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rational diagnostics

Indian Pediatr 2020;57: 734-740

Liver Biopsy in Children

 

Tebyan Rabbani, Johanna M Ascher Bartlett and Naveen Mittal

From University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA

Correspondence to: Dr Naveen Mittal, UT Health San Antonio, 7703 Floyd Curl Drive, MC-7816, San Antonio, TX 78229-3900, USA.
Email: [email protected]


 

 

Liver biopsy is the cornerstone of medical decision-making for a wide range of hepatic diseases in children. The indications for liver biopsy vary greatly depending on the ease of diagnosis with non-invasive tests, the need to stage of disease, and the role of histological evaluation in management of liver disease. Multiple methods of liver biopsy are available to the clinician and are utilized based on clinical circumstances, cost, and consideration of contraindications. Collaboration between the clinician and pathologist is important in order to handle the tissue sample appropriately and interpret the histology. The purpose of this paper is to provide a broad overview of liver biopsy indications, techniques, pre- and post-biopsy care and complications, interpretations, contraindications, recent advancements, and pitfalls that occur with liver biopsies.

Keywords: Chronic liver disease, Diagnosis, Histopathology, Management.




A
cute and chronic liver diseases in children are multifactorial. Liver biopsy is considered the gold standard for diagnosis, prognosis, and assessment of treatment response for liver diseases. With the availability of ultrasound guidance and effective and safe sedation in children, it has become a routine procedure in many parts of the world. The purpose of this article is to provide an overview of the role of liver biopsy in children which includes its indications, overview of the most common techniques used, complications that may arise, handling of the tissue properly, interpretation of results, contraindications, recent advancements, and the pitfalls of liver biopsy.

INDICATIONS FOR LIVER BIOPSY

Evaluation of liver tissue is critical in the management of various diseases of children as listed in Box I.

Box I Common Indications for Liver Biopsy in Children


• Etiology and severity of neonatal cholestasis

• Abnormal liver function tests and/or hepatomegaly

• Etiology and severity of acute liver failure

• Cryptogenic cirrhosis or portal hypertension of unknown etiology

• Staging of chronic hepatitis of infectious, autoimmune, or other causes

• Etiology and level of duct involvement in sclerosing cholangitis

• Subtyping of metabolic and genetic diseases of the liver

• Drug-induced liver disease

• Hepatic masses

• Systemic disorders that may present with either fever of unknown origin or multi- organ infiltration or involvement

• Post liver transplantation rejection

• Veno-occlusive or graft versus host disease in non-liver transplants

• Obtain tissue to identify and culture infectious agents

• Effectiveness of medications and treatment interventions for chronic liver disease

• Screening of relatives of patients with familial diseases in subclinical presentation

Modified from reference 2,11,19,31,33.

Diagnosis

Detailed history and thorough clinical examination are the first steps in evaluation of children suspected to have liver disease or hepatic involvement with systemic diseases. Non-invasive tests of blood, urine, and stool combined with appropriate imaging of the liver are deployed first and liver biopsy is reserved for further information. Over the last few decades, improvements in imaging techniques can help assess fibrosis in liver, provide high resolution images to assess the biliary tree, and highlight the nature of liver masses. Commercially available genetic and enzyme testing kits can provide confirmation of many liver diseases without liver biopsy. Newborn screening of all babies born in USA is helpful in capturing common but not all genetic and metabolic diseases.

Neonatal cholestasis is caused by a wide range of etiologies and, some causes need urgent intervention before irreversible damage occurs. Biliary atresia needs urgent diagnosis as Kasai procedure, earlier in the neonatal period has a higher success rate [1]. A timely diagnosis of many metabolic disorders can be corrected by removal of the offending agent or providing corrective medication. Initial laboratory evaluation of neonatal cholestasis consists of a comprehensive metabolic panel, complete blood count with differential, gamma-glutamyl transferase (GGT), prothrombin time (PTT), international normalized ratio (INR), direct and total bilirubin [2]. Abdominal ultrasound and hepatobiliary scintigraphy are useful adjuncts in diagnosis. However, liver biopsy remains the diagnostic gold standard for diagnosis of neonatal cholestasis [3], especially biliary atresia, as imaging of the anatomical abnormalities of biliary passages is difficult to assess at a young age [4]. Liver biopsy has the highest sensitivity (100%) in detecting biliary atresia with a specificity of 94.3% and an accuracy rate of 96.9% compared to other diagnostic modalities like magnetic resonance cholangiography (MRCP), ultrasonography, hepatobiliary scintigraphy or single-photon emission computer tomography [5].

