Liver biopsy in modern clinical practice: indications, methods and safety

Full Text

BACKGROUND

Serological testing and imaging modalities— computed tomography and magnetic resonance imaging—have become important diagnostic tools in hepatology, enabling practitioners to forgo biopsy in certain clinical scenarios [1, 2], nevertheless, morphological verification remains the gold standard in the diagnosis of many hepatic diseases. According to the guidelines of the American Association for the Study of Liver Diseases (AASLD), liver biopsy serves several distinct functions. First, it establishes diagnoses that can only be confirmed histologically—in cases of atypical clinical presentations or abnormal liver test results of unknown etiology. Second, it provides prognostic information regarding disease course (e.g., assessment of fibrosis as a precursor to cirrhosis in a patient with chronic hepatitis C). Third, it informs clinical decision-making and guides modifications to treatment strategy (e.g., monitoring disease activity in autoimmune hepatitis and evaluating relapse risk) [4, 5].

The diagnostic yield of the procedure varies considerably: the proportion of biopsies showing no histological abnormalities ranges from 0.6% to 48% across different studies; however, on average, biopsy provides high diagnostic value in approximately 15% of patients, allowing histological confirmation of conditions such as autoimmune hepatitis, primary biliary cholangitis, or metabolic dysfunction-associated steatohepatitis. Negative biopsy findings in the presence of autoantibodies among patients who did not meet the diagnostic criteria for autoimmune hepatitis at initial evaluation do not exclude this disease but rather underscore the necessity of close clinical surveillance of this patient cohort. It is also noteworthy that 14.2% of patients with an initially normal histological picture develop a specific hepatic disease within the subsequent 18 months, which may reflect either the pre-histological stage of the disease at the time of sampling or an insufficient biopsy specimen volume.

This literature review examines the various liver biopsy techniques with consideration of their indications and contraindications, the nature of potential complications, and approaches to enhancing the safety of the procedure.

INDICATIONS AND CONTRAINDICATIONS

Hepatic lesions of uncertain malignant nature represent the most common indication for biopsy [10–12]. The procedure is performed in patients with both diffuse and focal liver diseases, as well as in cases of suspected transplant organ rejection. Biopsy is valuable in the diagnosis of rarer conditions, including alpha-1 antitrypsin deficiency, hemochromatosis, primary sclerosing cholangitis, primary biliary cholangitis, granulomatous hepatitis, hereditary hepatic storage disorders, and systemic diseases such as sarcoidosis and amyloidosis. Biopsy plays an important diagnostic role in patients with persistently unexplained elevation of transaminases or markers suggestive of cholestasis (alkaline phosphatase, gamma-glutamyl transferase) [7, 9, 14], and in those with clinical manifestations of portal hypertension when non-invasive methods yield insufficient information.

Data on contraindications to liver biopsy are limited, and most contraindications are considered relative given the availability of periprocedural preparation strategies and alternative access routes [15–17]. For instance, in percutaneous biopsy, patient cooperation is essential (for needle positioning and breath-holding at the moment of biopsy). Alternatives include performing the procedure under general anesthesia or using a transvenous approach. In the presence of ascites, transvenous access or paracentesis as a first-line step followed by percutaneous biopsy are viable options. Other relative contraindications include coagulopathy, extrahepatic biliary obstruction, morbid obesity, amyloidosis, echinococcal disease, pregnancy, bacterial cholangitis, and focal hepatic lesions with a cystic component (owing to the risk of communication with bile ducts and the associated increased risk of biliary peritonitis following biopsy, or hemorrhage from highly vascularized lesions).

Absolute contraindications include hemorrhagic diathesis and bleeding tendency (prothrombin time <60%, international normalized ratio >1.2, activated partial thromboplastin time >35 seconds, bleeding time >7 minutes), thrombocytopenia (platelet count <70×10⁹/L), purulent processes in the liver, abdominal cavity, or pleural cavity; pyoderma at the puncture site; severe portal hypertension; and psychiatric illness or comatose state. The use of anticoagulant and/or antiplatelet agents prior to the procedure is not in itself an absolute contraindication but warrants careful attention in the context of periprocedural management decisions [20–22].

PERCUTANEOUS LIVER BIOPSY

Percutaneous liver biopsy was traditionally performed using the “blind” technique, in which the puncture site was determined by percussion and palpation [23]. Some authors have reported acceptable safety profiles with this approach, although post-procedural complications were noted [24, 25]. The use of ultrasound guidance (assistance) reduces the complication rate [2, 4] by enabling safe needle trajectory planning.

