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History
Percutaneous liver biopsy has been performed for more than 120 years. Although, there are reports of liver puncture carried out as early as 1825 by Recamier and by Stanley in 1833 to aid in diagnosis of purulent ecchinococcus, the first liver core biopsy was not performed until 1880 by Paul Ehrlich in Germany for the determination of glycogen in the livers of diabetic patients.[1] In 1895, L.Luatello reported on liver biopsy as a method of diagnosis, the cytomaterial examined as smear or teased-out preparation. F. Schupfer, in 1907, developed thicker needle for liver biopsy, allowing histological assessment of the tissue obtained.
Even after the first large series were reported in the 1930s by Huard and colleagues[2] in France and Baron[3] in the United States, the procedure was still regarded with apprehension. In 1938, I.Silverman further refined the technique of liver biopsy with the introduction of a new aspiration method using a modified biopsy needle, the ‘Vim-Silverman needle’. The concept of aspiration cytology was developed by Martin and Ellis in 1920s at the Memorial-Sloan Kettering Cancer center at New York.
Percutaneous liver biopsy was not widely adopted until 1957 when G. Menghini reported a new biopsy method, “Onesecond needle biopsy”: aspiration technique[4] using a thin walled, small caliber needle with sharply slanting bevel and without a trocar, which shortened the duration of the intrahepatic phase of the biopsy to a split second. This new technique marked the birth of histological liver diagnostics and since then, percutaneous trans-thoracic needle biopsy has been the standard method for obtaining liver tissue. It significantly expanded the use of liver biopsy, because of its safety and ease of performance and because of the sufficient quality and quantity of the tissue provided for various studies.
Indications
Percutaneous liver biopsy remains an important diagnostic procedure for the management of hepatobiliary disorders. Modern biochemical, immunologic, and radiographic techniques have facilitated the diagnosis of liver disease but have not made biopsy obsolete.
In each individual case the indication for liver biopsy depends on assessment of the risks relative to the potential benefits of the procedure. The benefit of liver biopsy is dependent on recognition of the pathognomonic lesion within the tissue sample obtained. Size and distribution of the different histological features and the size of the biopsy cylinder are, therefore, important determinants for the success of the examination. Whether or not a histological diagnosis may be useful for optimal management of a patient can best be judged if the clinical question has been well defined before the biopsy is performed. In a study liver biopsy confirmed the clinical diagnosis in 62.4% of the cases reviewed and fundamentally modified the diagnosis in 20.2%, concluding that liver biopsy remains an indispensable diagnostic procedure in the field of hepatology, since it can result in modification of the clinician’s diagnosis in one out of five cases.[5]
Even with modern advances in laboratory and imaging diagnostic technology, percutaneous liver biopsy ranks highly as a diagnostic method and is still performed when the clinical presentation or diagnostic test results are atypical or equivocal. In addition to being “gold” standard in establishing and confirming the diagnosis, the liver biopsy and the histology obtained is important in identifying the etiology, staging and determining the progression of disease and response to therapy.
Indications
1. Granulomatous hepatitis
Caused by infections like tuberculosis, schistosomiasis, drugs including allopurinol, isoniazid, systemic diseases like sarcoidosis, foreign body granulomas or post-transplantation granulomas. Many of these conditions present with unexplained elevation of serum alkaline phosphatase and/or aminotransferases and liver biopsy plays an important role in diagnosing this form of hepatitis and might help in establishing the etiology in most of these cases.
2. Drug-related hepatotoxicity
Hepatotoxicity accounts for approximately 3.5% of all adverse drug effects. Drug induced liver injury can range from mild acute hepatitis to chronic hepatitis, lobular to fulminant hepatitis, destructive cholangitis, hepato-cellular proliferation, veno-occlusive and neoplasms including angiosarcoma, hepatoma and hepatocellular carcinoma. Anabolic steroids, oral contraceptives, phenytoin, isoniazid, amiodarone, and alternative medicines such as herbal teas (eg, bush tea) are common offending agents. Liver biopsy is rarely indicated if a patient develops abnormal liver function tests while using a drug with well-described hepatotoxicity. However, biopsy should be considered in the following clinical situations:
1. The patient is undergoing treatment with a drug not previously associated with liver disease.
2. The patient has clinical evidence of underlying liver disease and develops symptoms that could be attributed to either the disease or the drug.
3. Various drugs are implicated and the pattern of histologic injury will help identify a specific drug, eg, Ito cell (stellate cell) hyperplasia in vitamin A toxicity.
