC for DVT, including patients with Child-Pugh class C LC, although these patients were more prone to bleeding as compared to those with Child-Pugh class A or B LC. A recent meta-analysis clearly demonstrated the efficacy of DOACs as compared to VKAs in patients with LC and DVT [46]. Also, in patients receiving DOACs, it was demonstrated a reduction of DVT progression with no pulmonary embolism. All these pieces of evidence sustain the routine DVT prophylaxis in admitted patients with LC [47]. In patients with low bleeding risk, DOACs could represent a safe method for VTE prophylaxis. For the rest of the patients mechanical DVT prophylaxis should be utilized.

# **Anticoagulation in COVID-19**

Coagulopathy and disseminated intravascular coagulation could represent complications in severe COVID-19 infection. The development of microthrombosis in the small pulmonary vessels could aggravate the respiratory dysfunction. Endothelial dysfunction and secondary antiphospholipidic syndrome development secondary to COVID-19 sepsis are the main factors contributing to thrombotic events, developed in patients with LC [48] and the prophylactic anticoagulant treatment should be included in the therapeutic protocol [49]. The AC treatment in LC should be based on the evaluation of risk factors as sepsis induced coagulopathy score ≥ 4. Anticoagulant treatment with LMWH (enoxaparin) or DOACs (rivaroxaban 10 mg daily) in Child-Pugh class A cirrhotic could be used in severe COVID-19 cirrhotic patients. In decompensated LC, before starting AC treatment, all the patients should have an endoscopic evaluation in order to diagnose esophageal varices. The prophylactic esophageal band ligation is indicated before AC, although this could postpone the AC [50].

# **Direct-acting Anticoagulant Treatment in Decompensated Liver Cirrhosis**

The indication of AC in patients with compensated LC is completely different compared to decompensated LC. Recently, Mort *et al*, found high rates of hemorrhagic complications in patients with decompensated LC treated with DOACs and this risk was not associated with DOACs dose, LC severity or laboratory parameters, confirming the fact that other factors may be associated with the risk of bleeding, which are not discovered until now [51]. The use of DOACs in decompensated LC is challenging, with low grade available evidence. Sharma *et al*, found that dabigatran has the same efficacy and hemorrhagic risk as VKAs in patients with Budd-Chiari syndrome and decompensated LC [52]. The recent literature does not certainly establish the role of DOACs in the treatment of thrombotic events in decompensated cirrhotic patients, and larger clinical trials are needed to confirm the safety of DOACs in Child-Pugh class A or B LC.

# **FUTURES CHALLENGES**

An ideal AC treatment for thrombotic events in cirrhotic patients is not yet discovered. Although there are no randomized controlled trials to confirm the use of DOACs in LC, these drugs are recommended off label for PVT treatment. All the trials designed to confirm DOACs safety in LC should have end-points mortality, major bleeding complications and decompensation rates.

During the last few years, many advances were made to understand the mechanism of thrombosis in patients with LC even a lot of the puzzle pieces are still missing.

The DOACs could represent an innovative treatment in LC, easy to be administrated, with no need of closely monitoring and with pleiotropic effects including in liver fibrosis development. Moreover, the safer profile of DOACs may reduce the risk of bleeding, particularly, in Child Pugh B class patients maintaining a good level of protection from thrombotic events.

DOACs are indicated for the treatment of acute PVT thrombosis in Child-Pugh class A or B liver cirrhosis patients on the awaiting liver transplant list. These

patients will receive the AC treatment until liver transplantation. For the patients with PVT and no indication for liver transplantation, DOACs are indicated, if acute symptomatic PVT is diagnosed or the patient is diagnosed with AF or VTE. It has to be mentioned that all DOACs are contraindicated in patients with Child-Pugh class C liver cirrhosis.

### **CONSENT FOR PUBLICATION**

Not applicable.

#### **CONFLICT OF INTEREST**

The authors declare no conflict of interest, financial or otherwise.

#### **ACKNOWLEDGEMENTS**

Declared none.

### **REFERENCES**

#### **344** *What is New in Gastroenterology and Hepatology Trifan and Gîrleanu*

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[http://dx.doi.org/10.1016/j.vph.2018.05.002] [PMID: 29886103]

[28] Nagaoki Y, Aikata H, Daijyo K, *et al.* Efficacy and safety of edoxaban for treatment of portal vein thrombosis following danaparoid sodium in patients with liver cirrhosis. Hepatol Res 2018; 48(1): 51- 8.

[http://dx.doi.org/10.1111/hepr.12895] [PMID: 28342265]

#### **346** *What is New in Gastroenterology and Hepatology Trifan and Gîrleanu*

[http://dx.doi.org/10.1016/j.chest.2020.08.1889]

© 2022 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **CHAPTER 29**

# **Latest Data on the Epidemiology, Pathological Classification, and Staging of the Combined Hepatocellular Carcinoma-Intrahepatic Cholangiocarcinoma**

### **Monica Acalovschi1,\***

*1 Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Romania*

**Abstract:** Combined hepatocellular carcinoma–intrahepatic cholangiocarcinoma (cHCC–CCA) is a primary liver cancer with features of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). This combined tumor represents 1% of all primary liver cancers, but recent studies have shown its increasing incidence and incidence-based mortality. The risk factors (identifiable in about 30% of the cases) are similar to those of HCC and CCA: cholestatic liver diseases, hepatobiliary flukes, toxins, liver cirrhosis of any etiology, and metabolic diseases such as obesity and diabetes mellitus. The first pathological classifications of cHCC-CCA described three types of tumors: collision, transition and intermediate tumors. Intermediate tumors develop from a cell intermediate between the hepatocyte and biliary epithelial cell. The 4th WHO classification of digestive system tumors (2010) was the first one to report cHCC-CCA as a distinct entity, with two main subtypes: classical type and cHCC-CCA with stem-cell features. The collision type was no longer accepted. In the 5th WHO classification (2019), the tumors of the subtype with stem cell features were recategorized as either HCC or iCCA. Due to the cHCC-CCA mixture of phenotype characteristics, the staging criteria have been also controversial. Presently, the cHCC-CCA tumors are staged by a similar algorithm as for iCCA: the TNM staging of HCC is used for clinical applications and prognosis, and the SEER staging is used for epidemiological studies. The growing interest in molecular research, genetic biomarkers identification, diagnosis and staging of these combined tumors will eventually lead to the development of effective therapeutical approaches.

**Keywords:** Combined tumor, Epidemiology, Hepatocellular carcinoma, Intrahepatic cholangiocarcinoma, Pathology, Tumor staging.

\* **Corresponding author Monica Acalovschi:** Iuliu Hatieganu University of Medicine and Pharmacy Cluj-Napoca, Romania; Tel. +40 264595649, Mobile: +40 722559970; E-mail<EMAIL_ADDRESS>
#### **INTRODUCTION**

Combined (mixed) hepatocellular carcinoma–intrahepatic cholangiocarcinoma (cHCC–CCA) is a rare primary liver carcinoma, an independent entity sharing features of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). The cHCC-CCA is an aggressive disease, with increasing incidence and a poor prognosis. Due to its rarity, the clinical, diagnostic, therapeutic, and prognostic characteristics of cHCC-CCA have not been entirely defined and are under constant research, as for all other types of cholangiocarcinomas (CCAs). The interest in this heterogeneous class of tumors, difficult to be diagnosed and with limited therapeutic options available, has been proved by the numerous publications in recent years, including the recent Expert European Consensus Statement (Cholangiocarcinoma 2020: the next horizon in mechanisms and management) [1]. Here we will review some of the topics related to cHCC-CCA.