A cohort study by H. Chi et al. identified complications in 5.6% of cases; the most common were pain, hemorrhage, vasovagal collapse, hemothorax, pneumothorax, hemobilia, and sepsis. The severity of pain did not differ according to the access route (intercostal versus subcostal) [27]. A metanalysis by G. Tian et al. [28] provided a comprehensive complication assessment, demonstrating that the incidence of hemorrhage did not exceed 1.3%, pain 4.2%, pneumothorax 0.02%, and vasovagal reactions 0.1%. The incidence of complications was not associated with the biopsy technique (fine-needle aspiration versus core needle biopsy), the number of needle passes (more or fewer than two), or needle diameter [28], but was significantly correlated with coagulation parameters (international normalized ratio and platelet count) [3, 29, 30]. Pre-procedural transfusion of fresh-frozen plasma and/or platelet concentrates did not reduce the risk of bleeding [29]. Liver cirrhosis combined with a low thromboplastin time was identified as an independent risk factor for post-procedural hemorrhage [31]. M. Mueller et al. [10] reported no association between complication or hemorrhage rates and the size of the focal hepatic lesion or patient sex. Furthermore, operator inexperience (fewer than 150 liver biopsies performed) was not identified as a risk factor for increased complication rates. Reported mortality rates following percutaneous biopsy range from 0% [32, 33] to 0.5% [34]. In a study by J. West et al., [35] the overall biopsy-related mortality within 7 days of the procedure was 2.1 per 10,000 punctures. This figure varied according to the indication for biopsy: 8 per 10,000 for malignancy, 1 per 10,000 for liver disease, and 0 per 10,000 for abnormal liver function tests. The overall incidence of miscellaneous complications (pneumothorax, hemothorax, hollow organ perforation) was 1.7 per 1,000 biopsies, and the hemorrhage rate was 6.5 per 1,000 biopsies.

The diagnostic quality of histological examination depends directly on adequate specimen size; the biopsy core should be at least 25 mm in length. The incidence of non-diagnostic specimen volume is approximately 1% [3].

TRANSVENOUS LIVER BIOPSY (TRANSJUGULAR OR TRANSFEMORAL)

Transvenous liver biopsy serves as an alternative to the percutaneous approach in patients with clinically significant ascites, hemostatic disorders, a small and firm cirrhotic liver, morbid obesity, or cases in which the ultrasound window does not permit clear identification of a safe puncture site [2, 4, 36].

The transjugular approach via the right internal jugular vein is considered the preferred method of transvenous access in this patient population [18]. This technique has demonstrated both efficacy and safety [37]. The incidence of complications—including vocal cord paralysis, tracheal injury, pneumothorax, arrhythmias, and death—ranges from 1.3% to 6.5% [38, 39]. The literature documents isolated cases of inadvertent carotid artery puncture without subsequent hemorrhage or infectious complications, as well as contrast agent pooling observed during introducer position verification [40]. A large study comprising 7,469 transjugular biopsies reported an overall complication rate of 7.1%. The most frequent complications were abdominal pain (1.6%), subclinical hepatic capsule perforation (1.4%), pyrexia (1.0%), and neck hematoma (0.8%). Mortality was 0.09%, of which 0.06% was attributable to hemorrhage and 0.03% to ventricular arrhythmia [36]. According to M.J. Sue et al. [41], the overall complication rate reached 10.5%, with serious complications occurring in 1% of cases (intraabdominal hemorrhage and infection, inadvertent renal biopsy, hepatic artery thrombosis, and massive hemorrhage from the jugular vein access site). Platelet count, international normalized ratio, and the number of biopsy passes did not significantly affect the risk of complications. A. Dohan et al. [42] reported a serious complication (intraabdominal hemorrhage associated with capsular perforation) in 0.59% of patients. Minor complications included self-limiting pain resolving within three hours in 10.3% of patients, supraventricular arrhythmia in 4.4%, and localized neck hematoma in 1.5% of patients. Compared with percutaneous biopsy, the transjugular approach demonstrates a comparable safety profile [43, 44] and is associated with less pronounced postoperative pain [45–47].

