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Original Articles: Hepatology

Liver Biopsy Can Be Safely Performed in Pediatric Acute Liver Failure to Aid in Diagnosis and Management

Chapin, Catherine A.; Mohammad, Saeed; Bass, Lee M.; Taylor, Sarah A.; Kelly, Susan; Alonso, Estella M.

Author Information
Journal of Pediatric Gastroenterology and Nutrition: October 2018 - Volume 67 - Issue 4 - p 441-445
doi: 10.1097/MPG.0000000000002096

Abstract

What Is Known

  • Liver biopsy is a safe procedure in children with chronic liver disease and is associated with a low incidence of major complications.
  • A definite etiology is not established in a significant percentage of pediatric cases with acute liver failure.

What Is New

  • In the subset of pediatric patients with acute liver failure, liver biopsy is associated with few major complications.

Pediatric acute liver failure (PALF) is a severe condition in which children without previous evidence of liver disease develop hepatic dysfunction. PALF can progress rapidly and often results in poor outcomes with up to half of patients dying or receiving liver transplantation (1). The causes are diverse and vary with age, and include viral hepatitis, drug toxicity, autoimmune hepatitis, and metabolic disease. Laboratory studies, imaging, and other testing modalities are typically employed to help determine the etiology of PALF. However, in 40% to 50% of cases the etiology remains unknown, so called indeterminate PALF (1,2). Recent studies have shown that many indeterminate cases may be immune-mediated (3–5). Clinicians have begun to describe these patients as having PALF associated with immune dysregulation based on elevated serum soluble interleukin-2 receptor levels, peripheral blood cytopenias, and prominent inflammation on liver biopsy (6). Given their immune active phenotype, evidence suggests these patients may improve with immunosuppressive therapy, and there is a growing trend toward treatment with corticosteroids (7). Examination of liver tissue histology can be a valuable tool in the PALF diagnostic evaluation (8). However, there is often a reluctance to perform liver biopsy in this setting due to safety concerns. Major complications including clinically significant bleeding and pneumothorax are rare after pediatric liver biopsy for any cause, with an incidence ranging from 0–4.6%, and death is extremely rare (9–17). The primary aim of this study was to review the incidence of major complications attributed to liver biopsies performed in the setting of PALF at a large pediatric center. Our secondary aim was to determine to what degree liver biopsy results contributed to PALF diagnosis and management.

METHODS

This was a retrospective single-center review of patients who underwent liver biopsy in the setting of PALF. Patients presented to Ann & Robert H. Lurie Children's Hospital of Chicago (LCH) from January 2006 through December 2016. Potential cases were identified through electronic medical record ICD-9 code search for acute hepatic failure and/or hepatic encephalopathy (570, 572.2) and procedure codes for liver biopsy and transcatheter biopsy (47000, 47001, 37200, and 75970). Patients were included if they met criteria for acute liver failure as defined by the Pediatric Acute Liver Failure Study Group (1) during their admission, were age 0 to 17 years, and had a liver biopsy performed at LCH during their admission for acute liver failure (ALF). As we were specifically interested in patients who might have been at increased risk of bleeding complications, only patients with INR of ≥ 1.5 within 24 hours before their liver biopsy were included. All INR values reported are before fresh frozen plasma (FFP) being administered. At LCH FFP is typically given before or during the biopsy procedure and INR measurement is not repeated. Medical charts were reviewed for patient demographic information, laboratory data, details of the liver biopsy procedure, patient outcomes at discharge, and final PALF diagnosis. We attempted to determine whether the liver biopsy results contributed to the final diagnosis or influenced clinical management, based on review of pathology reports and physician notes. In characterizing the contribution of biopsy to diagnosis, a score of ++ was given if liver biopsy resulted in the final diagnosis being made or a test being sent that confirmed the diagnosis. A score of + was given if the liver biopsy supported and confirmed the already suspected clinical diagnosis. For contribution to management, a score of ++ was given if based on liver biopsy the patient was started on a new therapy, and a score of + was given if the liver biopsy supported the suspected clinical diagnosis and contributed to the decision to continue or initiate therapy. It was noted whether blood products were given 24 hours before, during, or 48 hours post-biopsy. Procedure-related complications were defined as those that occurred during and up to 48 hours after the liver biopsy, determined by the treating clinicians to be related to the liver biopsy (including complications related to vein cannulation for transjugular biopsies), and resulted in some clinical sequelae or escalation of care. Major complications included hemodynamically significant bleeding requiring a blood transfusion or blood pressure support, bile leak, hemobilia, pneumothorax, hemothorax, biopsy site infection, sepsis, and death within 48 hours of the procedure. Maximum decrease in hemoglobin (Hgb) within 48 hours post-biopsy was recorded. A Hgb decrease of more than 2 g/dL attributed to biopsy-related bleeding but did not require any intervention was considered a minor complication. Minor complications, such as biopsy site pain, superficial hematomas, or complications related to procedural sedation were not recorded.