#### **Epidemiology**

#### *Epidemiology of Cholangiocarcinomas*

Cholangiocarcinomas (CCAs) are a group of malignancies with pathologic features of biliary tract differentiation. They have a heterogeneous anatomical location and pathology. Intrahepatic CCA (iCCA) arises from small intrahepatic bile ducts (above the second-order bile ducts), while perihilar (pCCA) and distal (dCCA) tumors arise from extrahepatic and large intrahepatic ducts, being anatomically extrahepatic CCAs. The three entities have distinct epidemiology, pathogenesis and management requirements. Presently, there is a growing interest in establishing the prevalence, risk factors, diagnosis and staging of these tumors, and identifying better therapeutic options.

Extrahepatic CCAs represent the most common type of CCA accounting for more than 80% of cases. Their incidence has remained stable or slightly declined during the past decades. Conversely, the iCCA, the second most frequent primary hepatic malignancy, has an increasing prevalence. The data of the Surveillance, Epidemiology, and End Results (SEER) registry for the interval 1973 to 2012 demonstrated an increasing iCCA incidence, and a stable incidence of extrahepatic CCAs [2]. Intrahepatic CCA may frequently be misdiagnosed as the metastasis of a cancer of unknown primary (CUP), therefore the authors analyzed in parallel the CUPs incidence. They observed a dramatic decrease during this time interval and suggested that improved clinical distinction between the two entities might have contributed to the apparent increase in iCCA incidence. Using the data of the SEER registry, Petrick *et al*. [3] evaluated the incidence of iCCA and HCC for a period of 25 years (1992 – 2016). They found increasing rates for

iCCA, due to better investigation possibilities, and an overall increased incidence of CCAs.

The most recent data comes from a systematic review and meta-analysis of 53 epidemiological studies published both in Western and Asian countries between 2008 and 2019 [4]. The incidence of primary liver cancers increased during this interval with an annual percentage change (APC) of +2.6 for HCC and a higher APC (+4.3) for iCCA. The increase occurred mainly in Western countries, whereas trends decreased in the Asian region, although still remaining high.

### *Epidemiology of the Combined HCC-CCA*

Intrahepatic CCA accounts for about 15% of all the primary hepatic malignancies [5]. The cells-of-origin of iCCAs are cholangiocytes, peribiliary glands and hepatic stem/progenitor cells. The hepatic progenitor cells have the potential to differentiate into either hepatocytes or cholangiocytes, depending on the damaged cell population, and represent the origin of cHCC-CCA. Intrahepatic CCA shows several histological variants (conventional, *i.e*. large-duct type and small-duct type, cholangiolocarcinoma and rare variants). The small-duct type and cholangiolocarcinoma occur more often in chronic viral liver disease and cirrhosis.

The cHCC-CCA is a very rare tumor, which shows features of both hepatocellular and biliary epithelial differentiation. The presence of cholangiocarcinoma elements in the tumor could be confirmed with cytokeratin 19 (CK19) and cytokeratin 7 (CK7) staining by immunohistochemistry. Generally, reports on these tumors were published decades ago mostly as small patients series or case reports. The first analysis of the prevalence of cHCC-CCAs in a series of patients with primary liver cancers was published by Allen and Lisa in 1949 [6], who found a prevalence of 14.2%. Later studies indicated a lower incidence. Taguchi *et al*. [7] mentioned a prevalence of 6.3% of the combined tumors among primary liver cancers.

In a SEER registry (1973-2003) comprising 22,583 patients with intrahepatic tumors, 282 patients had combined tumors (1%), 2,935 (13%) had iCCA and the remainder (85.7%) had HCC. In this study, the combined tumors had the poorest prognosis compared with the other tumors and the authors concluded that, when deciding therapy, "the combined tumors should be considered neither HCC nor CCA" [8]. A 1% prevalence of the combined tumors was also found by Berquist *et al*. [9], who retrospectively reviewed a population of 106,103 patients registered with primary liver cancers in another database, the US National Cancer Data Base (NCBD) (1998-2011). Most patients had HCC (90,499 - 85%), 14,463 (14%) had iCCA and 1,141 (1%) had combined tumors.

While keeping the proportion of 1% among primary liver cancers, the cHCC-CCA had a steadily increasing incidence, from 0.26 per 1,000,000 individuals in the year 2000 to 0.59 per 1,000,000 individuals in the year 2014 in the SEER database [10]. The derived APC was 3.84%, and more alarming was a sustained increase (APC 4.59%) of the cHCC-CCA incidence-based mortality during this interval.

#### **Risk Factors for Intrahepatic CCA and Combined HCC-CCA**

Many risk factors are common for all CCAs, independent of their site in the biliary tract (Table **1**). Most of them are associated with inflammation and cholestasis. Intrahepatic CCA also shares some risk factors with HCC, such as hepatitis B and C infection, non-alcoholic fatty liver disease, alcohol consumption, liver cirrhosis of any etiology, type 2 diabetes mellitus and obesity [11, 12]. In spite of the long list of risk factors, most CCAs arise in the absence of any predisposing risk factors, especially in Western countries.

A meta-analysis of the studies performed both in countries of high and low prevalence of hepatobiliary cancers showed a 10-20-fold increase in the ratio to develop iCCA for patients with cirrhosis of any etiology relative to patients without cirrhosis [13]. But in contrast to HCC, iCCA more often develops in a non-cirrhotic liver.

The prevalence of some of the common risk factors for HCC and iCCA is presently in transition. Chronic HBV and HCV infections are declining in many regions due to the public health measures. HBV infection is preventable by vaccination, and a long-term viral suppression could be achieved in patients with HBV-hepatitis. HCV has been removed from the blood supplies, and HCV infection is largely curable with DAA therapies.

The incidence of primary sclerosing cholangitis (PSC), an important risk factor for CCAs in Western countries, did not significantly change during the last few decades [14]. The AGA Best Practice Advices do not recommend surveillance for CCA in PSC patients with small-duct PSCs or those younger than age 20. However, they recommend surveillance for HCC by ultrasound, computed tomography, or magnetic resonance imaging, with or without α-fetoprotein, every 6 months, in all PSC patients having liver cirrhosis [15].

In the context of a better control of viral B and C infections, the increased risk of HCC and incident iCCA should probably be related to the worldwide increase in the prevalence of metabolic disorders (obesity, type II diabetes mellitus) and NAFLD. These factors have been shown to contribute to the increasing rates of liver cancer in many lower-risk countries. The NAFLD-related cirrhosis has a 1%-3% HCC risk per year, and has been included in the updated AGA Clinical Practice recommendations [16]. The growing obesity and diabetes epidemics suggest that primary prevention of obesity and diabetes treatment will be essential for reducing the incidence of liver cancer [17].

Considering the common risk factors for both iCCA and HCC, it could be postulated that a combined HCC-CCA tumor has similar risk factors. From a clinical perspective, surveillance strategies for preventing HCC might also improve the outcomes for iCCA and cHCC-CCA. However, because in less than 30% of the CCAs, a specific factor could be identified, there is no chance for a successful targeted surveillance in a population with predisposing conditions.

