Research and audit questions

In many aspects of liver biopsy, the evidence is weak. We recommend that there should be local and national audits for the major complications of liver biopsy; these should include evaluation of the various types of liver biopsy needle used to provide evidence for the safest and most effective needle units, and clinicians undertaking liver biopsies should ensure their own and centre’s complication rates are within accepted range; we recommend that there should be national standards, evidence-based where possible, about the training and competencies of those obtaining liver biopsies; we recommend that there is further research into the haematological parameters that preclude safe percutaneous biopsies and into interventions to reduce the risk of bleeding after liver biopsy

Introduction

A liver biopsy is a diagnostic test, which involves the removal of a small quantity of tissue from the liver, usually done under local anaesthetic, to allow microscopic examination of the liver.

Purpose of a liver biopsy

There are many causes of liver disease and it is sometimes difficult to diagnose and work out the best treatment using other tests such as non-invasive imaging techniques or blood tests.

The main reasons for a liver biopsy are to

• help clarify diagnosis;

• determine severity of liver damage or grade of tumour;

• help predict prognosis in a person with a known diagnosis;

• inform treatment decisions;

• monitor disease progression or response to treatment;

• obtain liver tissue for non-histological assessment (microbiology, biochemical, other);

• support research.

Meeting patient concerns

Some patients are anxious about having a biopsy, are unsure what it involves or why they have to have it, how long it takes or how much it is likely to hurt. The British Liver Trust has identified three key areas for improvement: communication, consent and post-biopsy information.

Risks of having a biopsy

Generally, liver biopsy is a safe procedure, but it is not free of risk. All invasive procedures have an associated risk of illness or disease (morbidity) or death (mortality). The reported risk of complications varies depending on the type of biopsy.

The risk of a biopsy needs to be balanced against the benefits that the findings of a biopsy will provide. The development of complications is not necessarily the fault or error of the healthcare professional. Some situations are associated with increased risk, such as where there is infection or obstruction in the liver or bile ducts, ascites (fluid in the abdomen) or pregnancy.

Complications

Complications are uncommon but there may be some mild pain or discomfort in the area of the biopsy. In a small number of cases there is some minor bleeding that soon stops.

After a biopsy, patients should seek medical advice when:

• Bleeding occurs from the site of the biopsy.

• The biopsy site becomes red, angry looking or swollen.

• A high temperature (fever) develops.

• The biopsy site is still painful after a few days and painkillers do not help.

In more severe and rarer cases, a blood transfusion and/or an operation is required to deal with the bleeding. On occasion it is possible for bile to leak from the liver internally. There is a small risk that the small wound will become infected after the biopsy.

Different techniques for undertaking a liver biopsy

There are various approaches to obtaining a liver biopsy.

What care should you receive after your liver biopsy?

Biopsies are usually done on the day and do not necessitate an overnight stay. You are expected to lie on your side and are observed for at least 3 hours to check there is no further bleeding. Any pain or discomfort experienced can usually be treated with painkillers.

The report may take 2 weeks or so to come back but if special tests are required, may be longer

Informed consent

Consent should be obtained from all patients prior to a liver biopsy in accordance with national guidelines. Consent must be voluntary, informed and the patient must have the mental capacity to decide. Information should be given orally and supplemented in written form using language that is comprehensible. The patient should be aware, in advance, of the benefits and risks of the procedure.

Where a biopsy is undertaken solely or partly for research purposes, patients must be fully informed and the procedure approved by the appropriate ethics committee/body in alignment with hospital regulations.

Monitoring after the liver biopsy

Patients are monitored so pain can be treated appropriately, and any complications detected and attended to early.

Discharge should happen only if your condition is stable—that is, when your circulation is acceptable/stable, there is no evidence of bleeding, blood pressure is normal and you do not have complaints of pain or shortness of breath.

Prior to discharge, you should be given oral and written instructions regarding further monitoring and day to day activities. This should include advice to rest and not drive motor vehicles, not to operate heavy machinery, not undertake strenuous activity or lift heavy objects for 48 hours.

If you experience any symptoms that would suggest discomfort, infection or injury, you should be instructed to contact the hospital and be provided with contact details how to do this.

What happens to the sample after the liver biopsy?

After the liver biopsy the sample is sent to a laboratory where it is assessed by a pathologist. It may take 2 weeks or more to obtain the report.

Samples from liver biopsies should be stored for 30 years. Reviewing biopsies over time can inform how the liver disease is progressing.

Professional responsibility

The decision to undertake a biopsy involves a number of clinicians with different specialist skills. You should have confidence that the decision to undertake a biopsy is correct and that the risks are carefully assessed.

All members of the team involved in the clinical decision-making should be aware of the risks and benefits in each individual case. Serious complications must be recorded and monitored.

Much clearer guidance on the competencies required and the training needed to undertake a liver biopsy should be developed.

Quality standards

For non-urgent biopsies, the interval between request and biopsy should be less than 4 weeks, regardless of which type of procedure is adopted.

All patients should be given oral and written information about the indications, benefits and risks of biopsy together with details of post-discharge support.

Clinical care

Following recent improvements in non-invasive tests, the indications for liver biopsy have decreased, although histology still remains invaluable in diagnosis and management of selected patients.7 There is no consensus on best practice.

