Complications of percutaneous liver biopsy with Klatskin needles- a 36-year single-center experience

Abstract

Background

Liver biopsy is the gold standard in evaluating liver diseases but is susceptible to complications. Safety data on aspiration needle biopsies remains limited.

Aim

To evaluate the safety of percutaneous liver biopsy performed with Klatskin needle.

Methods

Clinical and biochemical data were retrospectively retrieved from sequential subjects who underwent liver biopsy with Klatskin needle from 1978 to 2015. Subjects with complications underwent thorough chart reviews for hospital course.

Results

Of 3,357 biopsies performed, complications occurred in 135(4%) biopsies with 33(1%) resulting in major complications. Severe pain occurred in 78(2.3%) subjects and bleeding occurred in 21(0.6%) subjects. Biliary injury occurred in 8(0.2%) biopsies. Three subjects died as a result of massive intraperitoneal bleeding. Compared to viral hepatitis, biopsies performed with certain diagnosis had significantly higher odds of major complications: NRH (OR:17), DILI (OR:20), GVHD (OR:32) and HCC (OR:34). Subjects with major complications had higher pre-biopsy median AP (153 vs 78 U/L, p<0.001), ALT (105 vs 64 U/L, p<0.05), AST (62 vs 47 U/L, p<0.02), along with marginally lower total bilirubin (1.0 vs 0.7 mg/dL) and albumin (3.7 vs 4.0 g/dL, p<0.001). By multivariate backward logistic regression, platelets ≤100 K/uL and aPTT>35 were independent risk factors of post-biopsy bleeding.

Conclusion

Klatskin needle liver biopsies are safe with rare procedural morbidity. Our data suggests certain acutely ill subjects and those with systemic illnesses may be at higher risk of major complications. Clinicians should weigh the risks and benefits of liver biopsy in these patients with other alternative approaches.

Introduction

Since the first liver aspirate performed in 1883 and the first percutaneous biopsy in the 1920s, the role of obtaining liver tissue has been an invaluable tool in the evaluation, staging and monitoring of liver disease (1,2). Today, the most commonly used liver biopsy devices include core-aspiration needles (Menghini, Jamshidi, or Klatskin) and sheathed cutting needles(3). Despite advances in medicine, such as imaging of the liver by ultrasound, computed tomography and magnetic resonance and liver stiffness measurement by vibration-controlled transient elastography and MR elastography, liver biopsy continues to be the diagnostic “gold standard” in the evaluation of various liver diseases and a mainstay in medical management(4). This is because newer modalities are often unable to provide diagnostic specifics that require direct visualization of hepatic tissue. Histologic examination allows for the evaluation of unexplained liver diseases(5), drug-induced liver injury, or for establishing diagnosis of systemic disorders with hepatic manifestations such as graft-vs-host disease(6) and nodular regenerative hyperplasia(7). Further, in diseases such as autoimmune hepatitis, liver biopsy remains a mainstay in diagnosis and disease management(8).

Despite the established utility of liver biopsy in the management of liver disease, this invasive procedure is not without drawbacks. Aside from pre-procedural patient anxiety and procedural costs, the most important aspect of liver biopsy is the risk for post-procedure complications. The different types of complications associated with liver biopsies and its rates have been well studied over the past 30–40 years, with several professional societies establishing guidance on performance and safety of this procedure(3,9). Minor complications include moderate to severe biopsy-related pain(10,11) or peri-procedural hypotension. The most common major complication is post-biopsy bleeding, which occurs in 0.8% and 1.8% of liver biopsies performed(12–16). Other major complications include injury to other viscera including gallbladder and biliary injury and pneumothorax among others(17,18). Procedure-related death is a rare event, occurring in 0% to 0.14% of cases in published literature(12–17), and is almost always a result of major bleeding. Several factors are thought to influence complication rates including, biopsy of mass lesions, advanced liver disease, low platelet counts(19) and impaired coagulation status(20). Some studies have attempted to address operator experience(17,21–23), however, the literature remains unclear in regard to the impact of these variables.

