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Introduction   

A liver biopsy is a medical procedure that involves the extraction of a small liver tissue sample for microscopic analysis [1]. This procedure is essential when key diagnostic, prognostic, or therapeutic information is not obtainable through non-invasive methods, or for research purposes [1]. Liver biopsy continues to be the definitive method for diagnosing a variety of liver disorders [23]. As techniques have advanced, it has become a safe and valuable tool for hepatologists treating a wide range of liver diseases. 

The clinical utility of liver biopsy has transformed since its initial use for determining glycogen levels in diabetic patients [23]. With the introduction of the “one-second needle biopsy of the liver” by Menghini in 1958, liver biopsies became a standard medical procedure, recognized for their diagnostic importance [2]. 

In treatment contexts, liver biopsies are indispensable for monitoring conditions like autoimmune hepatitis under steroid and immunomodulator therapy. Detecting active disease through histologic information can signal a high relapse risk when considering the discontinuation of treatment, whereas histological improvements can validate effective treatment adherence, thereby making liver biopsies a crucial tool for guiding and refining therapeutic approaches [3].  

Despite their historical importance in diagnosing conditions like neoplasms and post-transplant complications, the role of liver biopsies is evolving due to advancements in clinical diagnostics and non-invasive techniques [2]. The rise of effective treatments for diseases such as viral hepatitis B and C has lessened dependence on liver biopsies [4]. The use of machine learning and artificial intelligence in analyzing comprehensive liver tissue data will provide new methods for automating diagnosis and prognosis, impacting the future utility of liver biopsies in clinical practice [5].  

Although alternatives to biopsy, such as serological tests and imaging techniques, continue to evolve, liver biopsies remain essential for assessing liver fibrosis, a critical marker of disease progression or response to treatment [6]. Advances in fibrosis evaluation, like the progressive-indeterminate-regressive (PIR) system, enable the observation of dynamic changes in fibrosis without the need for sequential biopsies [7].  

As technological advancements progress, there is a growing development of new methods for three-dimensional visualization, digital morphometry, and cellular content analysis. Artificial intelligence and machine learning enhance these developments, which automate the analysis and interpretation of data. Less invasive and more precise technologies will shape the role of liver biopsy moving forward.  

Clinical Indications for Liver Biopsy  

Liver biopsy has numerous clinical applications categorized into three fundamental areas: diagnosis, prognosis, and treatment management [3]. Liver biopsies are indispensable for diagnosing conditions like autoimmune hepatitis, identifying Wilson’s disease by quantifying copper in the liver tissue, and evaluating overlap syndromes such as autoimmune hepatitis with primary biliary cholangitis [3][8].  

The recommendation for a liver biopsy can influence the management or treatment of a patient, such as in diagnosing or assessing the severity of Nonalcoholic Fatty Liver Disease (NAFLD), the most common indication for a liver biopsy [9]. Liver biopsies are also vital for evaluating the extent of damage in various liver diseases, such as chronic hepatitis B or C, primary biliary cholangitis, hemochromatosis, detecting cirrhosis for predicting the risk of hepatocellular cancer and others, or in cases of unexplained liver disease or abnormal liver function tests [3].  

Liver biopsy plays a fundamental role in the post-transplant setting to assess liver function and distinguish between graft rejection and disease recurrence [10]. Although there is an increase of noninvasive markers, the presence of fibrosis remains a key prognostic indicator in chronic liver diseases [11]. 

Providers triage liver biopsy procedures based on clinical differential diagnoses. A laparoscopic liver biopsy allows for the assessment of the liver’s gross features which providers prefer in specific scenarios including concurrent surgeries or when lesions are difficult to access. However, the procedure comes with higher costs and increased risks of complications [1]. Providing pathologists with comprehensive clinical details, including liver enzyme levels, exposure history, and viral and autoimmune serologies, is essential for ensuring efficient and precise tissue processing and analysis. 

Patients with liver disease may show abnormal hematological parameters that traditional metrics like platelet count and prothrombin time may not reflect [12]. For non-lesional biopsies, the recommendation is a transvenous approach if the INR exceeds 1.4, while for lesional percutaneous biopsies, the recommendation is an INR under 2.0 [1].  

Current evidence does not recommend the use of fresh frozen plasma to mitigate bleeding risks [1]. Effective communication among the clinicians involved—the requesting physician, the practitioner performing the biopsy, and the histopathologist—is essential for successful patient outcomes.  

Contraindications  

The primary risks associated with percutaneous liver biopsy include bleeding, organ perforation, sepsis, and in rare cases, death [1] [13]. Bleeding is the most common complication, occurring in up to 10% of cases, with serious bleeding incidents occurring in less than 2% [14]. Factors such as advanced age, existing comorbidities, and the patient’s coagulation status can elevate these risks [1][15]. The mortality rate from liver biopsies remains low, at less than one in 1,000 [15].  