At LCH, we recommend all PALF patients have a comprehensive diagnostic evaluation including review of exposures to medications and supplements, serum acetaminophen level, testing for hepatotropic viruses, screening for AIH, and testing for alpha-1-antitrypsin deficiency. In addition, patients 3 years of age and older are screened for Wilson disease, and patients less than 3 years of age or with a consistent presentation are screened for metabolic or mitochondrial disorders. For this study we did not evaluate the workup for each PALF case, but accepted the final diagnosis as listed in the medical record.

Transjugular liver biopsy is the preferred method at LCH for patients with INR ≥1.5 who are at least 10 kg (typically the lower weight limit for transjugular biopsy). Patients <10 kg may undergo either percutaneous biopsy or surgical biopsy at the discretion of the clinical team. At LCH it is standard practice for patients undergoing a percutaneous liver biopsy to receive FFP if their pre-procedure INR is ≥1.5 and a platelet transfusion if their platelet count is <50,000 cells/μL. Given the decreased risk of bleeding, transjugular or surgical biopsies can be safely performed without correction of coagulopathy, however pre-treatment with FFP or platelets may be given for the same parameters, at the discretion of the physician. Our post-biopsy monitoring protocol includes frequent vital signs assessment and evaluation of the biopsy site. HemoCue point-of-care checks are done at 2 and 6 hours post-biopsy, and if the value is more than 2 points lower than the pre-biopsy Hgb level a whole blood Hgb is measured for confirmation and the physician is notified (18).

Data are reported as percentages if categorical, mean ± standard error if normally distributed, or median with interquartile range if not normally distributed. This study was approved by the LCH Institutional Review Board and the requirement for informed consent was waived.

RESULTS

ICD-9 code search identified 85 patients with PALF during the time period of our study. Fifty-four (64%) were excluded because they did not have a liver biopsy performed. An additional 5 patients were excluded because they did not have an INR ≥1.5 at the time of their liver biopsy. This resulted in a final cohort of 26 liver biopsies performed in 26 patients with PALF that met our inclusion criteria (Table 1). The majority of patients (n = 22, 85%) had ALF due to primary liver disease: 10 indeterminate diagnosis, 3 immune dysregulation, 3 mitochondrial disease, 2 acetaminophen toxicity, 1 autoimmune hepatitis, 1 Epstein-Barr virus (EBV) infection, 1 Wilson disease, and 1 primary hemophagocytic lymphohistiocytosis (HLH). Four patients presented with malignancy before developing ALF: 2 with acute lymphoblastic leukemia (ALL) who developed ALF secondary to HLH, 1 with ALL who developed ALF secondary to L-asparaginase toxicity, and 1 with Wilm's tumor who developed ALF secondary to sinusoidal obstruction syndrome. Patients were 54% male, with median age 6.3 years (range 0.3–16.7), and median weight 18.3 kg (range 6.9–97.0). Most biopsies (n = 17, 65%) were transjugular, with 5 (19%) percutaneous and 4 (15%) surgical. A needle biopsy was taken in 25 cases with 13 (52%) using a 19 gauge, 5 (20%) an 18 gauge, and 7 (28%) a 16 gauge needle. A median of 3 passes (range 1–7) into the liver were taken to obtain tissue. Of the surgical procedures, 1 case had a wedge biopsy and the remaining 3 had core biopsies. Before biopsy, median INR was 2.1 (IQR = 1.73–2.9) and median platelet count was 147,000 (IQR = 94,000–188,000) cells/μL. Table 2 compares patient characteristics by method of biopsy. Median INR was slightly higher for transjugular (2.4; IQR = 2.0–3.7) compared to percutaneous (1.8; IQR = 1.6–2.4) or surgical (1.8; IQR = 1.5–2.0) biopsies. Twenty-three (88%) patients received blood product transfusions before or during their biopsy procedure, primarily to improve coagulation status. Eighteen patients were given FFP alone, 1 patient was given FFP and cryoglobulin, 1 patient was given FFP and recombinant factor VIIa, and 1 patient was given cryoglobulin alone. One patient was given a platelet transfusion alone for a pre-biopsy platelet value of 32,000 cells/μL that improved to 178,000 cells/μL. One patient with ALF secondary to ALL and HLH received multiple blood products pre-biopsy including FFP, platelets for pre-biopsy platelet value of 52,000 cells/μL that improved to 63,000 cells/μL, and packed red blood cells for a Hgb of 6.4 g/dL that improved to 11.5 g/dL at the time of biopsy. Three patients did not receive any peri-procedure blood products: 2 had transjugular biopsies (INR 1.5 and 2.1, respectively), and 1 had a surgical biopsy (INR 2) and there were no complications. Three patients had pre-biopsy platelets <50,000 cells/μL, but given that the procedure was transjugular platelet transfusion was not deemed necessary, and there were no complications.