The Liver Diseases Branch of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) at the National Institutes of Health (NIH) has performed percutaneous liver biopsies for a myriad of primary parenchymal liver diseases, systemic disorders and for acute unexplained liver injury for both clinical care and clinical research purposes for over 36 years. Thus, we sought to identify and characterize the incidence of liver biopsy complications, identify potential risk factors for experiencing a major liver biopsy complication and to describe the clinical course of subjects with major complications.

Methods

Study Setting

This retrospective study was performed using a cohort of patients who underwent liver biopsy at the Clinical Center of the National Institutes of Health from June 1978 to April 2015. The analysis included all subjects who underwent a liver biopsy as a part of a clinical research study performed by the Liver Diseases Branch of the NIDDK or for clinically indicated purposes as part of a hepatology consult evaluation at the NIH Clinical Center. As routine practice, all subjects were required to refrain from NSAID or aspirin use for at least 10 days, underwent pre-biopsy laboratory examination including a complete blood count (CBC) including platelet count, hepatic panel, prothrombin time (PT)/international normalized ratio (INR), and a 6 hour post-biopsy CBC.

Liver Biopsy Specifics

Before 1988, identification of a suitable liver biopsy site was performed via the transthoracic palpation/percussion technique. Beginning in 1988, identification of a suitable biopsy site was performed by a radiologist in the radiology suite with transthoracic ultrasonography before the biopsy. Starting in 2002, a transthoracic, image guided liver biopsy technique was instituted in which the liver biopsy operator performed a bedside ultrasound at the time of liver biopsy. All biopsies were performed in right lobe of the liver percutaneously by fellows-in-training under the supervision of an attending hepatologist or solely by an attending hepatologist. Biopsies were performed with a 16-gauge Klatskin core aspiration needle (Becton-Dickinson Co., Rutherford, N.J., U.S.A. and Popper & Sons Inc., New Hyde Park, N.Y., U.S.A.) with few exceptions where a “Tru-cut style” spring-loaded device (Argon Medical Devices, Athens, T.X., U.S.A) was utilized for known cirrhotic patients (<1%). Sedation was administered during the procedure with meperidine and midazolam. Post-procedure, patients were monitored on bed rest for 6 hours and most patients remained overnight for study related purposes. For biopsies performed as a part of a clinical research protocol, subjects were admitted to the NIH Clinical Center at least 12 hours before the liver biopsy and were closely monitored for at least 24 hours after the biopsy. Post biopsy, subjects were brought back to the outpatient clinic for follow-up 1–2 weeks after the procedure for evaluation and review of biopsy findings. For biopsies performed for clinical consultative purposes, patients were either already admitted for evaluation and therapy of their primary diseases and the liver biopsy was performed during their inpatient stay with extensive post-biopsy monitoring as inpatients or they were admitted for the purposes of the liver biopsy and also monitored closely for at least 24 hours after the biopsy and were also brought back to the outpatient clinic for evaluation and review of results.

Liver Histopathology

The review of liver biopsies was done by an expert hepatopathologist (D.E.K.). Clinical fellows-in-training and the hepatopathologist maintained a manual record of data pertaining to biopsy-related complications along with histological scoring since 1978. Liver biopsies were scored for the degree necroinflammation, fibrosis and evaluated for definitive diagnosis, as appropriate. Necroinflammation was scored via the modified histologic activity index (HAI) scoring system(24). Hepatic fibrosis was scored either via METAVIR(25) or Ishak scoring systems(26).

Data Collection

Patients’ demographics including age (at time of liver biopsy), gender and diagnosis were collected and analyzed using the NIH Biomedical Translational Research Information System (BTRIS). Laboratory data were largely collected via electronic medical records (EMR); lab values on consult patients and on cases dating back prior to the introduction of EMR were captured through direct chart review by V.K.T and O.E. In total, pre-biopsy labs were retrieved on 2733 procedures, which were used for inferential analysis.