The transfemoral approach is employed in situations where transjugular access is technically unfeasible—for example, in the setting of internal jugular vein thrombosis. F.Q. Li et al. [48] described thin hepatic parenchyma (less than 10 mm) and an acute angle between the hepatic vein and the inferior vena cava in the frontal plane as additional indications for this approach. J. Cynamon et al. [49] reported favorable outcomes with large-bore needle biopsy via the transfemoral transcaval technique: technical success was achieved in 97% of cases, histological diagnosis was established in 95.5% of patients, and complications occurred in 3% of patients. The most serious complication of the transfemoral approach is hepatic capsule perforation, arising when biopsy is performed from a vein located near the ostium of the right hepatic vein. Other known complications include transient pain in the lower thoracic region, neck, or right shoulder during introducer advancement into the middle or right hepatic vein—which resolved spontaneously following completion of the procedure— and femoral vein hematoma [39]. J.F. Cadranel et al. [2] described a single case of hemoperitoneum in a patient with alcoholic liver disease.

LAPAROSCOPIC (SURGICAL) LIVER BIOPSY

Laparoscopic (surgical) liver biopsy is most commonly performed intraoperatively upon detection of macroscopic hepatic abnormalities during a planned surgical procedure. Tissue is obtained using needle devices or by wedge resection [4]. In patients with severe coagulopathy (international normalized ratio >1.5 and/or thrombocytopenia <50×10⁹/L, von Willebrand disease, or hemophilia), mini-laparoscopy allows macroscopic assessment of the liver as well as prophylactic or therapeutic coagulation [50].

The complications of laparoscopic liver biopsy correspond primarily to the general surgical risks associated with laparoscopic procedures. The incidence of self-limiting abdominal wall hemorrhage does not exceed 1.6% [50], while major complications occur in 0.2% of cases [51]. A retrospective study by M.G. Beckmann et al. identified complications in 2.7% of patients: hemorrhage requiring blood product transfusion, bile leakage, and oozing from the biopsy site managed by intraoperative coagulation. Following mini-laparoscopy, delayed hemorrhage from the hepatic biopsy site or abdominal wall was recorded in 0.7% of cases, and intestinal perforation in 0.3%. Mortality (0.07%) was attributed to severe hemorrhage [52]. In a cohort of 1,788 patients, the incidence of serious complications (delayed intraperitoneal hemorrhage and intestinal perforation) was 0.39%. Minor complications (11.3%) included discomfort or pain, mild respiratory depression, and vasovagal reactions; mortality was less than 0.1% [53]. A. Hoffman et al. [54], in a study of 1,071 participants following mini-laparoscopic biopsy, found no significant differences in hemorrhage severity between patients with viral or autoimmune hepatitis, while hemorrhages requiring argon plasma coagulation occurred significantly more often in patients with liver cirrhosis.

A comparison of mini-laparoscopy and percutaneous biopsy complications demonstrated that the incidence of complications requiring hospitalization exceeding 24 hours or readmission (hemobilia, intraabdominal hemorrhage) was 0.2% and 1.0%, respectively. The overall complication rates were not significantly different (8.8% versus 5.8%) and were more commonly attributable to pain requiring additional analgesia. Complications specific to mini-laparoscopy (bile leakage and intestinal perforation during Veress needle insertion) were successfully managed by intraoperative coagulation or conservative therapy [51].

ENDOSCOPIC ULTRASOUND-GUIDED LIVER BIOPSY (EUS-BIOPSY)

Endoscopic ultrasound (EUS) is currently employed not only for diagnostic purposes but also for a range of therapeutic interventions: drainage of fluid collections and ablation of pancreatic cysts, administration of cytoreductive agents, pancreatobiliary procedures, and others [55]. This versatility makes EUS-guided biopsy an attractive alternative to the percutaneous approach in patients for whom concurrent examination of the upper gastrointestinal tract, pancreas, or biliary system is indicated [56–58]. The diagnostic accuracy of EUS with fine-needle aspiration or biopsy (EUS-FNA/FNB) in detecting the number of hepatic metastatic foci exceeds that of computed tomography [59], however, access to the liver via this route is anatomically limited. When the transducer is positioned in the duodenal bulb or gastric antrum, visualization of the gallbladder, right hepatic lobe, and portal vasculature is achievable. Positioning the transducer in the proximal stomach provides access to the majority of the left hepatic lobe [60]. In contrast to percutaneous biopsy—which typically samples a single lobe—a key advantage of the EUS approach is the ability to perform bilobar sampling [61].