# **Pathological Classification of cHCC-CCA**

The first pathological classification was that of Allen &Lisa [6], followed by Goodman *et al*. [18] and Taguchi *et al*. [7]. Three types of pathological aspect of the cHCC-CCA tumors were identified, with small changes in the description:

● Type I (collision tumors) (type A in the Allen &Lisa classification): "coincidental" occurrence in the same liver: HCC and iCCA develop independently and separately;

● Type II (transition tumors) (type B in Allen &Lisa classification), the largest group: contiguous tumors with intermediate differentiation and visible transition between HCC and iCCA: one tumor appears first, then it changes in the other type, completely, or incompletely;

● Type III (intermediate tumors) (type C in Allen &Lisa classification): the tumor develops from a cell intermediate between the hepatocyte and biliary epithelial cell and the cancer cells are able to be evaluated as either HCC or iCCA (progenitor cell / HPC / bipotential hepatic stem cells, CK7 + and CK19 +) and differentiate with both components. The tumor cells are almost indistinguishable from iCCA or HCC.

In 1989, the Liver Cancer Study Group of Japan classified cHCC-CCA into the same three subgroups: double cancer, combined type, and mixed type [19].

Xue *et al*. recently observed in their series of 133 patients with combined HCC-CCA tumors divided according to Allen &Lisa classification, that type B and C tumors are also distinct tumor subtypes in terms of their genetic expression: they found that type B tumors resemble more with iCCA, and type C tumors resemble more with HCC [20].

The 4th WHO classification (2010) first reported cHCC-CCA as a distinct entity and identified two main subtypes: the "classical" type, and the cHCC-CCA with stem-cell features. Three variants were described for the cHCC-CCA with stemcell features: a "typical" subtype, an "intermediate cell" subtype, and a "cholangiolocellular" subtype. The term collision tumors (type A and type 1, respectively, in the first classifications, *i.e*. different foci in the same liver) was no longer accepted.

In the 5th WHO classification (2019) of tumors of the digestive system (Table **2**), the "classical" form of cHCC-CCA persisted. The cell of origin of the classical cHCC-CCA would be a single form of bipotent hepatic progenitor cell capable of final differentiation into either hepatocytes or cholangiocytes. However, the subtype cHCC-CCA with stem cell features, present in the 4th WHO classification, was no longer accepted. Some of the cHCC-CCA subtypes with stem cell features have been recategorized as either HCCs or iCCAs. Distinctive diagnostic terms for intermediate cell carcinomas and cholangiolocarcinomas (previous cholangiolocellular carcinoma subtype) were recommended [21].

**Table 2. 5th WHO histological classification system of combined primary liver cancers (2019) (modified after Kim TH** *et al***. 2020) [22].**

\*present in the 4th WHO classification

Abbrev. ICC: intrahepatic cholangiocarcinoma; HCC: hepatocellular carcinoma; cHCC-CCA: combined HCC-CCA; CLC: cholangiolocarcinoma.

The definition and diagnosis of the cHCC-CCA could be established as hepatocytic or cholangiocytic differentiation within the same tumor by histopathological examination using hematoxylin and eosin (H&E) staining [22]. Within the cHCC-CCA tumor, the CCA component shows mucin-producing glandular structures within stroma, whereas HCC differentiation is characterized by Mallory-Denk bodies, bile canaliculi and a trabecular growth pattern. However, there are still no objective criteria for evaluating the amounts of specific components required for pathological diagnosis in the patients with biphenotyping tumors, and no specific cut-off values establishing a pathological diagnosis. And this might affect the accuracy of the systematic studies of primary liver cancers other than HCC and iCCA [21].

The *Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma* recommend specific immunostaining for detecting markers of HCC or progenitor cells for distinguishing cHCC-CCA from iCCA tumors only, if this information will change management" (Recommendation B1) [23].

### **Staging of the Combined HCC-CCA**

#### *Clinical Diagnosis and Imaging Characteristics*

The clinical diagnosis of cHCC-CCA in an early stage is difficult due to the anatomical location and growth patterns as well as the lack of specific symptoms. Most tumors are diagnosed by chance as an intrahepatic mass tumor. Preoperative biopsy of a nodule could be misleading, because it could reveal mainly one of the components of the tumor (CCA or HCC). The tumors could be diagnosed only in advanced stage disease based on clinical symptoms, often similar for both HCC and CCA. The Cancer Antigen 19–9 (CA 19–9) is the primary serum biomarker used in the diagnosis of CCAs [24]. However, a smaller proportion of patients with cHCC-CCA tumors have CA 19-9 elevation than patients with iCCA, and this might help in the distinction of tumors preoperatively [9].

More often, iCCA and cHCC-CCA have been detected in the liver during screening, being suspected to be HCC in patients with chronic hepatitis or liver cirrhosis. The final diagnosis was based on the pathological examination of the surgical specimens removed by liver resection or transplantation.

The imaging characteristics could be preoperatively suggestive for diagnosis. CT is considered the standard imaging method for the preoperative assessment of iCCA. MRI has similar accuracy to CT for diagnosis and staging. The most frequent imaging patterns displayed by iCCA on both CT and MRI are arterial peripheral rim enhancement with progressive homogeneous contrast agent uptake until the delayed or stable uptake during late dynamic phases. When gadoxetic acid is used, the washout should be read in the portal phase instead of in delayed phases to prevent misclassification between HCC and iCCA in a cirrhotic liver. CT and MRI have comparable performance in the detection of primary and satellite iCCA lesions, but CT imaging is superior for the detection of vascular enhancement and, thus, assessment of resectability [23, 24]. The *Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma* consider that assessment of resectability as well as of arterial and venous invasion, essential for tumor staging, are best performed using CT and/or MRI (Recommendation A1) [23].

More controversial is the use of CEUS, particularly in the setting of underlying chronic liver disease: iCCA exhibits, similar to HCC, a homogeneous arterial hyperenhancement followed by venous washout in almost 50% of patients. An ultrasonographic case-control study confirmed that some CEUS imaging features of cHCC-CCA, HCC, and iCCA overlap. In these cases, the combination of CEUS features with tumor markers (simultaneous elevation of α-fetoprotein and CA 19-9) is helpful in diagnosing the combined tumors [25].

## *Tumor Staging*

Different staging systems have been proposed in the last decades to categorize either HCC or iCCA. Most of these staging systems are meant to provide both prognostic information and therapeutic guidance: the Barcelona Clinic Liver Cancer (BCLC) algorithm, the Hong Kong Liver Cancer Staging System for HCC, and the TNM classification and other staging systems in the case of iCCA [26]. Until the 7th edition of the AJCC/UICCA staging, there was no distinct staging for iCCA. The further 8th edition changed some of the TNM categories in iCCA, trying to more accurately stratify prognosis in order to better guide treatment decisions [27].