Post-liver biopsy complications were separated into major and minor complications. Major complications included post-biopsy bleeding, visceral injury and death. Minor complications included significant pain requiring further evaluation and peri-procedural hypotension among others. Medical charts of subjects with major complications were reviewed for clinical course and peri-biopsy events including procedure note, clinical course and outcome. Additionally, 500 charts of subjects who underwent uncomplicated liver biopsies were reviewed on a randomly selected basis to evaluate for biopsy specimen size documented in the procedure note.

Statistical Analysis

Statistical analysis was performed using SPSS® Statistics for Windows, Version 21.0, Armonk, NY: IBM Corp. Summary statistics of baseline data was presented as frequencies with percentages and median with interquartile range (IQR), when appropriate. Given low event rates, comparisons between groups were performed using non-parametric tests including, Fisher’s exact test for categorical variables and the Mann-Whitney U-test for continuous variables. Significance was observed at p<0.05.

For analysis of hematologic parameters for risk of post-biopsy bleeding, binary logistic regression using backward stepwise method was performed to assess risk with PT> 13.5 seconds, aPTT> 35 seconds and platelet count ≤ 100.

Results

Liver Biopsy Demographics

A total of 3,357 percutaneous liver biopsies were performed with a Klatskin needle during the study period (Figure 1). Of these, 2795 (83.3%) were performed for clinical research studies pertaining to liver disease for clinically indicated staging or research tissue procurement and 562 (16.7%) were for clinical consultative purposes. The most common reason for biopsy was histologic staging of chronic viral hepatitis (2227 [66.3%] biopsies). This was followed by diagnosis and staging of cholestatic liver disease, predominately primary biliary cirrhosis (PBC) (223 (6.6%) biopsies), NAFLD (194 (5.8%) biopsies) and multiple co-existing liver diagnosis (113 (3.4%) biopsies) (Figure 2a).

Figure 1.

Subject Selection for Analysis

Figure 2.

(a) Subcapsular post-biopsy hepatic bleed, (b) Massive intraperitoneal bleed following liver biopsy, (c) Gallbladder injury seen at 4x with end of the needle biopsy (arrowhead) on the left and the piece of gallbladder on the right (arrow), (d) Gallbladder seen at 10x with gallbladder mucosa, the muscularis and the Rokitansky Aschoff sinus beneath the muscle.

Aside from the diagnoses above, there were a group of 382 clinical biopsies (11.4%) for abnormal liver tests that included mostly consultations with primary diagnoses including genetic immune deficiencies, graft-versus-host disease, primary hereditary hemochromatosis, sickle cell disease and glycogen storage diseases. Sixty-seven (2.0%) biopsies were undiagnosed and 11 (0.3%) had normal hepatic parenchyma.

Semi-quantitative histopathologic scoring was available on 2940 (87%) biopsies. Bridging fibrosis, F≥3 was noted in 1591 biopsies with 341 (12%) being cirrhotic. HAI scoring was available on these subjects as well with total HAI≥9 in 896 (31%) of biopsies. Viral hepatitis biopsies were most likely to have semi quantitative scoring making up 75% of the scored cohort.

Liver Biopsy Complications

Of 3,357 percutaneous liver biopsies, complications occurred in 135 subjects, resulting in a complication rate of 4.0% (Table 1). Minor complications were 102 (3.0%) and major were 33 (1.0%). Of the minor complications, severe pain occurred in 78 (2.3%) subjects and was the most common overall complication. Peri-procedural hypotension or vasovagal episodes requiring medical intervention occurred with 17 biopsies (0.5%). Other minor complications included acute migraine attack and atelectasis occurred in 2 (0.2%) subjects.

Table 1.