4. It is necessary to differentiate autoimmune hepatitis from drug-induced injury.
5. If there is concern that fulminant liver disease may develop and disease severity must be determined.
3. Methotrexate Therapy
Biopsy is also used as a screening test to identify the development of drug-induced fibrosis. Patients receiving methotrexate for psoriasis, rheumatoid arthritis or inflammatory bowel disease are required to undergo a pretreatment liver biopsy and then repeat biopsies after each accumulated dose of 1.5 grams. However, the utility of liver biopsy for surveillance of methotrexate-induced fibrosis is controversial. Some studies indicate that methotrexate use results in little hepatotoxicity and that surveillance biopsies are not necessary or costeffective.
4. Fever of unknown origin
Liver biopsy still remains part of the investigation of fever of unknown origin and may establish the cause of fever. The liver can be affected by the spread of infectious organisms from outside the liver; by primary infection by bacterial, viral, spirochetal, protozoal, helminthic, or fungal organisms; and by the systemic effects of granulomatous or lymphoproliferative disorders. The yield from liver biopsy in diagnosing infectious disease is variable. In a small study of 25 patients undergoing percutaneous liver biopsy for fever of unknown origin, the histologic examination provided useful diagnostic information in 9 cases (36 %) [6]. The liver biopsy had no diagnostic utility in the remaining 16 patients, half of whom had spontaneous resolution of the fever without a diagnosis being established.[6] Biopsy is most useful in evaluating patients with altered liver function tests especially elevated alkaline phosphatase levels, with hepatomegaly or with a mass in the liver. Special staining, immunohistochemistry, and culture techniques must be used as appropriate for identification of common and unusual organisms. Lymphoproliferative and granulomatous diseases (sarcoidosis, tuberculosis, lymphoma, metastatic carcinoma) that cause hepatic infiltration and fever may be diagnosed only by biopsy. Culture of biopsy material can help in the diagnosis of infections such as tuberculosis, Mycobacterium hominis tuberculosis, Mycobacterium aviumintracellulare, CMV, Histoplasmosis, Candidiasis
5. Metabolic and Genetic Disorders
Liver biopsy is an important method for studying and diagnosing familial diseases or diseases that involve a metabolic or storage disorder. It also helps to ascertain the extent of liver damage
Hemochromatosis
Liver biopsy is diagnostic and provides quantitative measurement of iron load within the liver parenchyma.
Laboratory tests that indicate iron overload (iron, total ironbinding capacity, and serum ferritin tests) are helpful for screening patients. Diagnosis in suspected patients has been largely replaced with the genetic analysis (C282Y-H63D) to differentiate Hereditary Hemochromatosis from secondary hemochromatosis and other causes of systemic iron overload. The HFE gene test will identify the 80% of hemochromatosis patients who carry the mutation. Liver biopsy determines the degree and location of stainable iron and the extent of hepatic fibrosis and allows measurement of total iron content and calculation of the hepatic iron index (hepatic iron concentration/ age).
Wilson’s disease
A decade earlier, liver biopsy was the only test to confirm the diagnosis and also for estimation of intra-hepatic copper deposition in liver. Although, still considered to be the gold standard test, is seldom performed due to the easy availability of less-invasive serum test and genetic analysis Diagnosis is generally made on the basis of clinical findings, slit-lamp examination of the cornea for Kayser-Fleisher rings, decreased levels of serum ceruloplasmin, and elevated 24-hour urinary excretion of copper. Liver biopsy is important for diagnosis, as the results of histologic examination alone may be misleading. Special histologic staining techniques used to measure copper levels may produce normal results, despite high levels of copper in the liver. A hepatic copper concentration >250 pg per gram of dry weight is diagnostic of Wilson’s disease.
a-1 antitrypsin deficiency
Deficiency of a-1-antitrypsin is the most common metabolic disease affecting the liver. Diagnosis of a-1-antitrypsin deficiency is suggested by decreased a-1-antitrypsin levels and is usually confirmed by genotypic analysis. Liver biopsy rarely done for diagnosis, may be helpful if the characteristic periodic acid-Schiff-positive, diastase-resistant globules are present, but the absence of such globules does not exclude the diagnosis.
6. Unexplained Cholestasis
Extrahepatic biliary obstruction
The advent of ultrasonography, computed tomography (CT) scanning, and endoscopic retrograde cholangiography have made liver biopsy unnecessary in most cases. However, 5% of extrahepatic cholestasis cases are diagnosed by biopsy because of the inability to visualize obstructed ducts or the failure to perform imaging studies before biopsy.
Intrahepatic causes of cholestasis
Damage or destruction of hepatocytes alters canalicular transport of bilirubin. Biopsy is needed to diagnose any of the many causes of intrahepatic cholestasis, which include viral hepatitis, alcoholic liver disease, primary biliary cirrhosis, primary sclerosing cholangitis (PSC), infiltrative diseases, infections, idiopathic recurrent cholestasis and drug-related hepatotoxicity. The need for liver biopsy in patients with intrahepatic cholestasis from primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) is more controversial. In chronic obstructive biliary tract disease, biopsy may be performed to show irrevocable damage and stage for liver transplantation.