Obesity in children has become a global problem with prevalence of over 19% in some populations including in India [6]. Liver ultrasound has previously been used to diagnose nonalcoholic fatty liver disease (NAFLD) based on the degree of echogenicity. However, echogenicity does not correlate well with steatosis or fibrosis and cannot distinguish between the two. Ultrasound quality also varies with technician’s skill level [7]. Transient elastography has been shown to accurately assess the degree of fibrosis by measuring liver stiffness but has not been fully adapted or validated for pediatric use [8]. Liver biopsy provides a reliable assessment of liver steatosis and fibrosis [7]; although, its use for diagnosis of NAFLD is debatable [9,10].

Prognosis

Liver biopsy can be used as a prognostic tool to assess disease severity and staging of fibrosis. The degree of fibrosis or types of cells found in the tissue sample facilitates risk stratification of morbidity and mortality [11]. Staging of fibrosis on biopsy can help determine the progression of NAFLD [12]. Additional screening modalities such as upper endoscopy to monitor for varices and hepatocellular carcinoma screening should be done when progression to cirrhosis is observed [13].

Hepatitis C infection can be diagnosed with laboratory values alone, yet LB is still regarded as the gold standard in staging and monitoring disease severity as determined by degree of fibrosis in adults [1,14]. Recent studies in children with Hepatitis C to evaluate direct-acting antiviral therapy did not require liver biopsy [15].

LB must be performed to properly stage and provide a prognosis in those with autoimmune hepatitis (AIH) [16].

Hepatoblastoma is the most common malignant tumor of the liver in children. Liver biopsy is performed to determine the classification of the hepatoblastoma into epithelial type or mixed epithelial/mesenchymal type. The epithelial type is further classified into the subtypes: fetal, embryonal, and small cell undifferentiated. The small cell undifferentiated hepatoblastoma subtype has a poor response to chemotherapy and a worse prognosis [17].

Managing Therapy

Liver biopsy can guide and cater management approaches. Specific treatment can be initiated or withheld based on the histological findings.

Measuring port-based plasma cell infiltrate can help predict a greater than 90% chance of relapse when monitoring treatment of AIH [18]. Withdrawing immunosuppression therapy for patients with AIH is predicated on LB results. After 1 to 2 years of normal biomarkers, liver biopsy is necessary to prove resolution of inflammation [16].

Prior to treatment, liver biopsy is recommended for children with Hepatitis B to assess necro-inflammation and stage of fibrosis [19]. Pediatric patients with chronic Hepatitis B who have moderate to severe necro-inflammation on liver biopsy are likely to benefit from antivirals or interferon treatment [20]. However, benefit is not established for children with mild necro-inflammation or fibrosis. Degree of fibrosis or cirrhosis on liver biopsy can also help modify treatment regimen, as interferon can cause further decompensation of liver function [21].

Pediatric acute liver failure is a clinical syndrome in which previously healthy patients develop rapid hepatic dysfunction. There is often a reluctance to perform liver biopsy in this setting due to safety concerns such as bleeding risks and an elevated INR. However, a recent single-center retrospective study demonstrated that liver biopsy was performed safely in most children [22]. LB assisted in the diagnosis of 62% of patients and aided in treatment decisions in 9 of 26 cases [22].

PRE-BIOPSY WORKUP

Preliminary laboratory evaluation prior to liver biopsy includes a complete blood count, prothrombin time/international normalized ratio, partial thromboplastin time, and bleeding time [7]. Some institutions recommend blood typing in case of procedural bleeding [11]. In order to minimize complications, imaging should be reviewed by experts prior to liver biopsy to evaluate for presence of biliary dilatation and concerning focal lesions such as a hemangioma [11]. Depending on the institution, liver biopsy may be done in an operating room or endoscopy suit. Appropriate sedation should be administered.

