Diagnostic Liver Biopsy

Practiced since the late 19th century, liver biopsy remains the criterion standard in the evaluation of the etiology and extent of disease of the liver. Paul Ehrlich performed a percutaneous liver biopsy in Germany in 1883. In the late 1950s, Menghini developed a 1-second aspiration technique, which led to wider use of the procedure and broadened its applications.

Since Menghini, the evolution of liver biopsy has been extensive. At present, percutaneous biopsies are performed primarily by specialists in gastroenterology/hepatology or by radiologists.

A variety of approaches may be utilized for obtaining a liver tissue specimen. These include a blind percutaneous approach after percussion of the chest wall, biopsy under the guidance of ultrasonography (US) or computed tomography (CT), intravascular tissue sampling via the hepatic vein, and intra-abdominal biopsy at laparoscopy or laparotomy.[1]  An endoscopic US (EUS)-guided approach has been described.[2, 3, 4, 5, 6]

The choice of one technique over another is based on availability, personal preference, and the clinical situation. Likewise, various needles are available for use, depending on the approach and on physician experience.

Although liver biopsy is generally safe and is considered the criterion standard for the evaluation of hepatic inflammation and fibrosis, sampling error, rare complications, and, occasionally, significant patient anxiety do occur. These factors have led to keen interest in the development of noninvasive tests for hepatic fibrosis,[7, 8] some of which are commercially available in the United States.

Although these tests hold promise for reducing the need for liver biopsy, most hepatologists feel that their clinical usefulness is limited at this time. The available tests appear to perform well at the extreme ends of the spectrum of chronic liver disease, but results vary considerably in the intermediate stages of disease that are frequently seen in clinical practice. Lack of validation of these tests in the community settings where they would most likely be used is also a potential shortcoming of the current testing methods.

Guidelines for the clinical use of liver biopsy have been developed by the British Society of Gastroenterology in conjunction with the Royal College of Radiologists and the Royal College of Pathology.[9]

Liver biopsy, in combination with history and physical examination data, is a powerful clinical tool for diagnosing and treating liver disease. Indications for obtaining a biopsy specimen, divided according to the type of clinical question framed, include the following:

• Evaluation of abnormal hepatic laboratory test results
• Confirmation of diagnosis and prognostication
• Suspected hepatic neoplasm
• Diagnosis of cholestatic liver disease
• Evaluation of infiltrative or granulomatous disease
• Following a case of liver transplantation to evaluate and manage rejection
• To evaluate unexplained jaundice or suspected drug reactions

The biopsy specimen may be used to identify or exclude possible etiologies for physical or laboratory abnormalities. Although various disease states may present similarly, diagnostic histologic patterns exist when used in the context of clinical presentation. For example, infiltration of the hepatic parenchyma by fat may exist in diseases due to alcohol abuse, hepatitis C, diabetes, obesity, or combinations thereof. For each disease state, histologic clues exist that distinguish one from the other.[10, 11, 12]

Liver biopsy plays little role in the determination of the organism responsible for systemic infection because blood cultures generally are revealing. The notable exceptions are intrahepatic tuberculosis and Mycobacterium avium complex (MAC).

Another indication for biopsy is the determination of the extent of histologic change present in a biopsy specimen. This involves scoring systems for the degrees of inflammation and fibrosis noted by the pathologist. Many systems exist for describing the microscopic findings, ranging from simplistic to complex. The majority of scoring systems report the degree of inflammation as the grade of the disease and the amount of fibrosis as the stage. An example here would be the finding of moderate inflammation (grade 3) in a specimen from a cirrhotic (stage 4) liver.

The third set of indications is the monitoring of the progression of disease or of treatment efficacy. For example, liver biopsy specimens frequently are used to evaluate and treat rejection following liver transplantation. Repeated biopsies are used less frequently to monitor progression of diseases such as primary biliary cirrhosis, chronic hepatitis C,[13] or alcoholic liver disease.

Regardless of the indication for the biopsy, identifying which information the procedure is anticipated to yield is important.

Contraindications for percutaneous liver biopsy are relatively few, but identifying contraindications is important to avoid the major complications associated with the procedure.