Do the existing staging systems for primary liver cancer apply to cHCC-CCA? The staging criteria for cHCC-CCA are controversial, due to their mixture of phenotype characteristics, and therefore it is not clear how they should be treated. Until very recently, no staging systems specific for cHCC-CCA were proposed. Combined HCC-CCA is presently staged by TNM and by SEER staging. Both staging systems are based for cHCC-CCA on the same staging algorithm as for iCCA (Table **3**). The TNM for HCC staging system should be prioritized for clinical applications in predicting cHCC-CCA prognosis [9, 28]. The epidemiological studies to date are using the SEER Program of the National Cancer Institute: localized cancer is limited to the anatomical site of origin without spread, regional cancer is limited to the nearby draining lymph nodes, tissues or organs by direct extension, and distant cancer has spread to distant noncontinuous parts of the body [10, 22].

**Table 3. TNM** *versus* **SEER staging of combined HCC-CCA.**

TNM classification: T1 solitary tumor with no vascular invasion (T1a ≤ 5 cm and T1b >5 cm), T2- a solitary tumor with vascular invasion or multiple primary

tumors (irrespective of vascular invasion), T3 - the primary tumor perforates the visceral peritoneum and, T4 - tumor involves local extrahepatic structures by direct invasion. N1 - regional lymph node metastases, M1 - distant metastatic disease. In the SEER general staging system for tumors such as cHCC-ICC, some TNM stage II tumors may be classified as localized and others as regional [22].

Combined HCC-CCA is a rare primary liver carcinoma showing differentiation toward hepatocellular and cholangiocellular carcinoma and demonstrating a great heterogeneity in terms of morphopathology. Epidemiological data indicates an increasing incidence of all primary liver cancers, including the combined tumors. Progress in molecular research, genetic biomarkers identification, diagnosis and staging represents the aspiration for the development of efficient approaches for treating these tumors.

# **CONSENT FOR PUBLICATION**

Not applicable.

### **CONFLICT OF INTEREST**

The author declares no conflict of interest, financial or otherwise.

# **ACKNOWLEDGEMENTS**

Declared none.

### **REFERENCES**

#### *cHCC–CCA What is New in Gastroenterology and Hepatology* **357**

Diagnosis. Korean J Radiol 2020; 21(10): 1115-25. [http://dx.doi.org/10.3348/kjr.2020.0091] [PMID: 32729276]

[22] Azizi AA, Hadjinicolaou AV, Goncalves C, Duckworth A, Basu B. Update on the Genetics of and Systemic Therapy Options for Combined Hepatocellular Cholangiocarcinoma. Front Oncol 2020; 10: 570958.

[http://dx.doi.org/10.3389/fonc.2020.570958] [PMID: 33102226]

© 2022 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **Endoscopic Therapy in Cholangiocarcinoma**

### **Marcel Tanțău1,\***

*1 Department of Gastroenterology, 3rd Medical Clinic, Cluj-Napoca, Romania*

**Abstract:** Cholangiocarcinoma is an aggressive tumor with a poor prognosis. In its early stages, the diagnosis is difficult and mostly incidental, for example during routine abdominal ultrasound we may see some indirect signs like biliary tree dilatation and rarely an intrabiliary three hypoechogenic lesion (extrahepatic cholangiocarcinoma) or focal hypoechogenic mass (intrahepatic cholangiocarcinoma).

The prognosis of the patients with metastatic and advanced unresectable extrahepatic cholangiocarcinoma is very poor. More than 50% of patients with jaundice are inoperable at the time of the first diagnosis.

The development of new minimally invasive techniques provides these patients a chance to symptoms relief, symptoms that sometimes impair the treatment (like jaundice), and a better quality of life.

Endoscopic treatment in patients with obstructive jaundice ensures bile duct drainage in preoperative or palliative settings. Relief of symptoms (pain, pruritus, jaundice) and improvement in quality of life are the aims of palliative therapy. Stent implantation by endoscopic retrograde cholangiopancreatography is generally preferred for long-term palliation. There is a vast variety of plastic and metal stents, covered or uncovered. The stent choice depends on the expected length of survival, quality of life, costs, and physician expertise.

**Keywords:** Biliary stents, Cholangiocarcinoma, Cholangioscopy, Endoscopic drainage, Endoscopic retrograde colangiopancreatography.

#### **INTRODUCTION**

Cholangiocarcinomas (CCAs) have a very high mortality rate worldwide [1]. Due to clinical asymptomatic behavior in the early stages in most of the cases, the lack of a standardized protocol for screening for early-stage disease and the limitations of using CA19-9 as a cancer marker, the diagnosis is delayed in most of the patients [1]. The ability to achieve a definite cytopathological or histopathological

\* **Corresponding author Marcel Tanțău:** Department of Gastroenterology, 3th Medical Clinic, 19-21 Croitorilor Street,400162, Cluj-Napoca, Romania; E-mail<EMAIL_ADDRESS>
> **Ioan Sporea and Alina Popescu (Eds.) © 2022 The Author(s). Published by Bentham Science Publishers**

#### **360** *What is New in Gastroenterology and Hepatology Marcel Tanțău*

diagnosis in patients with suspected CCA remains at 26–80% [1 - 4]. CCAs are divided into 3 types: intrahepatic CCAs (iCCAs), distal CCAs (dCCAs) and perihilar CCAs (pCCCAs) or Klatskin tumors. The majority of CCAs are perihilar CCAs (60-75% of cases). Distal CCAs are present in 15%to 25% of cases and intrahepatic CCAs account for 5% to 15% of cases [3, 4]. Magnetic resonance imaging (MRI) plus magnetic resonance cholangiopancreatography (MRCP) is the preferred imaging modality as it can assess resectability and tumor extent with a high accuracy [3, 4]. Endoscopic ultrasound (EUS) and fine needle aspiration guided by EUS is a useful technique in diagnosis and staging of CCAs (Figs. **1** - **3**) and should be always taken into consideration for CCAs clinical management.

**Fig. (1).** Upper endoscopic ultrasound. Klatskin tumor. A hypoechoic tumoral mass (blue arrow) at the level of hepatic hilum can be seen. In the center of the tumor was placed a biliary stent (orange arrow).

**Fig. (2).** Upper endoscopic ultrasound. Distal cholangiocarcinoma. On the left, a dilated distal common bile duct and a hypoechoic tumoral mass (blue arrow) can be seen. On the right is an image of the elastography examination with the tumoral mass colored in blue (hard tissue) (blue arrow).

**Fig. (3).** Upper endoscopic ultrasound. The liver with dilated intrahepatic biliary ducts (blue arrows).

Also, in patients with obstructive jaundice, intraductal ultrasonography may be useful for the assessment of bile duct strictures and local tumor staging [5]. Peroralcholangioscopy (POC) allowing direct visualization of the biliary tract with targeted biopsy of suspicious lesions has shown to be a useful diagnostic procedure in the evaluation of biliary strictures (Figs. **4** and **5**).

**Fig. (4).** On the left-endoscopic view, the Vater ampulla is accessed by cholangioscopy (in blue). On the right-cholangioscopic view with a tumoral mass at the level of the hilum (Klatskin tumor) (blue arrows).

**Fig. (5).** On the left- endoscopic view, the Vater ampulla is accessed by cholangioscopy (in bleu). On the right-cholangioscopic view with a tumoral mass at the level of the hilium (Klatskin tumor)(blue arrow), the right biliary duct is invaded (orange arrow).