BIOPSY TECHNIQUES

Percutaneous Liver Biopsy

The percutaneous liver biopsy is the most common modality as it is less invasive and less expensive than other approaches. It can be performed by physical examination or with ultrasound guidance.

The percussion-guided or blind method is the classic liver biopsy technique. It is performed by percussing over the right upper quadrant of the abdomen, at the mid-axillary region, to find the biopsy site. This method can be used for diffuse liver pathology and is the least expensive method of liver biopsy.

The image-guided method typically involves the use of ultrasound to mark the site of biopsy and can be useful when targeting a lesion within the liver. This method can provide a better tissue yield and decrease complications associated with liver biopsy [23]. While ultrasound may have an additional upfront cost, ultrasound guided liver biopsy may be cost effective when considering higher likelihood of complications that may occur with blind liver biopsy [23]. In a study of 102 pediatric patients who underwent an ultrasound guided liver biopsy or a blind liver biopsy, serious complications such as intrahepatic hematoma were higher in the blind liver biopsy group [24]. Kader, et al. [25], showed that ultrasound guidance prompted more optimal biopsy site selection in 25% of cases compared to previously determined locations with percussion.

The aspiration or suction-type needle uses steady suction with a syringe connected to the needle (Web fig. 1), which is advanced into the liver to aspirate tissue. For children, there is often a penetration limiter to monitor the depth that the needle can advance. This suction technique can lead to more tissue fragmentation.

The Tru-Cut needle is the most commonly used cutting-type needle. This device consists of an inner obturator with a wedge to entrap tissue fragment and an outer surrounding cutting sheath. The obturator is advanced into the liver and then the sheath is advanced to cut the liver and remove the specimen. These types of needles have been shown to provide better specimens in patients with advanced fibrosis or cirrhosis since they limit fragmentation or shattering of the sample [26].

Spring-loaded cutting needles trigger a rapid firing of the inner obturator needle and outer cutting cannula via semi-automatic or fully automated mechanism (Web fig. 2) [27]. These needles allow the user to perform the procedure without the ‘jabbing motion’ practiced in the aspiration and cutting-type methods. A study of 836 adult patients, showed that the spring-loaded automatic biopsy needles obtained larger specimen size compared to the Tru-Cut needle (1.7 mm vs 1.5 mm, P <0.05); however, the larger size was not clinically important [28].

Trans-jugular Liver Biopsy

Trans-jugular approach to liver biopsy is typically reserved for patients with severe liver disease with coagulopathies or ascites and in hematological conditions, where percutaneous liver biopsy is contraindicated due to the high risk of bleeding [29]. The biopsy specimen obtained by trans-jugular route is often regarded as smaller and more fragmented than percutaneous samples. Cholongitas, et al. [30] showed that percutaneous and trans-jugular modalities had similar yields for histological diagnosis. However, a recent study in India showed poorer tissue yield with trans-jugular than the percutaneous liver biopsy [31]. The technical successes and complications were similar between the two approaches, but overall had a lesser outcome for length of specimen, number of complete portal tracts, adequacy for reporting, and fragmentation [31].

Surgical or Laparoscopic Liver Biopsy

Wedge liver biopsy allows for direct visualization of the liver surface but traditionally was thought to have an increased risk profile. The laparoscopic method allows for larger specimen size, immediate control of procedure-associated bleeding, and ability to visualize tissue prior to biopsy [11,32]. According to the European Society for Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) position paper on liver biopsies, laparoscopic liver biopsy should be considered if increased risk of bleeding, ascites of unknown etiology, evaluation of abdominal mass, failure of previous percutaneous liver biopsy, and the requirement for a large biopsy sample for enzymatic analysis [33].

The advantages and disadvantages of different types of LB techniques have been summarized in Table I.