Contraindications for liver biopsy include the following:

• Increased prothrombin time (PT), international normalized ratio (INR) greater than 1.6
• Thrombocytopenia, platelet count lower than 60,000/μL
• Ascites ( transjugular route preferred) ^[14]
• Difficult body habitus (transjugular route preferred; transfemoral transcaval route may be an option, particularly for masses abutting the inferior vena cava ^[15] )
• Suspected hemangioma
• Suspected echinococcal infection
• Uncooperative patient

Patient preparation prior to undertaking a liver biopsy is essential. Ideally, education should begin during an office visit prior to the biopsy. The procedure must be explained to the patient in sufficient detail, with careful attention paid to anxiety and pain management issues.

On the day of the biopsy, review recent laboratory evaluation of prothrombin time (PT) and complete blood count (CBC), including platelets. Explain the procedure to the patient, and obtain informed consent.

Aspirin should be discontinued 1 week before the biopsy procedure. Nonsteroidal anti-inflammatory drugs (NSAIDs) should be stopped 3 days prior to the procedure. The patient may, or may not, be asked to complete an overnight fast. Eating before the procedure allows for gallbladder contraction, reducing the risk of gallbladder puncture. An empty stomach, however, may decrease the likelihood of postprocedure nausea and vomiting. This is an important consideration because many biopsies are performed with the patient under light sedation.

In most instances, the biopsy procedure is undertaken on an outpatient basis,[1] in accordance with the following recommendations derived from a statement by the American Gastroenterological Association (AGA)[16] :

• The patient must remain within 30 minutes of the facility at which the biopsy was performed
• The patient must be accompanied by a reliable person the first night after the procedure
• The patient should have no contraindications or conditions that increase the risk associated with the procedure
• The facility where the biopsy is performed should have an approved blood bank, laboratory, inpatient bed, and personnel available to the patient for at least 6 hours after the procedure; however, the American Association for the Study of Liver Diseases (AASLD) has recommended a routine observation period of 2-4 hours ^[17]
• Hospitalization should accompany evidence of bleeding, bile leak, pneumothorax, or pain requiring more than one analgesic dose

Various needles are available for obtaining a liver biopsy specimen. They may be divided into three broad categories as follows:

• Suction needles (Jamshidi, Klatskin, and Menghini)
• Cutting needles (Tru-cut and Vim-Silverman)
• Spring-loaded cutting needles

Each needle type has proposed advantages and disadvantages. Suction needles are thought to yield desirable sample size but may fragment cirrhotic livers. Conversely, cutting needles do not fragment liver tissue but may deliver inadequate tissue samples. Spring-loaded needles are thought to decrease the amount of time that the needle is in the liver but may increase patient discomfort due to the clicking noise of the triggering mechanism. Needle selection is largely a result of physician preference and experience.

After the patient is positioned and draped, administer local anesthesia with 1% lidocaine in both superficial and deep planes.

Place the patient supine, remove pillows, and elevate the right arm behind the head. The legs and feet may be angled to the left to further open the right intercostal spaces.

Various approaches may be utilized for obtaining a liver tissue specimen, including a blind percutaneous approach after percussion of the chest wall, biopsy under the guidance of ultrasonography (US) or computed tomography (CT), intravascular tissue sampling via the hepatic vein, and intra-abdominal biopsy at laparoscopy or laparotomy.[1]  An endoscopic US (EUS)-guided approach has been described.[2, 3, 4, 5, 6]

The choice of one technique over another is based on availability, personal preference, local expertise, and the clinical situation.[9] Likewise, various needles are available for use, depending on the approach and on physician experience.

Determination of biopsy site

With the patient appropriately positioned (see Periprocedural Care), percuss the right trunk to the point of maximum dullness during both inspiration and expiration. This frequently corresponds to a point along the midaxillary line at the second or third intercostal space above the costal margin. Mark this location with a surgical pen or other method. (See the images below.)

Percussion over the liver.

Marking the biopsy site.

US or CT may be useful for guidance (see the image below), particularly if obtaining a biopsy of a particular region or mass within the liver is desired. Some have advocated that all biopsies be performed under US guidance; however, whether this reduces procedure-related morbidity or is cost-effective has been controversial.[18, 19, 20, 21]

Ultrasonography of the liver.