T1
TABLE 1:
Patient characteristics; n = 26
T2
TABLE 2:
Patient Characteristics by Biopsy Type

There was 1 major procedure-related complication (3.8%), in a 9-year old female who presented with ALF of unknown etiology. She was treated with N-acetylcysteine after drug exposure history revealed several days of therapeutic acetaminophen use (serum level undetected). Transjugular liver biopsy was performed with 7 passes into the liver with a 19-gauge needle. Pre-biopsy INR was 3.1 and she received FFP during the procedure. A 3.8-g/dL drop in Hgb was noted within 48 hours post-biopsy (from 10.4 to 6.6 g/dL) which was attributed to biopsy-related bleeding. She was monitored in the intensive care unit and did not have any hemodynamic instability or clinical symptoms. No additional abdominal imaging was performed. Her Hgb stabilized after 1 pRBC transfusion with no further evidence of bleeding and she recovered from her ALF with her native liver. Liver biopsy was notable for prominent centrilobular necrosis suggesting injury secondary to acetaminophen toxicity. Based on this evidence, N-acetylcysteine therapy was continued and final diagnosis was chronic acetaminophen toxicity. There were no other major complications.

An additional 3 patients had an isolated decrease in Hgb of at least 2 g/dL (range 2.1–2.9 g/dL) within 48 hours post-biopsy that was attributed to biopsy-related bleeding. These patients had no hemodynamic instability or clinical symptoms associated with the Hgb decrease and no interventions were performed. Two patients with PALF-associated multi-system organ failure (MSOF) received multiple blood products before and after the liver biopsy, but were not judged to have biopsy-related bleeding. The first patient was a 9-year old male presenting with ALF secondary to mitochondrial disease who received FFP and recombinant factor VIIa before transjugular biopsy (INR 6.7). He continued to receive FFP, and platelet transfusions post-biopsy and died 2 days later from complications of his MSOF. The second patient was a 13-year old male with ALL who presented with ALF secondary to HLH. He received multiple blood product transfusions before and after liver biopsy for MSOF and lower gastrointestinal bleeding. He had a wedge liver biopsy performed during an open abdominal exploration. He died several weeks later from complications of MSOF, sepsis, and his underlying malignancy.

The majority of patients survived until hospital discharge (n = 22, 85%) while 4 (15%) died during the PALF admission. Of the 22 patients who survived, 18 (82%) were discharged with their native liver and 4 (18%) underwent liver transplant. Median duration of hospital admission was 11 days (range 3–118). Biopsy results contributed to establishing a diagnosis, as documented in the chart by the managing physician, in 16 (62%) cases, which are described in the Supplemental Table (Supplemental Digital Content, https://links.lww.com/MPG/B449). For the remaining 10 cases no etiology was identified and the final diagnosis was indeterminate ALF. In 9 of the 16 cases where a diagnosis was made, biopsy results helped guide treatment and management. This included 3 patients with ALF associated with immune dysregulation who were treated with steroids based on clinical features and an inflammatory infiltrate on biopsy. A pattern of centrilobular necrosis confirmed chronic acetaminophen toxicity in 2 patients, one with a negative and one with a low-detectable acetaminophen level, and influenced the decision to continue N-acetylcysteine therapy. Histology is not part of the diagnostic criteria for HLH, but characteristic liver biopsy findings (hemophagocytosis, predominance of CD8+ T-cells and macrophages) supported this diagnosis in 2 patients with high clinical suspicion, and influenced the decision to start treatment. For both patients, therapy was initiated with corticosteroids and later followed by chemotherapy when they progressed to meet accepted HLH diagnostic criteria. One patient with a positive antinuclear antibody titer and biopsy consistent with autoimmune hepatitis was treated with intravenous corticosteroids, and 1 patient with low serum ceruloplasmin, elevated 24-hour urine copper, and liver biopsy histology consistent with diagnosis of Wilson disease was treated with chelation therapy. In 7 additional patients, biopsy results contributed to making a diagnosis but did not significantly change management. This included 3 patients with abnormal mitochondria on electron microscopy who were diagnosed with mitochondrial disease and confirmed with subsequent genetic testing, 1 patient with sinusoidal obstruction syndrome, 1 with secondary HLH, 1 with L-asparaginase toxicity, and 1 with EBV infection.