The UK guidelines issued by the BSG were revised in 2004.2 3 Since then, there have been advances in technology that allow non-invasive assessment of the liver, better understanding of the clotting of blood and further information about the safety and risks of different needles. Review of practice around the UK (unpublished) suggests that the great majority of biopsies are obtained by radiologists under ultrasound guidance, but in a few centres some biopsies are still done on the ward without concurrent ultrasound guidance. There is considerable variation in many areas, such as the information given to patients, where the procedure is done, the haematological parameters allowing safe percutaneous biopsy, the competence required to do the biopsy, in the reporting of liver pathology and in professional accountability. An audit of the first 50 liver biopsies done in UK centres after 1 January 2008 showed that, of the 87 departments who responded, liver biopsy was done mainly by the radiologist (consultant 76%, trainee 19%, radiographer <1%), gastroenterologist (consultant 1%, trainee 3%), other (1%).8

The patient perspective

More work needs to be done to make the approach to liver biopsy completely patient facing. Patients have much anxiety about the procedure, often with a lack of understanding of what is involved, how long it takes and how much it may hurt. In 2017–2018, of the 1807 liver health enquiries received by the British Liver Trust helpline services, 23 were related specifically to liver biopsies. The online support community forum has been operational since 2012, and more than 3500 posts have discussed liver biopsies. Recently, the British Liver Trust reviewed the helpline services enquiries, liaised with their support group facilitator and collated feedback regarding commonly expressed concerns relating to their experience of liver biopsy. Three main areas of concern were identified:

1. Communication: Patients report clinicians saying they ‘needed a liver biopsy’ but not explaining why or discussing any alternative medical investigations.

2. Consent: Patients highlighted the importance of being given enough time to discuss the indications fully, alternatives, risks and benefits of liver biopsy as part of the consent procedure in a safe, quiet area, prior to the procedure taking place. Where possible, this should not be on the same day as the procedure and patients should have an opportunity to discuss any concerns (with healthcare professionals and with relatives and friends) and have time to come back with any questions and queries. Patients also expressed a need for the consent to be taken by a healthcare professional who was knowledgeable about liver biopsies.

3. Postprocedure care: Patients often reported being given little or no discharge information after the procedure, especially about pain, what analgesia to take and when/where to seek medical help, if needed.

The uncooperative patient

Patients may be unable to cooperate for a variety of reasons, including anxiety. During the process of obtaining a percutaneous liver biopsy, it is essential that the patient is cooperative as any untoward movement when the biopsy needle is in the hepatic parenchyma can lead to a tear of the liver and capsule, with subsequent significant bleeding and pain. If the patient is anxious, then sedation with midazolam can be considered, with no increased risk.11 General anaesthesia can be used when the risks are justified.

Extrahepatic biliary obstruction

Extrahepatic biliary obstruction is frequently stated to be a contraindication to liver biopsy because of the risks of biliary peritonitis, septicaemic shock and death.12 In one study, serious complications occurred in at least 2% of patients (including biliary peritonitis), and another study reported significant complications in 4% following percutaneous liver biopsy.13 With current imaging techniques (specifically, magnetic resonance cholangiopancreatography and endoscopic retrograde pancreatography), liver biopsy should be done for biliary obstruction only when there is doubt about the diagnosis and the benefit to the patient outweighs the risk.14

Where the biliary tree is dilated, a transjugular approach should be used because of the risks of biliary leak.

Bacterial cholangitis

The risk of inducing peritonitis and septic shock after liver biopsy has made cholangitis a relative contraindication. Bacteraemia after percutaneous biopsy of a non-infected liver occurs in up to 14% of biopsies.15 16

Ascites

Percutaneous biopsy of the liver in the presence of large volume ascites is considered a contraindication in many texts. The reasons for this vary and include technical challenges and the risk of uncontrollable bleeding into the ascites; however, the evidence for these concerns is weak. CT or ultrasound-guided liver biopsy in the presence of ascites does not seem to affect the complication rate.17 18

Notwithstanding these studies, if a liver biopsy is clinically indicated in a patient with large-volume ascites, an image-guided percutaneous biopsy following total paracentesis or a transjugular biopsy can be considered.

Amyloidosis

Because of early reports of haemorrhage and death of patients following liver biopsy,19 amyloidosis is often listed as a contraindication.20 One case series from 1961 showed an intraperitoneal bleed with conservative treatment in 1 of 18 patients.21 Current publications estimate the mortality of a liver biopsy in patients with amyloidosis at up to 5%.22 However, in patients who have had a liver biopsy for investigation of abnormal liver tests and who were unexpectedly found to have amyloidosis, the mortality and complication rate is lower than generally quoted. Since almost all patients with clinically significant liver amyloidosis have hepatomegaly and are of AL type, absence of serum and urine monoclonal immunoglobulins and serum light free chains makes such a diagnosis very unlikely.

If amyloidosis is strongly suspected, the diagnosis should be made by subcutaneous fat or rectal biopsy since most cases of amyloid are systemic. However, if suspicion is low and in hepatomegaly of uncertain aetiology, a liver biopsy can be justified, and we recommend the transjugular route.

Obesity

In the obese patient, it may be difficult to identify the liver by percussion. In this situation, the biopsy should be done under ultrasound guidance and in many cases the transjugular route might be preferable.

Pregnancy

Liver histology is rarely required in the management of the pregnant patient but may be helpful in the diagnosis of new onset liver abnormalities.23 In one small study, there was a small increased risk of premature birth, but no stillbirth was reported.24 In some non-life-threatening clinical conditions, it may be reasonable to wait until delivery of the baby. Thus, the benefits of biopsy need to be balanced against the risks to the mother and baby.

Focal lesions with a cystic element

Modern imaging techniques can often identify and categorise benign cystic lesions of the liver. Focal liver lesions with a cystic element may communicate with several structures, including the biliary tree, increasing the risk of biliary peritonitis after biopsy. Diagnostic fine needle aspiration may be used to evaluate these lesions.25–28 In the biopsy of focal lesions, risks may be increased if the lesion is highly vascular: the degree of risk will depend on whether the solid element of the lesion can be accessed without going through the cyst with the needle. Thus, the risk:benefit ratio will depend on the characteristics of the lesion.

Recommendation

• Where possible, risks should be minimised (such as sedation, drainage of ascites, biliary decompression) but biopsy is justified when the risks are outweighed by the benefits (strength of recommendation MODERATE; quality of evidence MODERATE).