In a retrospective study of 100 patients with chronic hepatitis C infection, Flemming et al investigated whether higher-quality biopsy specimens for the grading and staging of hepatitis C could be obtained with the help of US guidance (50 patients) or without it (50 patients).[13] The primary biopsy quality determination was made by assessing the number of complete portal tracts that were identifiable in the slides. The specimen's total length and degree of fragmentation provided secondary outcome measures.

The authors found that US-guided biopsies yielded higher-quality specimens than did the other biopsies, having a larger number of complete portal tracks (11.8 vs 7.4), a greater length (24.4 mm vs 19.7 mm), and less fragmentation, as well as a higher overall histopathologic quality assessment.[13] However, there was no significant difference between biopsies performed under US guidance and those that were not with regard to how effectively the specimens could be used to grade and stage chronic hepatitis C virus infections.

Contrast-enhanced US (CEUS) has been suggested as a potentially helpful tool for biopsy of a focal liver lesion, especially when the lesion is inconspicuous or invisible on standard US or when the initial biopsy was insufficient because of necrotic material.[22, 23] CEUS can also improve the characterization of focal liver lesions significantly and may thereby make many biopsies of such lesions superfluous. The World Federation for Ultrasound in Medicine and Biology (WFUMB) has issued guidelines for the use of CEUS in the liver.[24]

Insertion of biopsy needle

Once a suitable biopsy site has been identified, sterile technique is employed. Prepare the field with povidone-iodine solution, and place sterile drapes (see the images below). Administer a local anesthetic (1% lidocaine) in both superficial and deep planes. Patients occasionally describe experiencing a burning or shooting pain that radiates either transversely or to the right shoulder region. This pain is thought to represent contact of the anesthetic with the capsule of the liver.

Preparing the field.

Sterile drape application.

Once adequate anesthesia has been obtained, make a small nick in the skin with a surgical blade to allow introduction of the biopsy needle. Introduce the biopsy needle within close proximity to the upper aspect of the lower rib to avoid the intercostal nerve and vasculature.

As the needle is introduced, a series of several successive "pops" may be felt. Flush small amounts of saline contained in the syringe until resistance is encountered. The resistance is the liver edge; at this point, withdraw the needle slightly and flush it again to remove debris. Apply suction to the syringe, and ask the patient to expire and to hold his/her breath. This shrinks the lung field and minimizes the risk of perforating the gallbladder, while bringing the liver against the thorax wall. The biopsy sample is obtained. (See the image below.)

Biopsy needle inside the liver.

Apply pressure to the site, followed by an adhesive bandage. Roll the patient onto the right side (see the image below), and instruct him or her to remain in this position for 1 hour to help prevent bleeding or bile leakage. Obtain vital signs every 15 minutes for the first hour, every 30 minutes during the second hour, and then hourly until discharge.

Patient lying on right side.

The video below depicts US-assisted liver biopsy.

Some controversy remains as to what constitutes an adequate liver biopsy sample for accurate evaluation. In general, a sample that is 1.5 cm long and 1.2-2.0 mm in diameter and contains at least six to eight portal triads is considered adequate. This represents approximately 0.002% of the adult liver. Some hepatologists have advocated the use of 4-cm tissue samples to minimize sampling error, whereas others have found samples of 1 cm to produce minimal interobserver variability.[25]

Complications of liver biopsy occur rarely but are potentially lethal. Those listed below are the ones most commonly observed in clinical practice.

The majority (60%) of complications occur within the first 2 hours, and 96% occur during the first 24 hours following the procedure. Approximately 2% of patients undergoing biopsy require hospitalization for the management of an adverse event. Vasovagal episode and pain are the most common reasons for admission.

Pain occurs in approximately 30% of patients undergoing a liver biopsy. It often is described as a dull ache in the right upper quadrant or shoulder and typically is relatively short in duration, lasting less than 2 hours. This pain often responds to analgesics. Unrelenting severe abdominal pain is alarming, possibly indicating a serious complication such as intraperitoneal hemorrhage or biliary leak.