#### **362** *What is New in Gastroenterology and Hepatology Marcel Tanțău*

Surgery is the only curative treatment for both intrahepatic and extrahepatic CCA, but it is possible in only a minority of the patients. The goal is R0 resection. More than fifty percent of the patients with jaundice are inoperable at the time of first diagnosis. Locally advanced, unresectable CCA includes patients with macroscopic residual disease following resection, categorically unresectable disease at presentation or locally recurrent disease after potentially curative treatment. The prognosis of these patients is poor with a median survival time of < 6 months [6]. Relief of symptoms (pain, pruritus, jaundice) and improvement in quality of life are the aims of palliative therapy.

Additional treatment measures in CCA may include the following: stenting, radiofrequency ablation (RFA), photodynamic therapy (PDT), radiation therapy, chemotherapy. Stents can be placed *via* endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC) to relieve the biliary obstruction. Stenting may relieve pruritus and improve the quality of life. Using endoscopic retrograde cholangiopancreatography (ERCP) unilateral or bilateral plastic or metallic stents can be provided. RFA and PDT are effective in restoring biliary drainage and improving the quality of life in patients with nonresectable disseminated cholangiocarcinomas. Local radiotherapy combined with metallic stent placement is a new and efficient method in advanced cholangiocarcinoma.

### **Palliation of Obstructive Jaundice**

Endoscopic treatment of CCA with obstructive jaundice ensures bile duct drainage in preoperative or palliative settings [7]. Endoscopic procedures are the preferred palliative treatment options for patients with advanced or unresectable CCA. In patients with advanced hilar CCA, endoscopic biliary drainage *via* ERCP is more difficult than those with distal CCA [1]. If the transpapillary approach failed, other procedures can be considered: percutaneous transhepatic biliary drainage, endoscopic ultrasound-guided biliary drainage, especially hepaticogastrostomy or locoregional therapies including trans-luminal photodynamic therapy and radiofrequency ablation [1].

# **Preoperative Biliary Drainage**

There is some controversy in literature, whether preoperative biliary drainage should be accomplished prior to laparotomy for patients with obstructive jaundice [8 - 10]. In distal CCA, preoperative bile duct drainage is not always necessary and might be associated with an increased risk of cholangitis and postoperative infectious complications [7, 11].

#### *Cholangiocarcinoma What is New in Gastroenterology and Hepatology* **363**

Acute cholangitis, sepsis, bilirubin > 10 mg/dl, scheduled neoadjuvant therapy, the need for extensive hepatic resection are the indications for preoperative biliary drainage. The goal is to reduce peri- and postoperative complications [7, 12]. Cholestasis, liver dysfunction and biliary cirrhosis can develop rapidly with unrelieved obstruction and may influence postoperative morbidity and mortality after surgery [8, 13]. The definitive operation is deferring until bilirubin levels are less than 2 to 3 mg/dl.

There are different data regarding the benefits of preoperative biliary drainage in jaundiced patients with perihilar CCA. A meta-analysis of 11 studies showed no difference in the death rate or length of postoperative stay with and without preoperative biliary decompression, overall postoperative complication rate and infectious complication rates were adversely affected by preoperative drainage as compared with surgery without preoperative biliary drainage [13]. In cases of percutaneous transhepatic drainage, some studies reported the catheter tract recurrence rates up to 6% [11, 14, 15], the median time of recurrence being months.

### **Palliative Biliary Drainage**

The relief of symptoms (pain, pruritus, jaundice) and improvement in the quality of life are the goals of palliative therapy. Radiotherapy, photodynamic therapy, local ablation and embolization are the nonsurgical local therapy which can prolong the time to local failure (macroscopically positive margins only) or palliate local symptoms, pain or jaundice (unresectable or recurrent disease). For unresectable CCA, the guidelines recommend endoscopic bile duct drainage as the first approach.

# **Stenting**

Stent implantation by ERCP should be the standard procedure (Figs. **6** and **7**). Placement of a stent is generally preferred for long-term palliation. It has similar rates of successful palliation and survival and less morbidity compared with the surgical approach [16, 17].

The extent of decompression that is necessary to restore the sufficient bile flow while avoiding the risk of bacterial cholangitis, the optimal approach to placement of the stents, and the use of plastic or metal uncovered/covered stents are the major issues of biliary endoscopic stenting [1, 3, 18]. The goal of palliative drainage is to drain more the half of the biliary tree according to the Asia Pacific consensus, although it has been showed that jaundice may be clinically improved if only a quarter of the liver is drained [19]. Also, target stenting using previous superior imaging methods is preferred to be performed by a financial point of

#### **364** *What is New in Gastroenterology and Hepatology Marcel Tanțău*

view [19]. In cases of cholangitis, drainage of all suspected or infected intrahepatic segmental branches should be performed [1, 20]. In complex and difficult cases, a multimodality biliary drainage (transpapillary drainage in combination with percutaneous transhepatic biliary drainage) should be considered. Rendezvous technique, anterograde percutaneous transhepatic biliary drainage (PTBD) and transluminal stenting through stomach, duodenum or jejunum walls are the possible procedures using endoscopic ultrasound drainage (EUS-BD) in these cases. This approach can be performed even when a passage of a wire through a biliary stricture is not possible [21]. The technical success rate of PTBD is 60% -90%, morbidity rate 18%- 67% [22]. In some difficult cases, an external drainage may be required and the life quality of the patient may be decreased. EUS-BD technical success varies from 70% to 100% and the rate of possible complications goes up to 77% [23]. The technical success rates are similar in most studies, but a higher incidence of complications for PTBD than EUS-BD.

#### *Cholangiocarcinoma What is New in Gastroenterology and Hepatology* **365**

Regarding the biliary drainage *via* ERCP, in most cases, unilateral stent placement will be adequate because only 25 to 30% of the liver needs to be drained to relieve jaundice [29]. However, unilateral drainage alone may not relieve jaundice completely and may increase the risk of cholangitis due to contrast medium injection into the undrained bile ducts [18]. Unilateral stenting is technically easier and less expensive than bilateral stenting, with reintervention for stent dysfunction also being considerably easier. Previous studies have demonstrated bilateral stenting to be associated with longer stent patency as compared to unilateral stenting [30].

Some studies have shown a higher survival in patients with bilateral biliary drainage with a longer stent patency *versus* unilateral biliary stenting [31, 32] and no significant differences between unilateral and bilateral self-expandable metallic stents (SEMS) regarding the technical success or complications [32]. Another retrospective study [33] showed repeat endoscopic biliary drainage for stent occlusion was required more frequently in the unilateral plastic stent than in bilateral plastic stents (80.9% *vs* 34.2%, *P* < 0.001) as well as a significant difference in the cumulative stent patency period between unilateral and bilateral PS (*P* = 0.0004, hazard ratio [HR] = 2.24) as well as between unilateral and bilateral SEMS (*P* < 0.0001, HR = 3.69). These results highlight the superiority of bilateral stenting. However, several study results have similarly supported the superiority of unilateral stenting [30, 34, 35].