Total Number of Complications in patients undergoing percutaneous liver biopsy

Minor Complication	N	% of Total Biopsies
Severe Pain	78	2.3%
Vasovagal or procedural hypotension	17	0.5%
Others*	7	0.2%
Major Complication	N	% of Total Biopsies
Bleeding	21	0.63%
Gallbladder or Biliary injury	8	0.24%
Inadvertent Renal Biopsy	2	0.06%
Pneumothorax	1	0.03%
TIA	1	0.03%
Death (all bleeding)	3	0.09%

^*Include severe migraine attack and atelectasis

Major complications occurred with 33 biopsies (1.0%). Post-procedural bleeding was the most common major complication with 21 events (0.6%). Gallbladder or biliary injury occurred in 8 biopsies (0.2%). Other major complications included 2 inadvertent renal biopsies, 1 pneumothorax, 1 hypotension-induced cerebral transient ischemic attack. There were 3 deaths (0.1%) that were all due to massive intraperitoneal bleeding post-liver biopsy.

During the period until 1998, where the transthoracic palpation/percussion technique was utilized to identify a suitable liver biopsy site, 7 major complications had occurred. From 1998 through 2002 where transthoracic ultrasonography was performed in the radiology suite prior to biopsy, 19 major complications occurred. From 2002 onwards, when bedside ultrasonography was performed at the time of liver biopsy, 7 major complications occurred. On comparison of the occurrences of complications by total complications to total biopsies performed with each modality, no statistical difference (OR: 1.2 (0.5–2.9) p=0.08) was identified. Notably, since the initiation of bedside ultrasonography, no gallbladder or biliary complications had occurred.

Pre-biopsy clinical and laboratory differences among all major complications

Of the 3,357 percutaneous liver biopsies performed, complete pre-procedural clinical and laboratory data was available for 2,733 biopsies including all 33 with major complications (Table 2). Due to conversions from paper to electronic medical record (EMR) management and changes in EMR systems in the 1990’s, 623 subjects were missing pre-biopsy labs and could not be included in this portion of the analysis. Review of the medical records of these 623 subjects revealed no liver biopsy complications. Subjects with major complications were marginally older with a median age of 50.6 years compared to 45.8 years for all other subjects (p<0.05). Liver biopsies performed for consultative purposes had a higher percentage of major complications compared to research liver biopsies (33% versus 17%, p<0.02). Other basic demographic data was similar including gender and body-mass index.

Table 2.

Univariate Analysis of Basic demographics, clinical and laboratory features of subjects undergoing liver biopsy

Criteria	N	(a) No Major Complication	(b) All Major complications (n=33)	(c) Bleeding Complications (n=21)	P value
		Median (IQR), %	Median (IQR), %	Median (IQR), %	a vs b	a vs c
Age (years)	3357	46 (37–57)	51 (26–65)	51 (18–63)	0.05	0.35
Male, %	3357	61%	61%	67%	0.88	0.75
Consult Biopsy %	3357	17%	33%	33%	0.02	0.02
Pre-Biopsy Laboratory Data
AP (U/L)	2706	78 (63–115)	153 (93–593)	147 (79–658)	0.001	0.001
ALT (U/L)	2733	64 (32–116)	105 (54–147)	97 (56–138)	0.05	0.23
AST (U/L)	2733	47 (22–76)	62 (50–152)	61 (42–163)	0.02	0.11
Total Bilirubin (mg/dL)	2277	0.7 (0.4–0.9)	1 (0.7–6.5)	1.2 (0.7–11.3)	0.01	0.004
Albumin (g/dL)	2266	4.0 (3.6–4.2)	3.7 (2.6–3.9)	3.5 (2.6–3.9)	0.001	0.001
Creatinine (mg/dL)	2287	0.9 (0.6–0.9)	0.9 (0.8–1.1)	0.9 (0.3–0.9)	0.53	0.94
Platelets (K/uL)	2313	193 (148–242)	180 (97–262)	175 (86–251)	0.44	0.18
Platelets <60 K/uL, %	2313	0.30%	3.00%	4.80%	0.29	0.14
PT (seconds)	2259	12.9 (12.7– 14.0)	12.9 (12.6– 13.5)	13.0 (12.4– 13.3)	0.66	0.42
aPTT (seconds)	1901	29.8 (27.5– 32.6)	29.5 (26.9– 37.8)	30.2 (27.2– 38.5)	0.56	0.3
Biopsy Characteristic
Biopsy size (mm)	513	17 (13–23)	20 (11–36)	20 (11–33)	0.19	0.02