Operator and operator experience

Historically, gastroenterologists or hepatologists obtained most liver biopsies, as a 'blind' procedure. With the increasing use of imaging to help obtain percutaneous liver biopsies (PLBs), most biopsies are obtained by radiologists or gastroenterologists who have adequate training with use of ultrasound scanning (USS) assistance or guidance. With more recent expansion of skills, other groups of operators, such as clinical nurse specialists and physician assistants, have become adept at carrying out liver biopsies. It is worth noting that, in the UK and some other countries, training in obtaining a liver biopsy is not a requirement for training in gastroenterology and hepatology, although training should include an understanding of the indications, procedures, benefits and risk.29 In the USA, training in liver biopsy is not a requirement for level 1 training in hepatology but is a mandatory part of the formal advanced training process.30

No randomised trials have explored the impact of operator experience on outcome of liver biopsies. Non-randomised studies have highlighted the importance of operator experience to improve safety and success of liver biopsy, although this has not always been shown, but studies have been relatively small.31 Although there is no defined minimum number, the 1991 BSG audit recorded a higher, though not significant, complication rate of 3.2% in operators who had performed fewer than 20 liver biopsies compared with 1.1% in operators who had performed >100 liver biopsies.32 Other large published series have demonstrated similar findings, suggesting operator experience improves the quality of sample obtained.33–36 These studies emphasise the importance of carrying out a high volume of liver biopsy procedures, supervised by an experienced operator, before embarking on the procedure unsupervised, irrespective of the clinical background of the operator.

Recommendation

• Hospital policies should include a formal process and governance framework to ensure an operator is suitably experienced to undertake liver biopsies independently (strength of recommendation STRONG; evidence HIGH).

Percutaneous liver biopsy

Percutaneous liver biopsy refers to a biopsy taken by inserting a needle directly through the skin into the liver parenchyma. This method of biopsy always breaches the liver capsule with the attendant risk of intraperitoneal bleeding. Classification is based on whether image guidance is used and whether the biopsy track is plugged at the end of the procedure.

Typically, a PLB can be done safely in a procedure room on a ward, in the imaging department or, when clinically necessary, by the bedside (portable). It is vital that the room is a clean environment suitable for undertaking minor procedures and has easy access to consumables required for performing the biopsy (procedure packs, biopsy needles, etc). If ultrasound guidance is being used, the procedure room should be able to house the ultrasound machine and have the facility to reduce the ambient lighting.

There should be access to interventional radiology services, on site or through formalised transfer pathways to a referral centre, in the event of haemorrhage requiring embolisation.

Transvenous liver biopsy

Disorders of coagulation and/or ascites are common in patients with liver disease. Under these circumstances, conventional percutaneous liver biopsy would be contraindicated because of the perceived increased haemorrhagic risk. A transvenous route provides an alternative approach to liver biopsy, which potentially avoids breach of the liver capsule and reduces the risk of bleeding.

A transvenous biopsy requires the use of fluoroscopic guidance and needs to be performed in an angiography suite in the interventional radiology department. Inherently, these rooms are clean environments, often theatre grade, suited for performing such invasive angiographic procedures.

Endoscopic ultrasound (EUS) guided liver biopsy

With increasing experience in the use of EUS in the liver, several series have reported its use in performing both non-targeted and targeted liver biopsies, with diagnostic yield of 90–100% and a low complication rate, even when using 19 G needles.102–104 One recent retrospective, non-randomised, single-centre study105 of 90 patients found that the biopsy specimens obtained by the percutaneous route, compared with the EUS route, gave significantly more portal tracts (13 vs 5) and were more likely to enable a histological diagnosis (100% vs 93%), although those patients in the ultrasound group had a significantly shorter hospital stay (median hospital stay 3 vs 4.2 hours) and reported less pain (median pain score 0 vs 3.5). A tip-core biopsy needle delivers bigger samples than fine-needle aspiration biopsy needles.106

Laparoscopic liver biopsy

The laparoscopic technique is long established and is used in patients with coagulopathy where TJLB is unavailable or has failed. It is also used when biopsy of a focal liver lesion is required in the setting of severe coagulopathy. It enables direct visualisation of the liver and coagulation of the biopsy site to control any bleeding. Previous cross-sectional imaging can inform the surgeon of any anatomical contraindications to laparoscopic biopsy, such as a large abdominal aortic aneurysm or adherent small bowel loops. A laparoscopic biopsy is performed in an operating theatre with appropriate infection control techniques.

Laparoscopic liver biopsy may be done via a conventional laparoscopy or mini-laparoscopy, with the latter performed under local anaesthesia and conscious sedation.107 108 Laparoscopic liver biopsy generally entails performing liver biopsy through the laparoscope port using a long cutting-type needle. There is limited literature on this technique; however, a retrospective comparative study comparing laparoscopic liver biopsy using cutting-type needles with a percutaneous blind liver biopsy with a Menghini needle demonstrated its superiority in diagnosing background diffuse liver disease in patients with hepatocellular carcinoma.109 A further randomised controlled trial of laparoscopic liver biopsy versus PLB showed that the former, combining both macroscopic and histological assessment, was more sensitive for the diagnosis of cirrhosis and had a similar safety profile.110

The complications of laparoscopic liver biopsy include those of the laparoscopy itself.

Open wedge liver biopsy is also very occasionally performed, mostly in the setting of bariatric surgery, although its usefulness remains unclear but may help to identify fatty liver disease (see online supplementary appendix).111 112

Recommendations

• We recommend that there should be agreed formal pathways for access, in a timely fashion, to a regional or tertiary centre that can offer these facilities when clinically indicated (strength of recommendation STRONG; evidence WEAK).

Transjugular liver biopsy (TJLB)

Indications for TJLB are usually different from those of percutaneous biopsy so direct comparison of morbidity and mortality between the two approaches may lead to misleading conclusions. Kalambokis98 reviewed complications from TJLB in 64 series reporting 7649 TJLBs evaluating the quality of specimen and safety. Minor and major complication rates were 6.5% and 0.56%, respectively, and increased in children, but not with additional passes. In adults, mortality was 0.09% (haemorrhage 0.06%; ventricular arrhythmia 0.03%).