Bleeding comprises a second group of complications. Presentations include subcapsular or parenchymal hematoma, hemobilia, and free intraperitoneal hemorrhage. Pain 2 hours after the procedure should alert the clinician to the possibility of procedure-related bleeding.[26]

Intrahepatic or subcapsular hematomas are the most common of the bleeding complications and are noted on approximately 23% of postbiopsy sonograms. Such findings often are incidental, without associated clinical symptoms. They occur at similar rates after either blind or laparoscopy-guided modalities, but incidence may be influenced by needle type and imaging technique. Large hematomas are a rare cause of biliary obstruction. Symptomatic hematomas should be imaged by means of US but usually respond to conservative treatment with analgesics.

Hemobilia presents as biliary colic, gastrointestinal bleeding, and jaundice. It is a rare complication of biopsy; one study of 68,276 biopsies reported four instances of hemobilia. Clinical presentation ranges from chronic anemia to rapid exsanguination. Hemobilia typically develops later than other complications. The average time to onset of symptoms is 5 days after the procedure, but onset may occur earlier. Conservative treatment often is sufficient. However, if clinically significant hemobilia is present, angiography is the modality of choice because both diagnosis and intervention can be accomplished with a single procedure.

Biliary peritonitis is another noteworthy complication, albeit a rare one. Severe abdominal pain and vasovagal hypotension herald its occurrence. Analgesics and fluid management usually are sufficient, but persistence of the condition may necessitate endoscopic retrograde cholangiopancreatography (ERCP) with stent placement.

Intraperitoneal hemorrhage is the most serious of the bleeding complications. It is an early occurrence, most often observed during the first few hours following the procedure, though reports of this complication developing as late as 24 hours after the procedure have been noted. Late hemorrhage is associated with a poor outcome. The overall rate of occurrence of peritoneal hemorrhage in a large study was 0.32%. Factors associated with increased risk of free bleeding include increased age, hepatic malignancy, multiple needle passes, and cirrhosis.

Abdominal pain and persistent hemodynamic instability, presenting as tachycardia and hypotension, are typical of significant bleeding. Early diagnosis via US is preferred. Treatment includes aggressive fluid management and blood and platelet transfusion, if indicated. An angiographer and a surgeon should be alerted early in the process to facilitate rapid intervention if needed. Angiography with potential embolization is the preferred intervention.

A review by Midia et al found that bleeding of any kind occurred in up to 10.9% of image-guided liver biopsies (major bleeding, 0.1-4.6%; minor bleeding, up to 10.9%); however, the overall bleeding rate was below 2%.[27] Patient-related risk factors identified as being potentially indicative of an increased risk of postbiopsy bleeding included the following:

• Patient age >50 years or < 2 years
• Inpatient status
• Comorbidities or concurrent diagnoses
• Coagulation status (3.3% bleeding rate for international normalized ratio [INR] 1.2-1.5 vs 7.1% rate for INR >1.5)

Procedure-related risk factors included the following[27] :

• Needle size (cutting biopsy vs fine-needle aspiration)
• Presence of a patent track on postbiopsy US

Bacteremia, pneumothorax, and accidental biopsy of other organs are rare complications.

The frequencies of the various complications of percutaneous liver biopsy were reported by Reddy and Schiff to be as follows[28] :

• Pain (0.056-22%) - Pleuritic; peritoneal; diaphragmatic
• Hemorrhage - Intraperitoneal (0.03-0.7%); intrahepatic and/or subcapsular (0.059-23%); hemobilia (0.059-0.2%)
• Bile peritonitis (0.03-0.22%)
• Bacteremia
• Sepsis (0.088%) and abscess formation
• Pneumothorax and/or pleural effusion (0.08-0.28%)
• Hemothorax (0.18-0.49%)
• Arteriovenous fistula (5.4%)
• Subcutaneous emphysema (0.014%)
• Anesthetic reaction (0.029%)
• Needle break (0.02-0.059%)
• Biopsy of other organs - Lung (0.001-0.014%); gallbladder (0.034-0.117%); kidney (0.096-0.029%); colon (0.0038-0.044%)
• Mortality (0.0088-0.3%)