Liver biopsy

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Liver biopsy

Evangelos Cholongitas¹, Andrew K Burroughs¹ and Amar P Dhillon²

¹ The Royal Free Sheila Sherlock Liver Centre, Royal Free Hospital, and University College London, London, UK ²Histopathology Department, Royal Free Hospital, London, UK

Introduction

Since the introduction of the 1-sec Menghini needle technique in the early 1950s, liver biopsy (LB) has become the commonest procedure performed in clinical hepatology and remains an important tool in the differential diagnosis and therapeutic decision-making in patients with clinically diagnosed acute and chronic liver disease. Other indications include the evaluation of cholestatic liver disease (primary biliary cirrhosis, primary sclerosing cholangitis), the diagnosis and follow-up of treatment of heritable disorders (hemochromatosis, Wilson’s disease), and LB may be helpful in identification of systemic inflammatory or granulomatous disorders [1–5]. LB is useful in evaluating otherwise unexplained abnormalities of liver function tests, particularly in patients with fever of unknown origin [1–5]. In patients with non-alcoholic fatty liver disease (NAFLD), imaging techniques are sensitive for detecting fatty liver (especially moderate to severe steatosis) [6–9], but they cannot distinguish simple steatosis from steato-hepatitis and they cannot measure the degree of fibrosis [8, 10–12]. Thus, LB can confirm the diagnosis of NAFLD and identify the severity and the extent of fibrosis. Other indications for LB include the diagnosis of drug-induced liver damage and the diagnosis of neoplastic and other mass lesions, as well as conditions such as sarcoidosis and hema-tologic diseases. Finally, in the liver transplantation setting, LB is essential for diagnosis of acute or chronic rejection, recurrence of the primary disease, and characterization of additional intercurrent disease.

However, LB only represents approximately 1 /50000 of the total liver mass [13] and several studies have stressed this limitation, evaluating the optimal size of a liver specimen and the impact of heterogeneity and intra- and inter-observer variation on the histopathological interpretation of LB.

The status of LB is being challenged by non-invasive markers for the evaluation of fibrosis, both serum markers and types of transient elastography [14], but in reality LB and non-invasive surrogates are complementary investigations [15]. Furthermore, recent studies have tried to determine optimal standards for length and number of complete portal tracts for accurate evaluation of grading and staging in chronic viral hepatitis [16,17].

Percutaneous (PLB) and transjugular (TJLB) liver biopsy are the two main techniques. Laparoscopic LB is more invasive [18]. The needles used can be considered large, that is, an external diameter ≥1.0mm (14–19 G) and thin when <1.0mm (≥20G)) [19]. Suction (Menghini) or cutting (Trucut) needles are the most used.

Liver biopsy and its histological interpretation in chronic viral hepatitis

Although LB is an invasive procedure and should only be performed if it can offer significant and accurate diagnostic information, it is considered a key component during the initial work up of patients with chronic hepatitis C (CHC), and histopathology is the “gold standard” for assessing changes after antiviral therapy [20]. Although serological markers (anti-HCV) and HCV-RNA are very reliable for CHC diagnosis, LB is considered mandatory for grading (necroinflammatory activity) and staging (fibrosis) in most CHC patients [21,22]. LB can also reveal unsuspected additional diagnoses, complications of treatment and progression/regression of CHC. LB is useful for evaluation of steatosis and siderosis, which may affect both the natural history and response to antiviral therapy [23–27]. However, LB is not considered necessary before starting antiviral therapy in CHC patients with genotype 2 [21], and is currently being debated in CHC patients with persistently normal aminotransferase levels [28–31]. In chronic hepatitis B (CHB), LB is also a useful tool, because it provides important information concerning the severity of liver damage and the decision to treat [32]. In patients with e-antigen positive CHB, LB is recommended for those with elevated ALT/AST twice the upper limit of normal, while it is considered mandatory in the majority of patients with e-antigen negative CHB [32]. Regardless of the accepted utility of LB in identifying active HBV disease, the distinction between histologically inactive/active levels of inflammation and insignificant/significant fibrosis for the purposes of making therapeutic decisions has never been formally investigated.