In a Canadian retrospective review of 461 biopsies performed over a 7-year period, Gamble128 reported minor complications such as neck pain, haematoma at the puncture site, or fever occurring in 79 patients (17.1%). Two patients died, but the biopsy was considered a factor in one (overall mortality 0.5%). Bleeding occurred from the puncture site in the neck in 8 (1.7%), carotid artery puncture in 3 (0.7%) and intraperitoneal haemorrhage in 4 (0.9%). Capsular perforation occurred in 18 (3.9%) and resolved with Gelfoam in 17. Modification of the technique by taking the biopsy with the catheter positioned centrally rather than wedged peripherally reduced the occurrence of capsular perforation without affecting the success rate.

An analysis by McAfee129 found the reported mortality of TJLB was 0 in three major centres and ranged from 0.1% to 0.5% in three other centres. Velt,130 in a series of 160 patients, recorded only one case of pneumothorax and no deaths. Kis,131 examining complications of 166 TJLBs in 141 haematopoietic stem cell transplants at one institution, reported three major complications (1.8%), including one death. Complications may be greater in those biopsied after bone marrow transplantation.132

Endoscopic ultrasound-guided biopsy

Endoscopic ultrasound-guided liver biopsy (EUS-LB) may be a safe and effective alternative approach to percutaneous or transjugular biopsy in the evaluation of both benign and malignant diseases of the liver. It can offer higher resolution imaging of the liver and can detect smaller lesions than CT or US scans of the abdomen. Evidence suggests the superiority of EUS-LB for a targeted approach of focal lesions, with less sampling variability in heterogeneous parenchymal disease.133 Mohan and colleagues134 recently published an analysis of a systematic review and meta-analysis of reports of complications of EUS-guided liver biopsy. Of the nine study arms with 437 patients, the pooled rate of adverse events with EUS-LB was 2.3% (95% CI 1.1% to 4.8%, I²=0). On subgroup analysis, the adverse events rate with a 19 G fine needle aspiration (FNA) needle (vs other core biopsy needles) was 0.9% (vs 2.7%, p=0.28).

Laparoscopic liver biopsy

A retrospective study of 2731 consecutive patients undergoing diagnostic mini-laparoscopy at two university hospitals in Germany135 found that major complications occurred in 1.0% (n=27): these included delayed bleeding from the liver biopsy site or abdominal wall (0.7% of patients) and intestinal perforation (0.3% of patients). Two patients died after severe haemorrhage (mortality 0.07%); the other patients recovered without sequelae. The risk of bleeding was increased in patients with low platelets (OR=6.1), increased INR (OR=8.9), cirrhosis (OR=1.9) and portal hypertension (OR=2.1). Logistic regression showed a significant correlation only for the concurrence of low platelets and increased INR; bootstrap analysis identified INR >1.5 as a significant predictor. Prior abdominal surgery did not carry a significant risk for intestinal perforation unless abdominal adhesions were present.

Conclusions

The reported risk of death and complications vary. Some of the variation can be attributed to the inherent limitations in large retrospective studies, the lack of agreed definitions of complications, the clinical condition of the patient, the type of biopsy procedure and changes in practice over time.

Recommendation

When obtaining consent from patients, clinicians must use local data where available, tailored to the patient’s individual situation (strength of recommendation STRONG; evidence HIGH).

Coagulation testing

Understanding of the coagulation profile in liver disease has evolved since the previous guideline was written. Historically, it was assumed that the raised prothrombin time often seen in liver disease, commonly expressed as an INR, reflected a bleeding risk and that correction with plasma products, specifically fresh frozen plasma (FFP), would reduce/correct this haemostatic failure. However, more recent studies have shown quite the reverse; that there is often a prothrombotic state, and transfusion of FFP has been described as usually unnecessary, ineffective and potentially hazardous.139–145 A recent Cochrane review concluded that there is uncertainty about the utility and safety of prophylactic FFP use.146 Thus, use of FFP is rarely indicated.

Although there is reduced synthesis/consumption of many procoagulant proteins and reduced numbers of platelets, there is an increase in factor VIII and von Willebrand Factor and a reduction in natural anticoagulants. Haemostasis in chronic stable liver disease is often referred to as ‘rebalanced’ with a net effect of normal haemostasis or even a procoagulant state and this is reflected in more ‘global’ assays of coagulation in patients with chronic liver disease, such as thrombin generation and viscoelastic haemostatic assays.147–154 There appears to be a similar rebalancing in acute liver disease.155

The INR is only sensitive for fibrinogen, factor II, factor V, factor VII and factor X and does not test the haemostatic balance in a patient with liver disease. The INR has been shown to be a poor predictor of bleeding during liver transplantation, and this procedure is now often done without the need for blood product replacement.145 156

There is also a paucity of data to recommend a ‘safe’ minimum platelet number for procedures in patients with chronic liver disease, and whether platelet transfusion is effective.150 157 158 Common practice has been to consider transjugular over percutaneous biopsy in patients with a platelet count <50×10⁹/L and/or to transfuse platelets. There is no clear evidence regarding the efficacy and safety of platelet transfusions under these circumstances and increments may be poor and short lived in patients with portal hypertension.

More recent studies of thrombopoietin receptor agonists (TPO-RAs) have been shown to reduce the need for platelet transfusion in patients with cirrhosis requiring elective invasive procedures.103 138 159 160 It is plausible that TPO-RAs provides a more effective haemostatic effect than platelet transfusion. The treatment period required prior to biopsy is 9–14 days. Although not seen in all studies, TPO-RAs have been associated with an increased risk of thrombosis, including portal vein thrombosis,161 so should be used with caution in patients considered to be at higher risk of thrombosis, especially as these patients were excluded from trials. In the UK, NICE has recently concluded that lusutrombopag is recommended, within its marketing authorisation, as an option for treating severe thrombocytopenia (that is, a platelet count of <50×10⁹/L) in adults with chronic liver disease having planned invasive procedures; no recommendations were made about avatrombopag until it has an agreed list price in the UK.162