Table I Advantages and Disadvantages of Different Methods of Liver Biopsy
Method of Liver biopsy   Advantages Disadvantages
Blind Percutaneous • Least expensive method • Inability to sample focal lesions or avoid
• High tissue yields and less fragmentation reported risky areas
• Can be a bed-side procedure • Higher rates of complications over
image-guided liver biopsy
Image-guided • More optimal biopsy site and target • Lesser complication reducing cost over 
focal lesions blind liver biopsy method
• Need additional resources
-  Imaging machine and trained personnel
Transjugular • Safer in patients with low platelet, coagulopathies, • Technically challenging
ascites • Smaller size and fragmentation of tissue
• Also measure pressure readings   reported
• Age and size restrictions
Surgical or laparoscopic • Ability to biopsy focal lesions or get large sample • Most invasive method
size • Longest post-procedure hospital stays
• Useful with patients with abnormal anatomy, ascites. • Most expensive method
• Immediate control of procedure-associated bleeding
 

POST-BIOPSY CARE AND COMPLICATIONS

After the procedure, vital signs (blood pressure, heart rate, respiratory rate, oxygen saturation) should be followed and patients should be observed for any complications [33]. According to ESPGHAN [33], "minor" complications of LB in children include pain, subcapsular bleeding that does not require transfusion or prolonged hospitalization, infection, minor bile leak or hemobilia, and arteriovenous fistula. "Major" complications include bleeding, including hemobilia, that requires transfusion, surgery, or intensive care management; pneumothorax or hemothorax; and death.

Matos, et al. [34] observed patients for at least six hours after liver biopsy and discharged them if no complications occurred. Another study found that same-day observation for less than eight hours is well tolerated in low-risk children undergoing liver biopsy in outpatient settings [35]. Contact sports should be avoided for one week after biopsy [33].

Bleeding: If bleeding is suspected, a complete blood count and abdominal ultrasound should be obtained to assess for hematoma. However, if bleeding is thought to be life threatening, surgical intervention should never be delayed. In a study of 179 pediatric liver biopsy, 6% had a decrease in hemoglobin of more than 20g/L after biopsy, but none required transfusion [36]. In the same study, 4% developed a small hematoma at the biopsy site immediately after the procedure that was controlled with local compression. In a larger study of 469 pediatric liver biopsies, bleeding was reported in 2.8% of patients which increased with malignancies or post bone marrow transplant [37]. Liver-transplanted children are often treated with aspirin to prevent thrombosis of the hepatic artery. The bleeding incidence or complication rate did not increase with low-dose aspirin; however, low-molecular-weight heparin therapy and focal lesions were identified as risk factors [38]. Image-guided percutaneous liver biopsy with gelatin sponge embolization of the biopsy tract has recently been suggested as a strategy to minimize bleeding complications in high risk patients. The associated complications are minimal, and this can be considered as a first-line approach in the setting of coagulopathy [39].

Pain: Pain was reported in 59% of pediatric patients post-biopsy, which responded to acetaminophen [36]. Trans-ient pain was reported in 20% of patients in another study, most often localized to the liver biopsy site and/or to the right shoulder [40]. Prolonged pain warrants further examination to rule out intraabdominal complications.

Infection: Infection is a risk that can occur at the liver biopsy site or systemically. In a study of pediatric outpatient liver biopsy, only one patient became septic (0.2%) [41].

Arteriovenous fistula: Arteriovenous (AV) fistula after liver biopsy is a rare complication. One (0.2%) case of AV fistula was seen in outpatient liver biopsy setting (patient also had sepsis), and it resolved spontaneously [41].

Pneumothorax: This is a rare complication of liver biopsy. Only one pediatric case was reported in a study of 469 patients (0.2%) [37].

Bile leak: The rate of bile leaks was 0.6% in one study [37] after pediatric liver biopsy and was reported in only one (0.8%) patient who had bilious drainage from the biopsy site in another study [39].

Death: In a study of 469 pediatric liver biopsies, 3 (0.6%) deaths occurred; all of which had a history of malignancy or hematological disease [37]. In two other studies with 626 and 223 patients, no deaths were recorded [36,41].

SPECIMEN HANDLING AND INTERPRETATION OF RESULTS

The liver biopsy should represent the parenchyma and portal tracts. The amount needed for diagnosis depends on the type of disease because of the patchy, heterogeneous nature of some liver diseases. Focal disease and/or small specimen samples can misrepresent the histological picture. At least 11 portal tracts are needed for accurate specimen interpretation in adults [42], which is proportional to biopsy size. Larger length of biopsy can be attained with multiple passes, but at the cost of higher rate of complications [43]. The exact core length needed to diagnose liver disease is debatable, but currently a core 20mm in length and 1.8mm in diameter is recommended by ESPGHAN Hepatology Committee [33].