Several histopathological scoring systems have been developed in order to facilitate the comparison between different trials and to standardize histopathological observations of hepatitis. Although there are many such systems [33–36], all of them produce values for various categories of inflammation (grade) and fibrosis/architectural disruption (stage), and in fact they “score” (i.e. categorize) similar histological features. In the Knodell “histological activity index” system (HAI) [33], each of four histopathological axes of assessment (piecemeal/bridging necrosis, lobular inflammation, portal inflammation and fibrosis/architectural change) is assessed separately and assigned a “score”, which is in fact a “numerical” shorthand symbol for a descriptive category. None of the scores, in any of the scoring systems is actually a measurement, or a real number in the arithmetical sense. Currently, the most widely used histopathological scoring system is the “Ishak” [34], which assesses fibrosis in seven categories ranging from normal to cirrhosis and so has potentially more discriminant descriptive power than the “Knodell”. The METAVIR scoring system was designed for HCV chronic hepatitis specifically [36]. All of the histological stage scoring systems are a composite evaluation, and attempt to describe architectural changes as well as fibrosis, and all of the systems have several drawbacks [37]. The most common error in evaluating fibrosis is to use the stage scores as numerical data, such that stage 2 is considered to comprise twice the amount of fibrosis as stage 1. In fact fibrosis measurement is the only way to quantitate collagen (e.g. different cir-rhotic livers would all score 6 in the Ishak staging system, but might contain vastly different amounts of collagen) [37]. The proper measurement of collagen may be essential in some studies (e.g. to establish the effects of antifibrotic therapy), and then appropriate methodology (e.g. with image analysis rather than histological scoring) must be used [37]. On the other hand, specific measurement of LB collagen alone cannot address the issue of hepatic architectural disruption and nodularity per se, so that for routine diagnostic purposes histopathological examination may not only be sufficient, but is superior. If both evaluations can be performed, additional diagnostic and prognostic benefits may ensue [38]. Collagen proportionate area measured using Sirius red stained sections, with digital image analysis computerizsed techniques, correlates with hepatic venous pressure gradient and allows histological gradation of fibrosis in cirrhotic liver [38].

Different approaches of liver biopsy

Percutaneous liver biopsy

Percutaneous liver biopsy (PLB) is the commonest and quickest LB procedure [39]. It is commonly undertaken as a day case procedure. It is performed under local anesthesia with lidocaine, with the patient holding breath in expiration and it lasts just a few seconds [19, 40]. After biopsy, many physicians use a short observation period because most of the complications occur during the first few hours after the procedure [39, 41, 42].

Although PLB is considered a safe procedure, major and minor complications occur in up to 6% of patients and in 0.04–0.11% can be life threatening [13, 42, 43]. The most common complications include pain, hemorrhage (intra-peritoneal bleeding, hematoma (intrahepatic or subcapsu-lar) and hemobilia), infection, pneumothorax and inadvertent puncture of other intraabdominal organs. The complication rate is related to technical and patient factors. B4 Technical factors include: (1) the experience of the operator who performs the procedure (less complications especially for those units performing more than 100 biopsies per year) [44–46]; (2) the use of ultrasonography (US) either before or the time of LB [47–49]; (3) the size of biopsy needle (less complications for the fine-needle); and (4) the use of more than one pass [46, 50–54]. Patient factors (high risk group) include: (1) the nature of the underlying liver disease (the presence of cirrhosis and tumor increase the complication rate) [54]; and (2) impaired coagulation beyond current safe limits [42], that is, platelet counts less than 60000/mm³ and INR > 1.6. Patients with chronic renal insufficiency (serum creatinine greater than 1.5mg/dl) are also considered at high risk: they usually receive desmo-pressin 15–30 minutes prior to the procedure [42].

Pre-liver biopsy US helps to detect focal hepatic tumors (benign or malignant), cysts, ascites, intrahepatic biliary dilatation or hepatic anatomical variation. Regarding the impact of US guidance on complication rate, recent evidence suggests that real time US guidance, compared to US guidance in order only to identify the puncture site, does not give any advantage regarding safety or size of liver specimen [55]. Both approaches decrease minor and major complications [47–49], particularly the risk of hemorrhage [56], but there is no clear evidence of this benefit [57, 58], compared to the blind approach, where the liver is percussed. Routine use of US for diffuse liver disease is still debated and has not been established to be cost-effective related to time in hospital [48, 56, 59]. The lower bleeding rate under US guidance may be related to the use of fewer passes used to obtain an adequate sample [46, 51]. US does help the operator to avoid puncture of adjacent important structures [60, 61]; US changed the biopsy site in 21 (12.7%) of 165 patients in a prospective study [60]. The use of US may be especially important in obese patients, those with cirrhosis and patients with chronic obstructive pulmonary disease [56]. Although blind PLB is more commonly performed, it was found that US guidance was used by 56% of gastroenterologists and hepatologists in France [53]. In addition, Angtuaco et al. randomly sent questionnaires involving 260 members of the American Association for the Study of Liver Diseases and found that 75% had performed liver biopsies under US guidance [62]. Post-biopsy US is not routinely needed; usually it is performed in the presence of possible complications.