In a large retrospective study of patients having percutaneous liver biopsy,163 implementation of less stringent preprocedural coagulation parameters (INR ≤2.0, platelets ≥25 x10⁹/L) was associated with fewer haemorrhagic complication rates and a significant decrease in preprocedural FFP/platelet administration in comparison with using historical cut-off points (INR ≤1.5, platelets ≥50 x 10⁹/L). Of note, haemorrhagic complication rates did increase as the INR increased and platelet counts decreased, but preprocedural FFP and/or platelet transfusion did not have a significant effect on haemorrhagic complication rates. While the results of conventional clotting tests correlate poorly with duration of bleeding and blood loss following liver biopsy,164 165 some retrospective studies do show an increased bleeding with an elevated INR,32 135 although the INR is generally not an independent risk factor for bleeding.166 A plausible explanation is that changes in the INR and platelet count are a surrogate marker for liver fibrosis and portal hypertension, which in itself will be a risk factor for bleeding; however, attempts to correct these haemostatic changes may increase bleeding risk as haemostatic failure is not the underlying cause of bleeding and increasing the intravascular volume is likely to be counterproductive.

The recent guidelines from the American Gastroenterology Association138 include the recommendations that blood products should be used sparingly because they increase portal pressure and carry a risk of transfusion-associated circulatory overload, transfusion-related acute lung injury, infection transmission, alloimmunisation and/or transfusion reactions.

The following transfusion thresholds for management of active bleeding or high-risk procedures may optimise clot formation in advanced liver disease: haematocrit ≥25%, platelet count >50 x 10⁹/L, and fibrinogen >120 mg/dL. Commonly used thresholds for correction of the INR are not supported by evidence.

The large volume of fresh frozen plasma required to reach an arbitrary INR target, limitations of the usual target, minimal effect on thrombin generation, and adverse effects on portal pressure limit the usefulness of this agent considerably.

In contrast, decompensated liver disease with acute or chronic liver failure is associated with a progressive consumptive coagulopathy and hypofibrinogenaemia, often with hyperfibrinolysis. Spontaneous mucocutaneous and other bleeding manifestations may become evident at this stage. In one study, a platelet count <30×10⁹/L, fibrinogen level <0.6 g/L and activated partial thromboplastin time values >100 s were the strongest independent predictors for new onset of major bleeding.167 All but the most essential invasive procedures should be avoided under these circumstances. Acute kidney injury has also been associated with an increased risk of bleeding after paracentesis in patients with decompensated cirrhosis.168

Treatment with vitamin K should be considered in patients with an increased INR, which may in part reflect vitamin K deficiency; particularly in patients in intensive care, in patients with malnutrition, in patients using antibiotics and in patients with cholestatic liver disease.147 169

Increasing evidence shows that viscoelastic assays can be used to assess haemostatic status in patients with liver disease, with evidence that this can result in a reduction in blood products transfused.170–174 This has become increasingly established in liver surgery but more recently for other procedures. In a small randomised trial, De Pietri175 showed that in patients with cirrhosis and an INR >1.8 and/or platelet count <50×10⁹/L requiring invasive procedures, a thromboelastogram-guided transfusion strategy led to a significantly lower use of blood products (17% compared with 100% transfusion in the standard of care group) without an increase in bleeding complications; only one major bleed occurred, which was in the standard of care group. This has been shown in other open-label randomised studies.176 Viscoelastic testing has therefore been used successfully to reduce unnecessary prophylactic transfusions in patients with liver disease (in comparison with using the INR and platelet count). In contrast, in a single-centre randomised study of central venous catheter insertion in patients with cirrhosis, a thromboelastography-based strategy did not reduce blood transfusion compared with usual care; however, a restrictive protocol (no transfusion unless INR >5.0 or platelet count <25×10⁹/L) reduced transfusion without an increase in bleeding.177 It should also be noted that these assays have not yet been shown to reliably predict bleeding in patients with liver disease.150 178

Antiplatelet agents

The British Society for Haematology has produced guidelines on perioperative management of anticoagulation and antiplatelet therapy, although there are no specific recommendations for patients requiring liver biopsy.137 There is increasing use of P2Y12 inhibitors in patients with vascular disease and after arterial stenting (such as clopidogrel/prasugrel/ticagrelor). The antiplatelet effect persists for up to 7–10 days. It is common practice to pause these drugs approximately 7 days prior to elective procedures associated with a bleeding risk. Data in relation to transcutaneous liver biopsy are insufficient to recommend otherwise, and the haemostatic effects of P2Y12 inhibitors may be difficult to reverse (table 2). In a study of 8172 percutaneous ultrasound-guided intra-abdominal interventions, the frequency of bleeding was reported as significantly higher in patients taking medication interfering with platelet function or coagulation.34 In one retrospective study of CT-guided liver biopsies, aspirin use within 10 days had no significant impact on bleeding116; however, there was insufficient detail to determine whether closer proximity to biopsy time was a risk factor. The haemostatic effects of aspirin are more readily reversed, and indirect evidence suggests that treatment with aspirin can be paused for a shorter period (such as 3 days) prior to invasive procedures.179 180 Empirical experience (such as with post liver transplant biopsies) suggests that pausing aspirin may not be necessary and should be at the discretion of the operator if urgent. As with all clinical decisions, the risks of stopping anti-platelet drugs must be carefully considered and, where appropriate, consultant advice sought, especially in patients with recent stents/percutaneous coronary intervention if the procedure cannot be delayed.

Anticoagulants

Warfarin should be stopped 5 days before the procedure with point-of-care testing before the procedure to ensure adequate reversal (table 2). Bridging treatment with low molecular weight heparin should be started if deemed necessary.137

Direct oral anticoagulant drugs should be stopped for 2 days prior to the day of the biopsy or longer if taking dabigatran, depending on the renal function.181

Recommendations

For a non-lesional liver biopsy, we recommend a transvenous approach if the INR is >1.4 (strength of recommendation MODERATE; evidence MODERATE).

If a percutaneous targeted biopsy is required in a patient with stable liver disease, an INR of 1.5–2.0 is not a contraindication; however, the risk of bleeding may be higher in the context of liver fibrosis and portal hypertension (strength of recommendation MODERATE; evidence MODERATE).