AP: Alkaline Phosphatase, ALT: Alanine aminotransferase, AST: Aspartate aminotransferase, PT: Prothrombin Time, aPTT: activated partial thromboplastin time

Pre-biopsy laboratory data revealed some differences between those with major complications and those without complications (Table 2). Alkaline phosphate (AP) was significantly higher in the major complication group compared to those without complications (153 U/L vs 78 U/L, p<0.001) as was alanine aminotransferase (ALT) (105 U/L vs 64 U/L, p<0.05) and aspartate aminotransferase (AST) (62 U/L vs 47 U/L, p<0.02). Total bilirubin was significantly higher in the major complication group (1.0 mg/dL vs 0.7 mg/dL, p<0.01) and serum albumin was lower in the major complication group (3.7 g/dL versus 4.0 g/dL, p<0.001). Pre-biopsy serum creatinine, platelet count, prothrombin time (PT) and aPTT were not different between groups.

Histopathologic scoring was available for 23 out of 33 subjects with major complications. 11 of the 23 subjects had METAVIR Fibrosis scores ≥ 3 with 5 having cirrhosis. And of the 5 subjects with cirrhosis, 4 experienced a major complication of bleeding and one had gallbladder injury. The mean METAVIR fibrosis stage between those with and without major complications was not statistically different in the entire cohort or in the subset of patients with viral hepatitis.

Pre-biopsy clinical and laboratory differences in subjects with bleeding complications

In comparing the group with bleeding complications with those without bleeding, several differences were identified. AP was higher in the bleeding group compared to the group without bleeding (147 U/L vs 78 U/L, p<0.001). The bleeding group also had higher total bilirubin (1.2 mg/dL vs 0.7 mg/dL, p<0.01) and lower albumin levels (3.5 g/dL vs 4.0 g/dL, p<0.001). All remaining parameters were not significantly different compared to subjects without major complications (Table 1). On further assessment of hematologic parameters, the result of multivariate backward stepwise logistic regression revealed that aPTT>35 seconds with OR of 4.2 (CI 1.6 to 11.0, p<0.005) and platelet count ≤ 100 K/uL with OR: 4.1 (CI 1.5 to 11.1, p<0.01) were independent predictors of bleed risk. More importantly, PT>13.5 seconds was dropped out of the model for insignificance (Supplemental Table S1).

Etiology of disease in subjects with major complications

The etiology of liver disease in subjects who had complications was explored. As expected, because of the large number of biopsies performed in patients with viral hepatitis, it resulted in the highest number of total complications (n=86, 3.9%)

For minor complications, severe pain was most frequent with the highest occurrence in viral hepatitis at 58 biopsies (2.6%) followed by 8 (0.4%) in cholestatic liver diseases. Peri-procedural hypotension was also encountered highest in the viral hepatitis biopsies at 15 (0.7%) with the remaining 2 (0.1%) in cholestatic liver disease.

Major complications did not follow the same rate as the minor complications. Though viral hepatitis had highest number of major complications at 13, the major complication-biopsy ratio was at only 0.6%. Certain disease states had much major complication-biopsy ratio ranging from 16.7% in HCC to 3.2% in PBC. On further evaluation, the odds ratio for major complications was significantly higher in these disease categories including NRH at 17, DILI at 20, GVHD at 32 and HCC at 34 (Table 3).

Table 3.