Although fine-needle PLB should be avoided for grading and staging in chronic viral hepatitis patients, guidance fine-needle PLB (via US or computed tomography) is considered particularly useful for diagnosis of hepatocellular carcinoma (HCC) [18, 54]. Indeed, histopathology is often the only way to establish or exclude HCC and to differentiate malignant from dysplastic or benign (degenerative) lesions arising from a background of cirrhosis [63, 64]. Using current guidelines for diagnosis of HCC [65], biopsy is limited to tumors between 1–2 cm diameter [66, 67], which do not have both arterial hypervascularity and portal venous washout. However, there is the risk of malignant seeding [68]. A recent review showed the median seeding rate to be 2.29% for biopsy alone and 0.95% when associated with ablation techniques [69]. B4 This was confirmed by another review, where the risk of malignant seeding with biopsy alone was estimated at up to 2.7% [70]. B4

Plugged PLB is performed through a sheath following embolization of the biopsy track and it is used in patients with impaired blood coagulation. Plugged PLB is easier and quicker than TJLB (15 min vs 41 min respectively) and thus, it is recommended in cases of coagulopathy when TJLB approach is not available or has been performed unsuccessfully [71].

Menghini versus Tru-cut technique in PLB

It is considered that the Tru-cut needle produces larger and less fragmented samples compared to the suction needle [4, 47, 54], particularly in patients with advanced fibrosis or cirrhosis [72], but in our recent systematic review on the quality of PLB, we found that the Menghini technique yielded significantly longer samples (19.9 ± 6.6mm) compared to Tru-cut (14.3 ± 3.2 mm, p = 0.016), but without a significant difference in the mean number of complete portal tracts (CPT) (7.3 vs 6.9, p = 0.8). B4 This could be explained by the fact that the Tru-cut needle provides a maximum length of sample determined by the notch in the needle shaft (usually 20–25 mm) whereas with Menghini needle the length depends on the force of aspiration and operator experience. Finally, there are conflicting results regarding the relative safety of these two techniques: a retrospective study reported a higher rate of major complications with the Tru-cut needle as a result of its longer intrahepatic phase [18, 54], but another prospective study found no significant difference in complication rates related to the type of needle used [73]. B4

Quality of PLB for accurate histological interpretation

Diagnostically, PLB of ≥15mm length has been considered necessary for accurate diagnosis in chronic liver disease [74]; a review also concluded that six to eight complete portal tracts (CPT) should be present for precise diagnosis [13]. However, with the increasing need to assess fibrosis in chronic viral hepatitis, larger liver samples are needed to reliably assess grading and staging. Holund et al. [75] were the first to study the optimal specimen size for accurate assessment of necroinflammation and fibrosis. The studies of Colloredo et al. [16] and Bedossa et al. [17] established the minimum size for reliable scoring of LB for chronic viral hepatitis. In the first study 161 LB from CHC and CHB patients were evaluated, finding that a specimen of at least 20 mm long (of a 1.4 mm diameter, that is, 17 gauge biopsy) and/or containing ≥11 CPT was necessary for reliable assessment of grading and staging in chronic viral hepatitis [16]. Inadequate small samples tend to underestimate the degree of disease grade and stage. B2 In the second study the adequacy of LB samples was assessed using image analysis in 17 surgical specimens taken from CHC patients [17]. A 25mm long specimen (of a “virtual” 1 mm diameter biopsy) was the minimum length for reliable staging [17]. B4 Indeed, the CPT number is the most suitable parameter to compare different kinds of liver biopsy specimens (e.g. percutaneous versus transjugular, or Menghini versus Tru-cut, or using different needle sizes) [76].

Although the recommendation that an adequate LB should have 11 or more CPT, or be longer than 20–25 mm for the assessment of chronic viral hepatitis, has been accepted rapidly as the optimal standard, there are several additional considerations. An important implication of these studies is that more than one pass is likely for most PLB, in order to achieve an adequate liver sample size [16, 17]. Indeed, the mean length and number of CPT in series of PLB reported in the literature was 17.7 ± 5.8 mm and 7.5 ± 3.4 respectively, which are less than the optimal standard [76]. Interestingly, in the same review, US guidance and more experienced operators were important factors for the length of PLB, but not for the number of CPT [76]. Thus, based on documented series of PLB in the literature, the average length and number of CPT of PLB are both below the current optimal criteria for accurate histological interpretation [16, 17]. Therefore, more than one pass is likely to be needed, but this increases the risk of complications with PLB, making the minimum requirement for optimal PLB unrealistic and potentially more dangerous for the patient [46, 50, 51, 53]. B4

Evaluation of heterogeneity and inter-observer variation in histopathological hepatitis scores in PLB using the new sampling standard

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