We recommend FFP should not be used to correct an INR ≤2.0 prior to liver biopsy (strength of recommendation STRONG; evidence MODERATE).

We recommend that, where time allows, stopping aspirin 3 days prior to percutaneous biopsy should be considered, but the decision will depend on the indications for aspirin and the urgency of the biopsy (strength of recommendation MODERATE; evidence WEAK).

In patients with acute kidney injury or acute or chronic/decompensated liver disease, we recommend that liver biopsy should be avoided whenever possible as these conditions are often characterised by a consumptive coagulopathy and low fibrinogen, so these patients are at high risk of bleeding. Laboratory parameters associated with a particularly high risk of bleeding include a platelet count <30×10⁹/L, fibrinogen level <0.6 g/L and activated partial thromboplastin times >100 s. If liver biopsy is necessary for clinical management, a transjugular route should be used (strength of recommendation STRONG; evidence MODERATE).

We recommend that vitamin K depletion should be corrected before liver biopsy (strength of recommendation STRONG; evidence WEAK).

We recommend that patients with a history of abnormal procedure-related bleeding, unrelated to portal hypertension, should be referred for specialist haematology assessment prior to biopsy (strength of recommendation STRONG; evidence WEAK).

The routine use of global haemostatic tests is not recommended at this time (strength of recommendation LOW; evidence WEAK).

Where the platelet count is <50 x 10⁹/L, a transvenous approach is recommended, where possible (strength of recommendation STRONG; evidence MODERATE).

The effectiveness and risks of platelet transfusion for a platelet count <50×10⁹/L have not been established but can be considered (strength of recommendation MODERATE; evidence WEAK).

TPO-RAs are an alternative to platelet transfusion according to local protocol (strength of recommendation MODERATE; evidence HIGH).

Recommendations: when to stop anticoagulants and antiplatelet drugs—see table 2 (strength of recommendation STRONG; evidence WEAK).

Liver biopsy solely for research purposes

Material obtained from a liver biopsy taken specifically for research has provided invaluable information for understanding the pathogenesis and treatment of disease. However, when the patient will derive no direct therapeutic benefit from the procedure and will only accrue the risks of that procedure, the patient should be fully aware of this and give written consent.

If part of the liver biopsy done for diagnostic or therapeutic purposes is taken for research, or if additional passes will be done to obtain material for research purposes, the patient must be given this information and give full consent. The procedure will also need approval from the appropriate research ethics committee (or equivalent) and hospital board.

Recommendations

• Patients should be given information about the risks and benefits of the procedure, in advance of the procedure where possible (strength of recommendation STRONG; quality of evidence HIGH).

• Information should be given verbally and supplemented by information in written form or other media using language understood by the patient (strength of recommendation STRONG; quality of evidence HIGH).

• Information on risks should be readily understood and the following is recommended ‘of 1000 people like you having a liver biopsy, X will develop (complication)’ (strength of recommendation MODERATE; evidence WEAK)

• Consent should be confirmed in writing and local and national guidelines followed (strength of recommendation STRONG; evidence HIGH).

• Where a liver biopsy is done solely or partly for research, patients must be fully informed, and the procedure must be approved by the appropriate research ethics committee (or equivalent) and hospital regulations (strength of recommendation STRONG; evidence HIGH).

Role of antimicrobial prophylaxis

See section 'Prophylactic antibiotics'. Routine antimicrobial prophylaxis is not indicated except in the presence of biliary sepsis or a Roux loop in a liver allograft.

Percutaneous biopsy

Practice varies as to whether patients should be advised to be nil by mouth before a biopsy; some centres advise a minimum of 2 hours’ fast but there is little evidence on which to make a firm recommendation.6

For the procedure itself, the patient is normally supine, in a comfortable position, with the right hand resting comfortably behind the head or by their side. Where the patient is anxious, sedative medication may be used, according to local guidelines.

Once the site of biopsy is identified, the skin should be cleaned and then the patient is given a local anaesthetic, typically with 1% lidocaine. Where appropriate, the anaesthetic should be infiltrated into the capsule. As the liver moves during respiration, breathing while the biopsy needle is in the liver may cause laceration and bleeding. As a consequence, patients are usually asked to hold their breath while the needle is in the liver. Although there is some variation in practice, most centres advocate the operator taking the biopsy when the patient has taken a deep expiration as this will reduce the risk of pneumothorax. Whichever cycle of respiration is chosen, it is important that the biopsy itself is done during the same part of the cycle as used to identify the optimal site of biopsy.

Recommendation

• Percutaneous liver biopsy for non-lesional indications should be done with the patient holding their breath in expiration (strength of recommendation MODERATE; quality of evidence LOW).

After the procedure

After the procedure the patient is instructed to remain in the recumbent position for the duration of the post-procedure monitoring. Some centres advocate that the patient should lie on their right side, in the belief that that the pressure of the liver will reduce the risk of bleeding. In one small study,184 this was associated with more pain but no difference in complications. The duration of monitoring will be up to 8 hours, but for the low-risk patient with no post-biopsy complications, 3 hours' observation is usually adequate,119 although one recent study suggested that 1 hour is enough to recognise all major complications.185

Liver biopsy observations include monitoring the patient’s pulse rate and blood pressure every 15 min for the first hour,119 then every 30 min for 2 hours and then hourly for the remaining period. If the patient is hypotensive or tachycardic then they should receive 500 mL of 0.9% saline, unless contraindicated, and then re-evaluated.

The biopsy site should be checked every half hour for signs of bleeding.

Patients should be discharged only if they are haemodynamically stable with no evidence of bleeding, stable blood pressure and no new complaints of pain or shortness of breath.186

1. Before discharge, patients should be given oral and written instructions regarding further monitoring and daily activities. The information should also include details of who to contact and how to contact them, in the event of complications or other concerns. Instructions should include advice to rest for the remainder of the day and not drive any motor vehicles or operate any heavy machinery on the day of the biopsy. Strenuous physical activities such as running, contact sports or heavy lifting for 48 hours after the biopsy are discouraged, although the evidence for this recommendation is weak.