Although clear criteria for adequate specimen quality have not been definitively established [60], the tissue quality obtained via endoscopic ultrasound-guided biopsy is comparable to that of specimens obtained percutaneously or via transjugular access [62]. Fine-needle EUS-guided hepatic biopsy allows collection of a specimen adequate for histological evaluation (sample length approximately 15 mm with 6–8 portal tracts) regardless of the needle type employed [63–65]. Y.N. Lee et al. [66] reported that EUS-guided biopsy of solid hepatic lesions in patients with non-diagnostic prior percutaneous biopsy yields an overall diagnostic accuracy of 90.5% for malignancy and 85.7% for specific tumor type.

EUS-biopsy is a safe procedure with a serious complication rate of approximately 1–1.8% [67, 68]. B.P. Mohan et al. [69] reported a pooled adverse event rate of approximately 2.3% regardless of needle type. Isolated cases of hemorrhage have been reported [58]: in patients with coagulopathy and thrombocytopenia, this rate reaches 0,9% [70]. J. Nieto et al. [71], observed pain in 2% of patients, subcapsular hematomas in 0.5%, and bile leakage in 0.4%. Other studies have reported differing pain incidence rates: post-procedural pain was observed in 21.8% of patients and resolved within one hour following analgesic administration. Severe abdominal pain requiring hospitalization occurred in 1.8% of patients, with computed tomography evidence of a hepatic hematoma up to 3 cm in diameter identified in only one patient. R.A. Ching-Companioni et al. reported a post-procedural pain rate of 37.5%.

The types, indications, contraindications, and complications of liver biopsy techniques are systematized in Table 1.

 

Table 1

Types, indications, contraindications, and complications of liver biopsy techniques

Biopsy Type	Indications	Contraindications	Complications
Percutaneous	Hepatic lesions of suspected malignant nature [10–12] Diffuse and focal liver diseases [13] Transplant rejection [13] Rare hepatic diseases and conditions [9] Persistent unexplained elevation of transaminases or cholestasis markers [7, 9, 14] Portal hypertension when non-invasive methods are uninformative [6]	No absolute contraindications [15–17] Relative contraindications [4, 19–22]: Ascites Patient non-cooperation Coagulopathy and thrombocytopenia Extrahepatic biliary obstruction and cholangitis Morbid obesity Amyloidosis Echinococcal disease Pregnancy Focal lesions with cystic component Purulent processes in liver, abdominal, or pleural cavity Pyoderma at puncture site Severe portal hypertension Psychiatric illness or comatose state Anticoagulant/antiplatelet therapy	Pain [3, 27, 28] Hemorrhage [3, 28, 31, 35] Vasovagal collapse [3, 28] Hemothorax, pneumothorax [3, 28, 35] Hollow organ perforation [35] Sepsis [3] Death [32–34]
Transvenous: transjugular			Pain [36, 45–47] Neck hematomas [36, 41, 42] Hepatic capsule perforation and hemorrhage [36, 42] Vocal cord paralysis, tracheal injury [39] Pneumothorax [39] Arrhythmias [36, 39] Death [36, 39]
transfemoral			Hemoperitoneum [2] Hepatic capsule perforation [39] Pain [39] Femoral vein hematoma [39]
Laparoscopic (surgical)			Hemorrhage [40, 50–54] Bile leakage [40, 51] Intestinal perforation [51–53] Discomfort or Pain [53] Vasovagal reactions and respiratory depression [53]
Endoscopic ultrasound-guided			Hemorrhage and subcapsular hematomas [58, 70, 71] Pain [71–73] Bile leakage [71]

 

STRATEGIES FOR IMPROVING PROCEDURAL SAFETY

One approach to improving the safety of standard percutaneous liver biopsy in patients with coagulopathy and/or thrombocytopenia has been tract plugging—tamponade of the biopsy channel as the needle is withdrawn—first described in 1984 [74–76]. When comparing the transjugular approach with plugged percutaneous biopsy in patients with impaired coagulation, plugged biopsy was simpler, faster, and yielded larger specimens (12±5 mm versus 6±4 mm); however, 3.5% of cases required blood transfusion due to hemorrhage [77]. A comparison of standard percutaneous biopsy with tract plugging when obtaining more than three tissue samples from patients with malignant hepatic lesions ≥1 cm demonstrated that both techniques showed an absence of clinically significant or delayed hemorrhage, equivalent diagnostic value, and comparable safety [78].