DISCUSSION

This single-center review demonstrates that liver biopsy can be safely performed in most children with ALF due to a range of etiologies. In our series, 1 patient with post-biopsy bleeding requiring a blood transfusion was the only major complication (3.8%) and there were no procedure-related deaths. This patient received FFP before the procedure and underwent a transjugular biopsy with more passes into the liver (n = 7) than most cases. However, larger series have not identified increased passes as a risk factor for major complications in transjugular biopsies (12,19). Three additional patients had minimal post-biopsy bleeding not requiring any intervention. This is similar to the reported incidence in the literature of major complications after pediatric liver biopsy for any cause, with bleeding being the most common complication. A 2007 systematic review of transjugular liver biopsy complications found 3 major complications (1.9%) and 1 death (0.6%) in 4 pediatric studies that included 156 biopsies in 142 patients (12). In some publications, cancer or bone marrow transplantation have been identified as risk factors for major complications after liver biopsy in children (14,20). Our numbers were small (n = 5), but none of the patients with PALF and malignancy in our study had a major complication. The majority of adult studies report <1% incidence of major complications after transjugular liver biopsy (9,12,21). The reported incidence of major complications after percutaneous liver biopsy in children ranges from 0 to 4.6% (13–17) and may be increased in young infants (22). Pediatric patients who undergo liver biopsy as an outpatient procedure have the lowest risk of complications, with a major complication rate of 0–0.3% (18,23).

This is the first study to examine the risk of major liver biopsy-related complications in pediatric patients with ALF. Few adult studies have addressed this sub-group and report rare liver biopsy-related major complications in adults with ALF. This includes a series by Miraglia et al who found no complications of transjugular biopsy in 17 patients with ALF (24). Similarly, Donaldson et al reported no major complications of transjugular biopsy in 64 patients (10 pediatric) with fulminant liver failure (25). One major complication (1.4%) was reported in a series by Esposito et al of 74 patients with severe liver dysfunction who underwent transjugular biopsy (8). One pediatric study has reported that PALF is a risk factor for major complications after percutaneous liver biopsy (13). They identified 4 (1.5%) major complications after 275 biopsies in 190 children, 2 of which were in patients with ALF (1 with intra-abdominal hematoma and 1 with variceal bleeding).

Previous publications questioning the role of liver biopsy in PALF did so based on the assumption that biopsy in this setting is high risk and does not increase diagnostic yield or alter management (10). We found 1 major complication after liver biopsy for PALF, and histopathologic results contributed to the diagnosis in the majority of cases and in over half of those influenced treatment and management decisions. Determining to what degree a biopsy influences clinical decision making is a subjective assessment, however we would argue there are few cases where useful information is not gained by reviewing liver histology. A study of 30 consecutive transjugular biopsies in 27 children with liver disease (at least one-third with ALF) reported biopsy results changed the diagnosis in 30% and in most cases added valuable information (26). Adult studies have similarly reported that liver biopsy results confirmed the clinical diagnosis in most patients with ALF and in a smaller percentage either clarified clinical uncertainty, identified the presence of unknown cirrhosis, or altered the diagnosis (8,24,25). This is in agreement with the American Association for the Study of Liver Diseases recommendations, which state liver biopsy may provide important diagnostic information in patients with ALF and in some cases is helpful in making a specific diagnosis to guide therapy (27,28).

Limitations of this study include the small sample size and retrospective design. Given our reliance on documentation in the medical record, it is possible some minor biopsy complications may not have been recorded. However, it is very unlikely a major complication was missed, as this type of event would have been noted in multiple areas of the medical record. We also relied on physician documentation when determining to what degree the biopsy results influenced management, which is a subjective assessment.

In conclusion, liver biopsy can be safely performed in most pediatric patients with ALF and a 10-year experience at a large pediatric liver center resulted in few major complications and no procedure-related deaths. Clinicians should consider performing liver biopsy early in PALF, especially when the transjugular approach is feasible, since findings may guide diagnosis and therapy.

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Keywords:

interventional radiology; percutaneous ultrasound guided; transjugular

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