2. If a patient experiences any symptoms such as chills, high fever, difficulty breathing, excessive bright red bleeding from the biopsy site, severe chest, shoulder or abdominal pain, passing blood in the stool or increasing abdominal swelling, then they are instructed to call the hospital.

Recommendation

• Patients should be monitored for at least 3 hours after liver biopsy with regular clinical observations and measurement of blood pressure and pulse (strength of recommendation STRONG; evidence WEAK).

Outpatient day case liver biopsy

It is recommended that patients undergoing day case percutaneous liver biopsy should have no conditions that might increase the risk of biopsy; these include encephalopathy, ascites, malignancy, hepatic failure with severe jaundice or evidence of significant extrahepatic biliary obstruction, significant coagulopathies or serious diseases involving other organs, such as severe congestive heart failure or advanced age.187 Pragmatic issues that will affect the decision not to undertake day case biopsy includes the travel time between the hospital and patient’s home (or place of recovery), domestic situation and time of day that the biopsy is done.

Patients with a strong suspicion of malignancy should not be biopsied as a day case because such patients may have a higher risk of haemorrhage than patients without cancer.65

Day case biopsy should be done only where there is speedy access to a diagnostic laboratory, blood bank and in-patient facilities and when there are staff to observe the patient after the biopsy.

Recommendation

• Liver biopsy may be safely done as a day case procedure if there are no increased risk factors and the patient can be looked after when they have left hospital, can seek appropriate advice and access appropriate medical help if needed (strength of recommendation STRONG; evidence WEAK).

Size of biopsy

For medical liver biopsies, the core of tissue should be intact and of sufficient size to demonstrate the lobular architecture of the liver over several portal tracts. Portal tracts and hepatic veins are about 0.8 mm apart and therefore better seen on a biopsy of around 0.8–1 mm in diameter, such as is obtained using a 16 G needle. The size and integrity of the sample is particularly important when being taken to investigate the stage of fibrosis in chronic liver disease,188 or in diseases which affect the liver in a variable way—for example biliary disease.189 There is agreement that the minimum biopsy sample for clinical trials purposes should be 20 mm obtained with a 16 G needle.71

Good evidence shows that a biopsy containing 10 or fewer portal tracts results in underestimation of both the severity of the fibrosis stage and of the inflammatory grade in chronic viral hepatitis.64 In this study by Colloredo and colleagues, the proportion of biopsies showing at least bridging fibrosis was reduced from 41% in biopsies 30 mm x 1.4 mm to around 20% if the biopsy was as wide but 10 mm long, or 30 mm long but 1 mm wide. In another study, digital imaging was used to generate 'virtual biopsies' from a grid superimposed on resection specimens to find the size of biopsy required to reliably stage fibrosis. Modelling 2.5 mm increments 1 mm wide showed that a length of 25 mm was required to achieve a reproducible percentage area of fibrosis.66 The American Association for the Study of Liver Diseases (AASLD) position paper on liver biopsy recommends 'long and wide (an ideal size is 3 cm long after formalin fixation obtained with a 16 G needle)'.6 Transjugular biopsies are indicated for patients with increased risk of complications (see section 'Morbidity and mortality') and/or when venous pressure studies are also required. Transjugular biopsy devices have a narrower gauge, usually 18–19G needles, and therefore require multiple passes. It has been shown that four passes are required for optimal specimens.190

Recently, FNA specimens from the liver obtained under endoscopic ultrasound guidance have been introduced. These are used in endoscopic biliary investigation for painful jaundice and generate narrow fragmented specimens which may be sufficient to suggest the cause of jaundice (obstructive, hepatitic, late stage chronic disease) when no specific obstruction by stone or stricture has been identified by the examination.134 191 FNA specimens are not usually suitable for full histological assessment of diagnosis or disease stage.

Both side-cut and end-cut needles are widely used across the UK. There is little published evidence comparing the quality of biopsy samples obtained from different needles. The number of portal tracts in a given length of biopsy is variable and cannot be predicted from the biopsy length.67 76 A 16 G needle biopsy specimen was found to be intact significantly more often than with 18 G biopsy needles (71% compared with 24%) and to contain double the number of complete portal tracts per length of biopsy.76 Based on the above standard of an adequate biopsy being 20 mm in length and including >10 portal tracts, inadequate <10 mm and <6 portal tracts, with intermediate samples described as 'compromised', one audit showed an adequate rate of 24.7% and inadequate of 21.9% in biopsies between 2008 and 2011, which represented a significant improvement on pre-2008 figures.68 This study corroborated the effect of biopsy size on fibrosis stage, with cirrhosis diagnosed in 6.5%, 11.0% and 14.6% of inadequate, compromised and adequate biopsies, respectively, while the proportion reported as no fibrosis was 27.1%, 12.1% and 7.3%.

A second core may therefore be needed to provide sufficient biopsy tissue. There is concern that more than one pass for a medical liver biopsy increases the complication rate, although no clear evidence on this point exists.35 61 Pragmatically, a second pass should be considered if the biopsy core is <20 mm long and especially if the purpose of the biopsy is to investigate fibrosis stage or possible biliary disease.

The biopsy report should include both the length of the biopsy specimen, whether there is fragmentation and an approximate number of portal tracts. This gives an objective measure of the reliability of the sample.10 Some biopsy interpretation is possible even if the amount of liver tissue is small, but the pathologist should state in their report that the biopsy is too small to provide a full assessment of the liver disease.

Handling of biopsy

Routine needle core or wedge biopsies are submitted in formalin and are best sent free-floating rather than attached to blotting paper. Biopsies from patients with known risk of infection, including hepatitis B and C viruses, HIV and tuberculosis should be labelled according to the local generic policy for specimens with a danger of causing infection; in view of the small specimen size, needle core biopsies do not require additional time in fixative before processing.

Requests for fresh tissue sent for immediate frozen section analysis must be communicated in advance with the laboratory, with clear indications of the findings and procedures being undertaken. These will generally be biopsies of subcapsular lesions and sent as small wedges of tissue.