Frequency of Major complication by Disease Etiology undergoing percutaneous liver biopsy

Etiology of Liver Disease	Major Complication	Total Biopsies	% Major /Total	Odds Ratio (to Viral Hepatitis)	P value
Viral Illness	13	2227	0.6	-
Glycogen Storage Disease	1	45	2.2	3.8 (0.5–29.6)	0.68
Undiagnosed	1	67	1.5	2.6 (0.3–20.0)	0.88
Mixed Viral	1	113	0.9	1.5 (0.2–11.7)	0.83
PBC	7	222	3.2	5.5 (2.2–14.1)	<0.001
NRH	2	22	5.1	17.0 (3.6–80.5)	<0.001
DILI	4	39	10.5	19.5 (6.0–62.7)	<0.001
GVHD	3	19	15.8	31.9 (8.3–123.0)	<0.001
HCC	1	6	16.7	34.1 (3.7–312.3)	<0.05

PBC: primary biliary cholangitis, NRH: nodular regenerative hyperplasia, DILI: drug-induced liver injury, GVHD: graft-vs-host disease, HCC: hepatocellular carcinoma

Clinical course of Subjects with Major Complications

Bleeding Subjects

Of the 21 liver biopsies complicated with bleeding, 20 had complete charts for review. Nine subjects had a previous history of bleeding diathesis, one subject had 3 liver biopsy pass attempts and two subjects had 2 liver biopsy pass attempts. All but two bleeding complications were detectable in the first 4 hours post-biopsy.

Of the 20 subjects, ten had bleeding that was localized to the liver; 9 with subcapsular bleeding (Figure 2a) and 1 with an intrahepatic bleeding. The other 10 subjects experienced intraperitoneal bleeding (Figure 2b). There were no differences in prior history of post-procedure bleeding (5 versus 4), biopsy size (21.8 5.8 mm versus 23.0±13.0 mm) or number of pass attempts between localized and intraperitoneal bleeders. Additionally, there was no difference in the number of subjects requiring transfusion between localized and peritoneal bleeds, though the total units transfused were higher in peritoneal bleeders. Low-grade fever was a common feature and was present in 4 localized bleeds and 6 intraperitoneal bleeds.

Subjects with localized bleeding were more likely to have an initial presentation of right upper quadrant abdominal pain (n=9) compared to intraperitoneal bleeders (n=2) (p<0.01). Three subjects with localized bleeding experienced hypotension. For subjects with localized bleeding, the median length of stay was 5.5 (4.8–12.3) days. Two localized and two intraperitoneal bleeding episodes required interventional radiology for arterial embolization, however, the procedure was only successful in the localized bleeders.

In subjects with intraperitoneal bleeding, 6 of the 10 subjects (60%) had diffuse abdominal pain with peritoneal signs and hypotension as the initial presentation. In three peritoneal bleeders, including the two in whom arterial embolization was unsuccessful, surgery was attempted. All three of these subjects died due to intraperitoneal hemorrhage. The median length of stay for intraperitoneal bleeders was 5.0 (3.5–10) days.

All three liver biopsy related deaths followed a similar clinical pathway and occurred 48–72 hours after the procedure. All subjects were acutely ill prior to the procedure. One subject had decompensated HCV cirrhosis with multiple inpatient visits over the last 6 months who was biopsied for a focal lesion. The second subject had decompensated cirrhosis with underlying glycogen storage disease. The last subject had GVHD with hepatic involvement with a poorly engrafted bone marrow with severe GVHD with need for escalation of therapy to prevent liver failure. All developed hypovolemic shock from massive intraperitoneal hemorrhage and died from multi-organ failure and disseminated intravascular coagulopathy post-surgically.