Endoscopic biliary drainage can be performed using plastic or expandable metal stents (SEMS). There are a large variety of plastic and metal stents, covered or uncovered. While some studies showed benefits of metallic stents regarding the successful drainage and early complication rate, stent patency and survival [36 - 40], a systematic review concluded that neither stent type offered a survival advantage [41]. The decision to use one *versus* another should be guided by the expected length of survival, quality of life, costs, and physician expertise. Usually, SEMS should be considered for patients with a life expectancy of >3 months [18]. Plastic (polyethylene) stents are inexpensive, effective, can be easily removed or exchanged. The major disadvantage is a higher rate of occlusion by sludge and/or bacterial biofilm with cholangitis development and the necessity of multiple ERCPs. Instead, metal stents have a longer patency (approximately 8 to 12 *versus* 2 to 5 months) [18], higher costs and may not be removable. The high occlusion rate of plastic stents (average 42%) can be reduced by changing the stents every three to six months. Another way is to wait for a complication before changing the stent since many patients will die before the stents will obstruct. The preferred approach for patients who are expected to live beyond a few months is to replace the plastic stent with a metal one as soon as it is feasible [18]. Several trials showed that patency rates are not higher for covered stents, despite showing

#### **366** *What is New in Gastroenterology and Hepatology Marcel Tanțău*

significantly less tumor ingrowth. Tumor overgrowth and stent obstruction by debris and biliary sludge may be the cause [18]. Usually, in distal malignant biliary obstruction, the uncovered metal stents are used in patients with an intact gallbladder. For patients who have undergone prior cholecystectomy, the choice of a covered *versus* uncovered stent is individualized given the location and geometry of the stenosis. Patients with extrinsic compression may be adequately treated with an uncovered stent, while those with intrinsic and/or papillary tumors may benefit from a covered stent in an attempt to minimize tumor ingrowth. Covered metal stents are only used for distal biliary strictures because, with hilar tumors, deployment may inadvertently result in the occlusion of a major hepatic duct [18].

The stent-in-stent technique (Y stenting) and the side-by-side technique are other two endoscopic techniques for biliary drainage in CCA. By using the Y-stent technique, studies have demonstrated an 86.7% technical success rate and a 100% functional success rate regardless of the stent type [20]. For side-by-side stenting technique in hilar CCA, Lee *et al.* [29] reported a 91% technical success rate and a 100% functional success rate with no statistically significant difference between stent patency and median survival of the 8-mm and 10-mm groups. Another study [42] reported the use of a small (6-mm) introducer SEMS for bilateral biliary stenting for both techniques with no difference in terms of technical success, procedural time, rate of stent revision, and revision success rate.

The reported rate of stent dysfunction following hilar CCA biliary drainage was 45–57% due to tumor in-growth, tumor overgrowth, or stent migration. Given the fact that SEMS may be successfully revised in the majority of cases and that the second SEMS has a higher patency compared with plastic stents [43], it seems that SEMS is the best choice in cases of SEMS dysfunction.

Guidelines recommend prophylactic antibiotics in patients with placed plastic or metal stent for long-term palliation of obstructive jaundice after the first episode of cholangitis [1, 21]. In 5-10% of cases, endoscopic biliary drainage by ERCP will fail or will be incomplete. In these cases, multi-modality drainage should be considered [1].

### **Percutaneous** *versus* **Endoscopic Approach**

Several studies have shown a higher rate of successful palliation of jaundice and lower rates of cholangitis in the percutaneous approach rather than the endoscopic approach of biliary drainage in patients with malignant hilar obstruction (proximal CCA/gallbladder cancer) [44 - 46]. Bile leaks and bleeding are more frequent and morbidity and mortality are higher [47]. Percutaneous stents are usually left to open drainage externally to the body, less comfortable for the patient. Thus, an

initial endoscopic attempt at drainage is usually preferred, if possible [18]. Another technique is the combination of ERCP with percutaneous drainage.

### **Endoscopic Ultrasound-guided Biliary Drainage**

The use of endoscopic ultrasound-guided biliary drainage (EUS-BD) is feasible for a left system drainage procedure in patients with advanced CCA who failed transpapillary drainage [48, 49]. For hilar CCA, the procedure of choice is EUSguided hepaticogastrostomy, which allows left system access only. EUS-BD is performed in the same session, allows immediate internal biliary drainage. It is less invasive given that it affords a more accurate control as well as more access sites to the bile duct than the classical alternatives of PTBD or surgery [50]. EUSguided hepaticogastrostomy (HG) was first reported in a Billroth II patient with unresectable pancreatic cancer and failed ERCP due to tumor infiltration of the papilla [50]. After the identification of the biliary duct, the technique goes on with puncture and dilatation by EUS and a stent is placed across the bile duct into the digestive lumen. Literature data showed a 94% success rate and a 90.2% success rate. Peritoneal bile leakage and cholangitis are the frequent possible complications [50]. Early migration or the clogging of the plastic stents may lead to cholangitis [51, 52]. Bile peritonitis and biloma are more frequent in transmural SEMS placement [52]. Only a case of death was reported [53]. However, most of the complications are mild and can be conservatively treated. By combining an uncovered metal stent with a covered metal stent inside, the risk of leakage is minimized. The uncovered stent is initially deployed to provide anchorage and prevent migration. The covered stent is inserted coaxially and dropped in the first stent. In some cases, hepaticogastrostomy may be associated with a metal stent placement [52]. A fully covered SEMS [54] or a double pig-tail stent through the expanded SEMS may be used to prevent stent migration [55]. The advantages of EUS-HG over rendezvous or antegrade stent insertion are particularly relevant in patients with prior duodenal or biliary SEMS who experience recurrent biliary obstruction [56]. In cases of failure of all interventional options, surgical bypass should be considered as a last rescue procedure and typically it is performed only during an unsuccessful attempt at resection or it may be necessary in jaundiced patients in whom stenting is not possible due to tumor location.

#### **CONCLUSIONS**

Currently, endoscopic treatment in patients with CCAs and jaundice remains the first choice of biliary duct decompression, either preoperatively or with a palliative purpose. Endoscopic approach and EUS-guided biliary drainage are the preferable methods for jaundice palliation and they may increase the quality of

life and long-term survival in patients with locally advanced, unresectable or recurrent disease.

#### **CONSENT FOR PUBLICATION**

Not Applicable.

### **CONFLICT OF INTEREST**

The authors declare no conflict of interest, financial or otherwise.

#### **ACKNOWLEDGEMENTS**

I want to thank to Associate Professor Dr. Tanțău Alina who provided the endoscopic ultrasound images from her personal collection.

#### **REFERENCES**

#### **370** *What is New in Gastroenterology and Hepatology Marcel Tanțău*

drainage: multicenter, long-term analysis of approach, outcomes, and complications of a technique in evolution. J Clin Gastroenterol 2014; 48(1): 80-7. [http://dx.doi.org/10.1097/MCG.0b013e31828c6822] [PMID: 23632351]

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guided biliary drainage: results of a pilot study. Endoscopy 2007; 39(4): 287-91. [http://dx.doi.org/10.1055/s-2007-966212] [PMID: 17357952]

© 2022 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **Telemedicine in Hepatology, is it Time to Move Forward?**

#### **Ion Rogoveanu1** and **Bogdan Silviu Ungureanu1,\***

*1 Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, Romania*

**Abstract:** Telemedicine has been suggested as a potential alternative for specific medical situations and has even been embedded in some countries in their medical systems. Due to current time challenges, its involvement might be embraced more rapidly, since medical consultations have become difficult due to the COVID-19 pandemic. Patient's access to medical care might be hampered, thus, telemedicine might offer new opportunities for both the medical system as well as patients. Healthcare technology is under continuous evolution and the medical care is taking part not only with specific therapeutic medical devices, but also with remote medical information and monitoring. Patients suffering from chronic liver disease require personalized management plans according to their clinical and biological disease evolution, thus new alternatives should be considered for isolated locations. This may help us fight new global challenges that may surface in the years to come. In this chapter, we have discussed the current status of telemedicine and its implementation for the various liver diseases over the years.