Absolute contraindications include an uncooperative patient, which can increase the risk of complications, and an elevated risk of bleeding—an International Normalized Ratio (INR) that exceeds 1.5 or if the platelet count is below 60,000 [3][34]. Biopsies are contraindicated in patients with suspected vascular tumors of the liver due to the increased risk of bleeding [3].  

Relative contraindications include ascites, where percutaneous biopsy is challenging and carries a higher risk of complications, thus making the transvenous route preferable [1][3]. In obese patients, the presence of excessive adipose tissue complicates the procedure, and a transvenous approach may minimize the risk of biopsy [1][3].  

Common Biopsy Methods  

There are various techniques used to obtain liver biopsies including percutaneous, transjugular, laparoscopic, and intra-operative methods, each offering distinct advantages and challenges [2]. Ultrasound guidance can minimize risks during liver biopsies [1]. If ultrasound use is not viable, it is prudent to obtain imaging within three months before the procedure [1].  

During cholecystectomies and other procedures, intra-operative biopsies can visualize liver abnormalities. Physicians prefer these biopsies for their ability to sample identifiable areas, although wedge biopsies may not be ideal for assessing liver fibrosis and inflammation [16].  

Additional biopsy methods include transfemoral, which uses the femoral vein, endoscopic ultrasound-guided biopsies performed through an endoscope in the duodenum, and laparoscopic biopsies which allow for direct visual inspection and targeted sampling of the liver [1]. Providers base biopsy selection on the patient’s medical condition and the clinical objectives. 

The percutaneous, ultrasound-guided liver biopsy, known as the Menghini method, is a simplistic, rapid, and cost-effective method [17]. Although complications are rare, they can include hemorrhage and bile leakage [1][13]. The percutaneous approach is standard in most medical settings, with the transjugular method preferred for patients with significant ascites or coagulopathy [3]. The transjugular route also facilitates the measurement of intrahepatic portal pressures, essential for diagnosing and managing conditions like cirrhosis, though it may yield smaller, fragmented samples complicating pathological assessments [18].  

Laparoscopic liver biopsy provides detailed insights by allowing a macroscopic examination of the liver and enables immediate coagulation if bleeding occurs [19]. This method is suitable for patients at higher risk of complications. The transjugular route is beneficial for patients with severe coagulopathies and involves risks associated with catheter placement [20]. In cases of uncertain liver conditions, a trans-jugular approach enables targeted biopsies and reduces the risk of non-representative samples [20]. With this method, the passage of a catheter occurs via the jugular vein, allowing the collection of tissue samples, and reducing bleeding risks [20]. 

Histological examination remains essential for diagnosing liver diseases when liver function anomalies are unexplained [1]. Standard staining techniques such as trichrome, hematoxylin, and eosin (H&E), and others are crucial for a comprehensive evaluation of liver disorders [2][21]. Advancements in histologic evaluation, such as digital slide scanners and new microscopy techniques like Clearing Histology with MultiPhoton Microscopy (CHiMP), are transforming liver biopsies, enhancing the efficiency and quality of liver disease diagnosis and management [2] [22]. 

The function of liver biopsy has shifted from a diagnostic tool to a means of prognostic assessment [23]. Liver biopsies continue to have value in several scenarios: (I) cases of viral hepatitis that have atypical presentation; (II) patients dealing with multiple concurrent disorders; (III) liver diseases of unknown origin; and (IV) situations where the outcomes of non-invasive tests are conflicting or do not align with clinical observations [2][9]. Nonetheless, the future role of liver biopsy may diminish as advancements in technology provide less invasive methods that can detect changes in liver structure and function with greater precision and reliability.  

It is fundamental to acknowledge the advancement of technologies that enable three-dimensional visualization of liver tissue, digital morphometry, and cellular content analysis, surpassing the capabilities of current techniques like immunohistochemistry [2]. The integration of artificial intelligence (AI) and machine learning (ML) into these technologies further revolutionizes their analysis and interpretation, automating processes and enhancing diagnostic precision [5][24]. 

Complications 

Complications from liver biopsies are rare, yet some patients might experience mild discomfort or pain at the biopsy site [1]. Serious complications occur in about 1% of cases in comprehensive studies, with a mortality risk estimated at 0.2% [3]. Minor bleeding can occur, which often resolves without intervention.  

Post-biopsy patients should seek medical attention if there is noticeable bleeding from the biopsy site, signs of redness, swelling, inflammation, or if a fever develops [1] [25]. If non-alleviated pain persists for several days, it is advisable to consult a healthcare provider. Signs that may warrant overnight hospital observation include severe abdominal pain or shoulder tip pain unrelieved by a single dose of parenteral analgesic, hypotension, or tachycardia following the procedure [1] [25].  