Gallbladder and bile duct injury

Gallbladder and biliary injury occurred with 8 subjects (Figure 2c and 2d). Gallbladder puncture was diagnosed in 6 biopsies and 2 had intrahepatic bile duct injury. Liver biopsy pass attempt data was available in 6 subjects. Five subjects had a single pass attempt and one subject had 2 pass attempts. The mean biopsy size was 20±18 mm. Fever and right upper quadrant pain were the predominant features. Conservative management was attempted in all subjects with four subjects started on empiric antibiotics for fever. While five subjects recovered without surgical intervention, three with gallbladder puncture required cholecystectomy. The mean length of stay was 11±5.3 days. Most notably, after institution of bedside ultrasound in 2002, there have been no gallbladder or biliary injuries.

Discussion

In this large retrospective analysis of liver biopsy complications at a single-center with variable liver diagnoses, we provide the first comprehensive description of liver biopsy complications with a Klatskin core-aspiration needle over a 36 years period. In addition to confirming several published experiences related to liver biopsy complications, we also identified several new findings including the risk of complications being higher in diagnoses other than viral hepatitis and differences in clinical presentations of localized and intraperitoneal post-biopsy bleeding. In our cohort, the overall (4%) and major (1%) complication rate of percutaneous liver biopsy was comparable to other descriptions utilizing other liver biopsy needles (12,15–17,19,22,27,28). Similar to previous descriptions, post-biopsy pain was the most common overall complication while bleeding was the most common major complication(3). In those with post-biopsy bleeding, no single coagulation or hemostatic parameter was able to distinguish between bleeding subjects when compared to non-bleeding subjects.

Although there is widespread use of sheathed cutting needles, various clinicians continue to utilize core-aspiration needles such as the Klatskin, Menghini or Jamshidi. While sheathed cutting needles (such as the “tru-cut” style needles) are more advantageous in biopsies performed in cirrhotic patients (due to fragmentation of tissue by suctioning forces of core-aspiration needles), core-aspiration needles have a greater trough length which allows for obtaining more liver tissue in a single pass(3). Thus, the use of core-aspiration needles, despite being technically more difficult with the requirement of maintaining suction, may have advantages in certain scenarios especially given that the risk of post-procedural bleeding increases with increasing number of passes (12,16) and cutting needles may have a slightly higher risk for complications (15,29). In our cohort, we demonstrated a similar post-biopsy bleeding rate at 0.6% compared published reports of cutting needles(13,15). Although this is not a direct comparison, it does give further evidence that the rate of major complications with percutaneous liver biopsies is quite low when performed in multiple different settings.

Although our description is uniquely with a Klatskin needle, our complication rates appear to be in line with other reports utilizing core-aspiration needles, namely the Jamshidi and Menghini needles. In a large cohort that reported their experience with the Jamshidi needle, the rate of major complications was similar to our experience (0.9% vs 1.0%, respectively)(30). Regarding the Menghini needle experience, two large studies have described a major complication rate ranging from 0.1–0.3%(13,15) and a rate of severe pain at 3%. Although this is not a direct comparison, these rates at face value appear similar. While a direct comparative study between core-aspiration needles would aid in identifying superiority, this is unlikely to occur given the widespread use of cutting needles for its simplicity.

We found that the risk of post-biopsy bleeding was increased in subjects who had the combination of an elevated aPTT and thrombocytopenia less than 100 K/uL but not with elevated PT. The coagulation defects in liver disease have been described(31–33) with a complex milieu of derangements of PT, aPTT, d-dimer, fibrinogen and thrombocytopenia. The defects in aPTT can occur with relative reduction in factor VIII as the liver disease worsens in both the acutely ill patients and those with underlying chronic liver disease(34,35). Thrombocytopenia is usually seen in progression of portal hypertension in cirrhotics, in acute illness or reduced bone marrow production in patients who have liver GVHD. Interestingly, PT, which is the function of the extrinsic pathway of hemostasis and dependent of hepatic production, was not found to be an independent risk factor for post-biopsy bleeding. This finding is similar to a recent piece published by Drolz et al.(36), who compared coagulation parameters in major bleeding in critically ill patients with cirrhosis. Further confirmation of our findings is needed in patients undergoing invasive liver biopsies.