**Keywords:** Electronic consultation, Hepatitis C, Liver disease, NAFLD, Store and forward, Telemedicine.

#### **INTRODUCTION**

Nowdays, when we feel utterly defenseless in front of the COVID-19 pandemic, the use of special medical care, although strongly associated with improved survival rate in patients with liver pathologies, is not always feasible or in accordance with each individual`s need in protection against the virus. Conventional approach regarding the healthcare services (one-to-one meeting between the patient and the medical personnel) is becoming rather difficult. The subject of telemedicine has not been exploited enough, creating knowledge gaps that were meant to be filled in this short amount of time given by lockdowns worldwide. Telemedicine is an innovative method that offers care remotely, using

**Ioan Sporea and Alina Popescu (Eds.) © 2022 The Author(s). Published by Bentham Science Publishers**

\* **Corresponding author Bogdan Silviu Ungureanu:** Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, Romania; Tel: 0351 443 500; E-mail<EMAIL_ADDRESS>
different types of electronic communication, with great advantages for all the parties involved, such as physicians, patients or even hospitals or governments.

Defined by the American Telemedicine Association (ATA), telemedicine is the exchange of medical information from one site to another *via* electronic communication to improve a patient`s clinical health status [1]. On the other hand, *TeleHealth* offers a more broadly general concept and includes other forms of devices to communicate and even remote patient monitoring. Because of the pandemic, telemedicine became an indispensable way to provide clinical care, used for the monitoring of patients, self-management plans, treating different conditions and even for educational purposes, limiting the exposure of patients and medical practitioners. This path of care delivery is needed to be embraced and integrated more efficiently in our routine, as new technologies develop, offering a wider range of medical procedures to be made and highlighting the inefficient resource utilization for diverse acts for which telemedicine promises alternatives.

According to a report from 2017, from 15 different leading causes of death in the United States, which were accountable for almost 80% of total deaths, chronic liver diseases and cirrhosis were on the eleventh place, climbing a place in the ranking report compared to 2016 [2]. Responsible for approximately 2 million deaths in one year worldwide [3], liver diseases ask for new strategies regarding medical care, quality of life and survival rate improvement.

**Fig. (1).** Telemedicine concept in liver disease.

#### **Electronic Consultation and Monitoring**

Electronic consultation, although a term used for decades, has expanded, including a wide variety of means such as video, email, phone calls or even multimedia messages, used both by healthcare workers and by patients, facilitating the medical practice in inconvenient times for a proper traditional consultation. Telemedicine embraces an increase in its use in daily practice as technology improves and as access to a computer or a smartphone became almost universal. A study made by the Pew Research Center`s Internet and American Life Project found that in 2013 almost 91% of adults owned a mobile phone [4]. As patients become more connected to the digital sphere, it feels like a natural service to be addressed, looking for a more comfortable and easy access to a basic need.

### *HCV*

With almost 71 million people suffering from chronic HCV infection, the prevalence remains high, with an estimated 1,75 million new individuals infected annually, highlighting the continuous rise of this disease [5]. Telemedicine has been used for many years for hepatitis C in rural and impracticable populations and one durable example is the ECHO program, Extension for Community Healthcare Outcomes, which targets specialized primary care providers to help develop skills through problem-based learning with video conferences to subspecialty health practitioners. This method is an effective tool to initiate treatment of HCV in incarcerated patients or those who are located in remote regions. The study also shows that there is no difference in SVR in patients who underwent telemedicine consultation or the traditional clinic visit. Adverse situations were estimated as lower in the ECHO program, compared to the on-site visit, 6.9% *versus* 13.7% [6], giving a new perspective regarding the management of hepatocellular carcinoma and cirrhosis. Collaboration with other medical specialties through telemedicine is another point of interest. Ensuring direct antiviral therapies may have adverse drug reactions, especially skin lesions, which may require a rapid dermatology consultation. Involving a teledermatology service would allow a unique collaborative model and may be the starting point for other potential therapies [7].

More studies emphasized that telehealth is as useful in managing HCV therapy as face-to-face consultation and sustained virologic response rates are not different (93% telehepatology *vs* 89% specialty care p=203) [8]. Thus, access to modern therapies may have similar outcomes and serve as valid options alternatives. Another study by Schulz *et al*. [9] suggests that by their telehealth use for HCV treatment, they saved a median of 634 km of patient travel which is definitely a

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saving in costs for patient's expense. A program that integrated hepatitis C services (IHCS) in Melbourne Australia focused on providing healthcare services in smaller cities through telehealth consultations. Even though technical difficulties were encountered in less than 10% of consultations, the SVR was rather similar. Moreover, the authors also suggested that in these situations, telehealth has an important role in reducing the carbon footprint by avoiding extensive travelling for an on-site consultation, and this may be extended on a larger scale.

Other institutions such as correction facilities or prisons benefited from HCV treatment through telemedicine [10, 11]. Prisons are known to be major points for HCV infection and also lack of specialized therapies since is difficult to transfer inmates to hospital clinics. Telemedicine surpassed these barriers and improved both communications with prison physicians as well as direct access to the patients. In an observational study performed in Madrid, 163 patients were found positive for HCV infection. The telemedicine consultations were performed once a week in special conditions by a close-up camera and also by accessing laboratory and radiology findings. The SVR obtained were no different than other regions of Spain, and when there were failures in patient monitoring continued for the second course therapy. They also measured the degree of satisfaction, which was considered high, especially since they had no case of reinfection during the program.

Risk population groups, such as opioid abusers may benefit from telemedicine therapy and monitoring if HCV is associated. A pilot study [12] on 45 HCV infected opioid user disorder on methadone were treated with telemedicine-based encounters and despite the fact they were skeptical of the results, after finishing the program they were more confident in following such programs.

Besides using local physicians or nurses, a collaborative practice agreement with pharmacists may serve as a key instrument for HCV therapy in difficult to reach places [13, 14]. Monitoring the "cascade of care" for HCV patients may be done with the help of the pharmacist which can use the telehealth option for additional information. Thus, more patients may benefit from viral therapy and the goals promoted by the World Health Organization to eradicate HCV by 2030 may be achieved.

# *HBV*

Hepatitis B is a common liver infection with a great potential of a life-threatening condition, affecting in 2015 an estimated number of 257 million people worldwide. As the prevalence of HBV is dependent on socioeconomic status, having a higher incidence in low-income countries, a proper method to combat the

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transmission is through education and vaccination programs. Mother to child transmission and in between persons are the two main factors of spreading the virus and the idea of promoting an easier access to the means of protection and screening programs is an inexpensive and efficient measure that should be taken by the governments. Teleconferences or even electronic consultations could have a great impact on the high rates of infection with hepatitis B virus, preventing the unsafe practices. Furthermore, detection of HBV infection and the use of antiviral therapy among patients with chronic infection were associated with a lower risk of developing hepatocellular carcinoma, emphasizing the need of early diagnosis and treatment, which could be efficiently made using telemedicine or simple video calls, in order to perform a face-to-face consultation.