Pain is the most common complication following a liver biopsy, reported in up to 84% of patients [1][25]. This pain occurs at the biopsy site or the right shoulder, indicative of a subcapsular hematoma [3]. While the pain can be manageable with pain relief medications, ongoing severe discomfort may require further investigation for conditions including bile peritonitis or hemorrhage leading to hospital admission and radiological assessment [1][3].  

Bleeding is another potential risk of liver biopsy. The risk of fatal hemorrhage in patients without malignancy stands at 0.04%, and nonfatal hemorrhage at 0.16% [26]. Those with malignancies face higher risks [26]. Bleeding can present in various forms: free intraperitoneal bleed, intrahepatic/subcapsular hematoma, and haemobilia [27]. Free intraperitoneal bleeding, often due to liver laceration, can lead to hemodynamic instability and severe abdominal pain, requiring immediate hospitalization and angiographic, embolization or surgery for stabilization [28].  

Intrahepatic or subcapsular hematomas present with pain, tachycardia, and a mild drop in hemoglobin levels and are manageable with conservative treatment [29]. Haemobilia, which may cause gastrointestinal bleeding, biliary pain, and jaundice, ranges from mild to severe and might necessitate endoscopic or radiological interventions [30]. 

In severe and less common cases, complications such as hemorrhage may necessitate a blood transfusion or surgical intervention [1][3]. There is also a small risk of internal bile leakage from the liver and infection at the biopsy wound, which requires prompt medical evaluation to manage.  

Transient bacteremia following liver biopsy has clinical significance but may require special consideration in cases like primary sclerosing cholangitis or post-transplant scenarios, assessed on an individual basis without routine antibiotic prophylaxis [1][31]. Bile peritonitis, which may develop secondary to the puncture of the gallbladder or dilated bile ducts during the biopsy, can present abdominal pain, fever, and leukocytosis. Treatment often includes fluids and antibiotics, with endoscopic procedures or surgery required in rare instances [32][33]. 

Patient Preparation for Liver Biopsy  

For a patient undergoing a liver biopsy, it is important to confirm blood clotting ability is sufficient to prevent excessive bleeding after the procedure. Providers compile a detailed list of all medications, including over-the-counter drugs, herbal supplements, and vitamins.  

Patients may need certain stop medications prior to the procedure to lower the risk of bleeding. These include aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen and naproxen, anticoagulants such as warfarin, certain cardiac medications like abciximab, dipyridamole, ticlopidine, and clopidogrel, and some herbal supplements such as fish oil or ginkgo biloba [25].  

Patients should not eat or drink anything for six hours before the biopsy. In some cases, a light breakfast, and a small amount of fat, like butter or margarine, with breakfast may facilitate the emptying of the gallbladder, which could reduce the risk of gallbladder injury during the biopsy [25].  

Conclusion

The liver biopsy has evolved from a simple diagnostic tool to an essential element in prognostic assessment and therapeutic management across a range of liver diseases. Developed for measuring glycogen in diabetic patients, its applications have expanded with the advent of Menghini’s “one-second needle biopsy” technique in 1958 [2]. Today, liver biopsies play a critical role in diagnosing conditions like autoimmune hepatitis, Wilson’s disease, and various overlap syndromes, and they remain indispensable for managing complex cases such as NAFLD and chronic viral hepatitis [3][8][23]. 

The procedure is also vital in post-transplant care to distinguish between graft rejection and disease recurrence. Despite the development of non-invasive diagnostic techniques, liver biopsies continue to be crucial for assessing liver fibrosis—a key indicator of disease progression or therapeutic response. Recent advances in technology and molecular analysis enhanced by AI and machine learning, are transforming liver biopsy from a diagnostic to a more dynamic tool capable of detailed tissue characterization [5].  

However, the use of liver biopsy is not without risks. Complications, while rare, can include pain, bleeding, and more severe consequences such as organ perforation and sepsis [1][3]. Patients must be prepared and monitored, with careful consideration of contraindications and potential complications. Preparation includes a review of medications that might exacerbate bleeding risks and fasting guidelines to minimize procedural complications. 

Despite the inherent risks and the advent of less invasive diagnostic methods, the future of liver biopsy looks to integrate these innovative technologies, reducing the need for invasive procedures while maintaining the diagnostic and prognostic utility of tissue analysis [2]. As the field advances, liver biopsy may remain a valuable tool in the hepatologist’s arsenal, guided by developments in medical technology and enhanced by safer, more precise diagnostic capabilities. 

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