The clinical and histological findings help dictate how best to assess the specimen. Often, the tissue sample is fixed in formalin to allow for histochemical (hematoxylin and eosin or Masson trichrome) and immunohistochemical staining for examination under light microscopy. The specimen can be frozen in liquid nitrogen at -80°C for PCR studies, genetic analysis, biochemical analysis, or molecular analysis. The specimen can be fixed in glutaraldehyde and processed for electron microscopy for certain metabolic storage disorders or progressive familial intrahepatic cholestasis. Culture of a portion of the specimen may be indicated if infection is suspected. The tissue may also need quantitative copper analysis for Wilson disease. The tissue sample can also be stained for iron if an iron overload disease is suspected.

It is vital that the pathologist investigating the tissue sample be experienced with liver diseases. The diagnosis should be determined in collaboration with the hepatologist/gastroenterologist and pathologist. If the diagnosis is uncertain, a second opinion from a liver pathologist should be obtained [44].

Table II Contraindications to Percutaneous Liver Biopsy
Potential contraindications Solutions recommended
Prolonged PT or INR >1.5 FFP or factor concentrate; transjugular approach in older children; tract embolization.
Platelets <60,000/mL Platelet transfusion before liver biopsy; trial of propranolol; transjugular approach if still concerns after transfusion.
Prolonged bleeding time Blood products
Hemodynamically unstable Critical care to stabilize
Vascular lesions within liver Real-time image guidance liver biopsy
Infection of hepatic bed/cholangitis Appropriate antibiotics
Uncooperative patient General anesthesia
Ascites Drainage of fluid or transjugular approach
Intrahepatic biliary dilation Plugging of the tract
Peliosis
Hemangioma Real-time image guidance liver biopsy
Morbid obesity Transjugular approach
Hydatid disease Surgical resection of cyst

 

CONTRAINDICATIONS

There are no established laboratory cutoff values for patients at risk for bleeding. However, INR >1.5 and platelet count <60,000/mL indicate an increased risk for bleeding and may require transfusion prior to liver biopsy [33,40]. In patients with ascites, percutaneous liver biopsy should be avoided due to risk of bleeding and/or biopsy site leakage of fluid, potentially leading to peritonitis [33]. A transjugular liver biopsy is recommended in these circumstances. Other contraindications include vascular tumors, echinococcal cysts, morbid obesity, extrahepatic biliary obstruction, and bacterial cholangitis [40]. The management of different contraindications of percutaneous liver biopsy are mentioned in Table II.

PITFALLS OF LIVER BIOPSY

The sample size from the biopsy must be enough for accurate interpretation. LB is associated with sampling variability because disease can be focal and heterogenous and tissue may not always be extracted from the areas of highest yield. The standard specimen from a LB typically only represents 1/50000th of the liver; thus, sampling error can be significant and approach 20-30% [40].

RRECENT ADVANCES

Thrombocytopenia is a contraindication to percutaneous liver biopsy and thus can delay diagnosis and staging of disease. However, newer advances have recently been made discovered to aid in this problem. An Indian study showed that propranolol corrected thrombocytopenia in 62.7% of children who previously were not able to undergo liver biopsy due to hypersplenism-related thrombocytopenia [45]. The US-FDA approved Doptelet (avatrombopag) to treat thrombocytopenia in adults with chronic liver disease who are planned to undergo a medical procedure [46]. Advances in imaging with Fibroscan/ US elastography to stage fibrosis, MRCP to evaluate bile ducts, MRI with EVOST (a gadolinium-based contrast agent) to assess nature of liver tumors, and MRI derived proton density fat fraction (PDFF) to quantitate fat in liver are some of the tests gaining popularity. Wide availability of these modalities may reduce the dependence on LB in the near future.

Key messages

• Liver biopsy, although invasive, can assist in diagnosis, prognosis, and direct therapeutic management of numerous pediatric liver diseases.

• Complications of liver biopsy are rare and most commonly consist of localized pain or bleeding.

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