The risk of a major complication stratified by etiology was another important finding in this study. Similar to prior descriptions of an increased risk of bleeding in hospitalized patients, patients who experienced a major complication in our cohort were usually acutely ill and underwent an urgent liver biopsy for clinically indicated purposes for diagnostic, management or prognostication purposes(37). In our cohort, the diagnoses with acute illness or underappreciated liver disease included GVHD, DILI and NRH. Subjects that underwent a liver biopsy for the diagnosis of GVHD of the liver post-stem cell transplantation often had lower platelets due to incomplete marrow engraftment and poor coagulation parameters due to suboptimal nutritional status and declining hepatic function. Patients with severe DILI can be acutely ill with impaired coagulation due to impaired liver function(38). NRH is generally present in advanced hematologic diseases and connective tissue diseases with the severity of liver disease being under-appreciated(39). Overall, subjects that experienced a major complication displayed mildly higher liver enzymes and worse markers of hepatic synthetic function, which further suggests more active or advanced liver disease. The survey study by Piccinino et al, has similar findings with an increase in risk of complications with subjects who had biopsies for diagnoses other than viral hepatitis(15).

Another important finding in this study was the ability to characterize the pain and timing of major complications as our patients were routinely kept overnight post-liver biopsy. Patients with gallbladder and biliary injury typically presented with RUQ pain with low-grade fever as their initial presentation. Patients with subcapsular bleeding presented with localized RUQ or shoulder pain whereas those with intraperitoneal bleeding presented with diffuse abdominal pain with peritoneal features. Regarding the timing of presentations, although a majority of the complications occurred within 4 hours, two patients experienced late post-biopsy bleeding at 10 and 48 hours and one subject with gallbladder injury presented with right upper quadrant pain diagnosed 24-hours post-procedure. Since most biopsies are performed on an outpatient basis, this highlights the importance that post-biopsy complications may be identified late and patients should be informed to maintain a high level of awareness to seek medical care if symptoms arise.

This study has several limitations. First, a subset of subjects was missing laboratory data with inferential analysis especially for hematologic and coagulation studies making inferential analysis for bleeding risk difficult. Second, procedural data for number of passes during biopsy was not available for the entire cohort. Finally, the complication event rate was low, therefore, more sophisticated inferential analysis was not possible. However, this study represents the only series evaluating the safety of percutaneous liver biopsy by Klatskin needle in patients with varied etiologies of liver disease.

In conclusion, although percutaneous liver biopsies can result in complications ranging from severe pain to death, these are rare occurrences. The benefits of this invasive procedure still outweigh the potential risks, however, with the appropriate patient selection, these risks may be minimized. Education of patients regarding procedural risks and post procedural monitoring may help to identify complications before they become life threatening. In the era of continued medical advances such as novel fibrosis biomarkers and advanced imaging techniques, percutaneous liver biopsy with the Klatskin aspiration needle is a safe diagnostic and staging modality with rare procedural morbidity and mortality.

Abbreviations

ALT

alanine aminotransferase

AST

aspartate aminotransferase

AP

alkaline phosphatase

TBili

total bilirubin

Alb

serum albumin

aPTT

partial thromboplastin time

INR

International normalized ratio

CBC

complete blood count

HCC

hepatocellular carcinoma

Ishak

Ishak fibrosis score

HAI

histology activity index

AASLD

American Association for the Study of Liver Disease

NIH

National Institutes of Health

NIDDK

National Institute of Diabetes and Digestive and Kidney Diseases

PBC

primary biliary cholangitis

NAFLD

nonalcoholic fatty liver disease

NRH

nodular regenerative hyperplasia

DILI

drug-induced liver injury

GVHD

graft-versus-host disease

RUQ

right upper quadrant

SD

standard deviation

BTRIS

NIH biomedical translational information system

IQR

interquartile range

CI

confidence interval