Novel approaches aimed at enhancing safety and reducing the cost of liver biopsy are currently under development. Among these is the use of natural orifice transluminal endoscopic surgery (NOTES)) [79]. Available data on this approach remain limited. Experimental evidence has confirmed the technical feasibility of NOTES-guided liver biopsy, with hemorrhage occurring in one case. K. Steele et al. reported the feasibility of peritoneoscopy with liver biopsy performed via a gastrotomy incision in patients with morbid obesity; the procedure provided adequate visualization of the abdominal cavity and yielded satisfactory biopsy specimens. M. Ryou et al. demonstrated experimentally that both transvaginal and transcolonic access routes provide sufficient endoscopic visualization of the upper abdominal cavity (liver, gallbladder, spleen, and stomach). However, maneuvering the endoscope within the abdominal cavity presents significant technical challenges, which currently limits the widespread clinical application of NOTES [83].

Robotic technologies represent a promising direction for future development, offering procedural stability and ergonomic advantages through three-dimensional articulation, enhanced precision, and improved operator ergonomics [84, 85]. Reports on the application of robotic systems in liver biopsy remain sparse. Notably, use of the multi-degrees-of-freedom MASTER robotic system within a NOTES framework has been described [86, 87]; this system enabled two transgastric liver resections to be completed without laparoscopic assistance in under nine minutes, yielding tissue samples measuring up to 21 mm [88]. The majority of existing robotic systems have been developed based on ex vivo models and require further evaluation in clinical studies [89].

CONCLUSION

Liver biopsy with subsequent histological examination retains its diagnostic importance in the verification of both focal and diffuse hepatic diseases. Contemporary biopsy techniques demonstrate a favorable safety profile across all access routes, with a mortality rate not exceeding 0.5%. The evolution of traditional percutaneous biopsy from the blind technique to ultrasound-guided intervention has substantially reduced the risk of intra- and post-procedural complications. When percutaneous access is not feasible, clinical practice offers several effective alternatives: transvenous approaches (particularly transjugular and transfemoral) and endosonography-guided biopsy (EUS-biopsy), as well as laparoscopic (surgical) resection for intraoperatively detected abnormalities. To improve procedural safety in patients at high risk of hemorrhage, biopsy tract plugging is employed.

Transluminal endoscopic procedures (NOTES) and robotic technologies represent promising directions for further development; however, their widespread implementation in clinical practice requires additional research.

Accordingly, the current armamentarium of liver biopsy methods allows individualization of technique selection for each patient, ensuring an optimal balance between diagnostic yield and procedural safety.

Additional information

Author contributions: D.N. Panchenkov, D.A. Astakhov, study conception, critical revision, manuscript editing; M.V. Zinovsky, A.A. Keshvedinova, literature review and data analysis, manuscript drafting. Thereby, all authors provided approval of the version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Funding source: The study had no sponsorship.

Disclosure of interests: The authors declare no conflicts of interest related to this publication.

Statement of originality: In conducting this study and preparing this manuscript, the authors did not make use of previously published materials.

Data availability statement: The authors confirm that all data are presented within the article and/or its supplementary materials.

Generative AI: Generative artificial intelligence technologies were not used in the preparation of this article.

About the authors

Mikhail V. Zinovskiy

Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies

Author for correspondence.
Email: mishandrix@mail.ru
ORCID iD: 0000-0003-0730-5993
SPIN-code: 7517-5590
Russian Federation, Moscow

Aishe A. Keshvedinova

Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies

Email: aishe1998@mail.ru
ORCID iD: 0000-0002-0045-2715
SPIN-code: 1577-0901
Russian Federation, Moscow

Dmitriy A. Astakhov

Russian University of Medicine

Email: astakhovd@mail.ru
ORCID iD: 0000-0002-8776-944X
SPIN-code: 6203-5870

MD, PhD

Russian Federation, Moscow

Dmitriy N. Panchenkov

Federal Research and Clinical Center of Specialized Medical Care and Medical Technologies; Russian University of Medicine

Email: dnpanchenkov@mail.ru
ORCID iD: 0000-0001-8539-4392
SPIN-code: 4316-4651

MD, PhD, Professor

Russian Federation, Moscow; Moscow

References

Supplementary files