If the clinical differential diagnosis includes Wilson’s disease, a separate core of tissue should be taken for copper estimation by the chemical pathology department; this should be wrapped in moistened paper, but not floating in formalin or saline. The same process would be used for iron content, but this is now rarely required. If the clinical diagnosis includes acute fatty liver of pregnancy, the liver biopsy should be sent fresh for frozen section for fat, since microvesicular steatosis in that condition may not be visible in fixed paraffin sections. Fresh samples for fat and freezing for metabolic disease may also be taken from paediatric patients; this is outside the scope of these guidelines. If a focal infective lesion/abscess is suspected, an additional fresh sample may also be sent to microbiology.

Detailed guidance for the processing, staining and reporting of liver biopsies is available in the Royal College of Pathologists 'Tissue pathways for liver biopsies' document.10

Communication between clinician and pathologist

Pathology reporting

Liver biopsies are received by most pathology departments in the UK and elsewhere. The Royal College of Pathologists tissue pathways document recommends that biopsies are reported by pathologists who have sufficient knowledge of hepatology to formulate a report that deals with the clinical question. Outside hepatology centres, it is recommended that there is a local lead histopathologist responsible for liver biopsies, and that the reporting pathologists work in close communication with local clinicians, ideally by a regular clinicopathological conference. This helps to maintain their expertise and to identify biopsies and cases which may benefit from a second opinion. They should have time for regular continuous professional development activity in liver pathology, and at least one member of the department should undertake some form of external quality assurance in liver pathology. When late post-transplant biopsies are taken in the patient’s local hospital, it is recommended that these are referred to the relevant transplant centre for review.

For pathologists working in hepatology centres, there should be at least two consultants with specialist interest in liver pathology to ensure adequate cover, to support a regular clinical meeting for biopsy discussion and provide a referral service within the hepatology network. For transplant centres, a review service for transplant biopsies taken elsewhere should be provided.

There have been studies of circumstances when the original diagnosis on a liver biopsy is amended through specialist review as a result of clinical referral. Bejarano found major discrepancy in 28% that would affect management, and minor discrepancy in 37% biopsies; interpretation errors were the most common for chronic cholestatic disease and cirrhosis.192 More recently, Paterson found a discrepancy in 59% of reviewed cases, although this included those sent for a second opinion as well as clinical referral, again with biliary disease as the the most common type of discrepancy and also highlighting issues with autoimmune disease and vascular abnormalities. A detailed clinical review found 61% of discrepancies affected clinical management.193 A third review found a discrepancy rate of 38% with 70% (26% of all referred cases) assessed as having a major clinical impact.194

Many specialist groups and societies give advice on when to take a liver biopsy in various disease categories and awareness of these guidelines will help pathologists in constructing relevant reports (see online supplementary appendix A). It is strongly suggested that because of the challenges in diagnosis and also management implications, specialist review should be considered in new diagnoses of autoimmune disease, problematic biliary disease, including overlap entities and suspected vascular diseases, as a matter of routine.

Long term storage of biopsy specimens

Review of previous biopsy material, sometimes going back over many years, can provide important information concerning the progression of liver disease, or of the nature of liver disease in a relative of a patient who may have an inherited disorder. Tissue blocks and glass microscope slides of tissue samples from living patients are normally stored for at least 30 years. If a shorter time is being considered, then blocks that provided the basis of a diagnosis of rare diseases or inherited genetic predisposition should be considered for permanent retention. In practice, it would be extremely laborious to select such material, and the histology archive is generally preserved for 30 years.195

Recommendations

• The clinical indication for liver biopsy should be clearly communicated to the reporting pathologist by the requesting clinician (strength of recommendation STRONG; evidence HIGH).

• It must be clearly indicated if the biopsy is targeted at a focal lesion (‘tumour biopsy’) or taken for investigation of diffuse parenchymal disease (‘medical liver biopsy’) (strength of recommendation STRONG; evidence HIGH).

• For percutaneous medical liver biopsy, the specimen should be obtained with a 16 G needle and measure >20 mm in order to provide adequate tissue for examination. Consider a second pass if a smaller specimen is obtained, especially for investigation of fibrosis stage or possible biliary disease (strength of recommendation MODERATE; evidence HIGH).

• For targeted biopsy from a focal lesion, an 18 G needle is recommended; we recommend that an additional biopsy is obtained from the non-lesional tissue (not adjacent to the lesion) to evaluate background liver disease and can be done using the same needle (strength of recommendation STRONG; evidence HIGH)

• We recommend that for transjugular biopsies, at least two biopsies are taken (strength of recommendation STRONG; quality of evidence HIGH).

• The biopsy report should clearly deal with the clinical indication for the biopsy and conclude with a concise diagnostic summary (strength of recommendation STRONG; quality of evidence HIGH).

• For biopsies obtained outside a specialist liver centre, we recommend that the reporting pathologist should have access to second opinion from a liver centre (strength of recommendation STRONG; quality of evidence HIGH).

Audit

As practice is changing with the development of new diagnostic tests and investigations, and with new methodologies and technologies, lessons learnt from the past may be less relevant for providing informed consent. We suggest that

• There should be agreed standards nationally and internationally for the definitions of adverse effects.

• Both hospitals and professional organisations should conduct periodic audits of practice and outcomes; professional organisations should set up national databases for significant adverse events.

Training and competencies

• We recommend that there should be clear guidance for the establishment of competence for liver biopsy with respect both to training and current practice.

Coagulation and bleeding

As more is understood about the causes of bleeding after liver biopsy, we suggest that more research is required to

• Develop the most appropriate measure(s) of the risk of bleeding.

• Agree the safest way of managing a patient’s need for ongoing anticoagulation or antiplatelet therapy and liver biopsy.

Biopsy needles

Technologies for taking liver specimens are improving and new needles are being introduced.

• We recommend that there should be more comparative audits that compare the efficacy of different needles with respect to safety, adequacy of specimen and cost.