While most of the telehealth programs are similar to HCV infection, for Hepatitis B, chronic patients require follow-ups regularly every six months, as the infection can have multiple courses, progressing with complications in different phases of the disease [15]. While the need for a consultation is imperious, unfortunately patients do not comply with the guidelines proposed by specialists, or cannot simply conform to the recommendations made by the doctor because of their lack of access to medical care. By using electronic consultations, patients reduce the wait time and travel expenses for a face-to-face consultation. In order to facilitate the communication between the health care provider and the patient, a mobile texting application called HepTalk, designed especially for hepatitis B care, was used as a secure channel which proved a great potential in education, engagement and improvement of their access to health. HepTalk provided effective and secure communication, fast response and reduced patient expenses, not being limited by any geographic boundaries or by the lack of transportation means [16].

### *Non-Alcoholic Fatty Liver Disease (NAFLD)*

NAFLD is a pathology characterized by histological alterations with lobular inflammation and hepatocyte ballooning, associated with a rapid progression of fibrosis, which affects approximately one billion individuals worldwide [17]. Along with metabolic comorbidities, such as obesity, hyperlipidemia and type 2 diabetes, NAFLD is becoming a major cause of liver disease-related morbidity and mortality [18]. Despite pharmacological discoveries, healthy choices regarding daily life remain the best approach for therapy. The frequency of metabolic risk factors in NAFLD expresses the unhealthy life-style and requires a better management of nutrition and creates a terrain for screening, making electronic consultation not only a follow-up requirement, but also a method to carry this public health problem through prevention. App stores for both Android and Apple gained popularity for weight loss applications as more and more people

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recognize that dietary intake and physical activity are key factors for healthy bodies.

Although liver biopsy is still the gold standard for detecting and staging fibrosis in NAFLD, ultrasonography (US) remains the preferred method given the fact that is non-invasive, with no risks and low costs. Online consultations could offer the opportunity for less experienced doctors to collaborate with specialists and interpret the findings of ultrasonography, establishing the best suited steps for the management of the disease in either rural or impracticable regions. Fibrosis progression occurs at a rate of 0.09 stage/year3 , which is a sluggish move to cirrhosis, giving time for both the medical personnel and the patient to counteract the disease with lifestyle changes and efficient medication.

Surveillance, as well as monitoring programs for NAFLD require a first evaluation based on ultrasound and fibrosis score to assess the disease. For example, a study on 700 patients has focused on monitoring individual fibrosis parameters over a 5 years period [19]. The web-based group was introduced to a Cloud/Saas e-learning platform by individual user-id and password. The main reasons they chose this option were either distance or job-related reasons. The main objective was to achieve long term results by implementing sessions of group counselling which consisted of a questionnaire and a motivation to change especially on their diet and habitual physical activity. While interaction was not always available, patients had the option to centralize food diaries and send them by e-mails. After a two years follow-up when compared to the other group that went for regular visits with the physician, there were no notable differences. The main disadvantage of this type of monitoring remains the fact that many patients were lost during the follow-up. However, the ones that agreed to continue with the program obtained a 10% weight loss, and the biological status improved in time. Challenges still prevail for monitoring programs in NAFLD since they require engagement and high motivation due to high periods of time to obtain results. Telehealth programs are an option, but they should be well addressed, with an easy-access platform and also interactive to maintain the patient's motivation.

A small population randomized Asian study [20], introduced a mobile app nBuddy (Nutritionist Buddy) to monitor dietary and lifestyle changes of 55 patients with NAFLD. A remote support of 6 months was done by the mobile app, after a single face-to-face meeting. The app consisted of step monitoring, which increased gradually each week, a weight tracking system to assess weight loss progression and food choices each day to ensure diversity and healthy diet. All of these were maintained with automated reminders. The results were significant with improvement on the baseline characteristics.

However, even though NAFLD status could be monitored through apps or webbased programs, it still depends on the patient's motivation and their understanding of the disease.

### *Autoimmune Hepatitis*

As a chronic disease, autoimmune hepatitis (AIH) requires long-life management for both therapy and disease evolution. All patients should visit their physician for biochemical remission or relapse assessment. This might be done by involving technology and avoiding the patient's presence within the medical clinic. A study performed in Turkey during the COVID-19 pandemic involved 46 AIH patients that were monitored electronically by forwarding their blood tests, by live-video interaction used to assess patient's characteristics and also by text messaging as general reminders [21].

## *Alcohol-associated Liver Disease*

Alcohol consumption is often associated with liver diseases, since it exacerbates liver injury. Heavy drinkers are more prone to develop cirrhosis, rather than NAFLD patients and also mortality is higher when alcoholic hepatitis is involved. As specialized medical care is concentrated in urban areas and heavy alcohol consumers inhabit rurally or out of reach places, telemedicine promotes a way of access for this type of population. Electronic consultation is a possible resource for this group of patients, but healthcare providers should be aware of the limitations of this method. Alcohol consumers who did not have a prior interaction to the digital sphere and who may not be as prepared to the use of a monitoring application as alcohol consumers who are smartphone users for a while. These type of patients would probably give worse results during a consultation, rather than the ones already familiar with technology although at an equal state of health [21].

Most of the available studies are based on data storage on available patients with alcoholic liver disease or are focused on alcohol abstinence and patient's behavioral monitoring. Alcohol relapse may be delayed or even avoided if other means of monitoring are embedded, such as mobile apps with different reminders and sessions that focus on patient psychological status. In an ideal matter, using a digital intervention might help patients that are unable to address a physician to identify a potential risk of relapse and also become a predictive model for alcohol use. On the other providing digital support material, might also be a solution, since timeline reminders *via* e-mails, SMS technology, or app notifications might be introduced to enhance the telehealth necessary environment to aid the patients.

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Nonetheless this might be even more relevant, if patients require a liver transplant intervention, and the patient needs to be in close contact with the transplant team [22 - 25].

One of the major objectives of possible digital interventions on patients with alcoholic liver disease is to provide effective support so that abstinence is reached. Miniaturized sensors may offer related data on measuring alcohol consumption, however, they are difficult to be accepted by patients and require time to be inserted in clinical care.

### *Chronic Liver Disease Complications*

Telehealth offers various options for patients with the chronic liver disease while focusing on the same objective which is delaying complications. Disease progression might be remotely monitored by using phone apps or tablets on weight gain or treatment adherence. Similar to heart failure disease, where telemonitoring offers more opportunities, even in cost savings between 5000 and 50.000 \$ per year, per patient, cirrhotic patients could also benefit more from teleconsultation or telemonitoring [26]. Either wireless blood pressure monitors, pulse oximeters and different scales are efficient in chronic liver disease complication identification. Infections, bleedings, fluid overload may be preventable if disease monitoring is ensured. For example, a mobile app "Patient Buddy App" [27] focuses on medication adherence which it is of utmost importance in cirrhosis monitoring, weight gain along with sodium intake and may help prevent readmission of decompensated patients. Also, smartphone implementation of different scales, such as the Stroop test for hepatic encephalopathy is an important addition to this field [29, 30].

### *Liver Transplant Evaluation*