Primary biliary cirrhosis
It is frequently diagnosed by the presence of laboratory abnormalities alone (positive antimitochondrial antibody tests usually associated with an isolated alkaline phosphatase level that is out of proportion to levels of other liver enzymes). Biopsy confirms the serological diagnosis and permits histologic staging and determination of prognosis.
Primary sclerosing cholangitis
The diagnosis of PSC rests almost entirely on cholangiographic findings, and the radiologic image of a diffusely strictured biliary system has supplanted histopathologic criteria for diagnosis.
Liver biopsy is diagnostic in only one third of patients with PSC and may show the characteristic “peri-ductal” pattern of fibrosis. Two third times nonspecific histologic abnormalities are typically found. Nevertheless, by demonstrating the degree of biliary fibrosis, biopsy may help to determine optimal timing for liver transplantation.
Infiltrative diseases
An increase in bilirubin or other liver test abnormalities may result from primary hepatic or metastatic tumors. By the time jaundice occurs, much of the liver has been replaced by tumor, and prognosis is poor. Jaundice can occur early when malignancies obstruct the bile duct (eg, cholangiocarcinoma, metastatic adenopathy). Hodgkin’s and non-Hodgkin’s lymphoma can manifest as diffuse hepatic infiltration with cholestasis. Liver biopsy is generally diagnostic.
Infections
Infections can cause jaundice directly through obstruction of ducts (eg, ascaris), cholestasis (eg, tuberculosis), or hyperbilirubinemia associated with sepsis and endotoxemia (cholestasis lente). In the septic patient, liver biopsy will reveal cholestasis with minimal inflammation, but biopsy should be deferred in very ill patients.
7. Transplantation
Biopsy of donor liver may be indicated to evaluate conditions which might effect graft-survival like excessive steatosis. The use of liver biopsy after liver transplantation is increasing, and policies on histological monitoring vary between liver transplant units. Some units perform routine biopsies on day 7 after transplant to assess acute rejection, whereas others do annual review biopsies at which abnormalities are frequently seen.[7] Liver biopsy is also useful in the diagnosis of invasive cytomegalovirus infection and in assessing recurrent disease.[8,9]
8. Hepatic Neoplasms and Other Focal Lesions
Diagnosis of space-occupying lesion is one of the traditional application of liver biopsy and even remains useful today, as more and more SOL are being identified as incidental findings or during routine screening for cancer or other conditions.
FNA might be able to provide tissue diagnosis in most of these cases. Core liver biopsy may be necessary to provide sufficient tissue for immunohistochemistry for identifying unknown primary. Biopsy of focal lesions should be done only after clinical and imaging data have confirmed a solid mass. Biopsies must not be performed on cysts, abscesses, or hemangiomas.
If biopsy of a focal lesion is necessary for diagnosis, it is best obtained by ultrasound- or CT-guided fine-needle aspiration. A solid tumor in a cirrhotic liver or an alpha fetoprotein level>400 ng/mL in the presence of a solid tumor is diagnostic of hepatocellular carcinoma, and biopsy rarely adds to management. However, increased a-fetoprotein levels in the setting of active liver disease without a focal lesion may reflect a diffuse tumor and in such cases biopsy may be helpful.
The role of percutaneous liver biopsy in the diagnosis of focal liver lesions depends largely upon the clinical picture. In most patients with malignant hepatocellular carcinomaultrasound scanning, CT, and measurement of serum afetoprotein will allow a diagnosis to be made (in the context of a space-occupying lesion in a cirrhotic patient). Similarly, a patient with a history of colonic resection for neoplasia who presents with a solitary lesion in the liver associated with raised serum carcinoembryonic antigen, may not require a biopsy of the lesion to make the diagnosis of a potentially resectable metastasis. Liver biopsy also carries a documented risk of seeding tumors down the biopsy track.[10] The magnitude of this risk is currently unknown. Modern imaging techniques can also help to define other types of focal hepatic lesions such as hemangiomata and focal nodular hyperplasia. In these situations, some experts believe that the risk of bleeding after biopsy of a malignant tumor is greatest when the tumor is superficial and so recommend traversing normal liver before sampling tumor tissue. Fine needle aspiration biopsy may be a safer option if material for histological examination is required in the case of a suspected angioma.[11]
9. Unexplained Hepatomegaly
The liver may enlarge as a result of various insults, including amyloid disease, Cushing’s syndrome, genetic metabolic disorders, alcoholic liver disease, cryptogenic cirrhosis, and neoplasms. Biopsy can often identify the cause of hepatomegaly and perhaps exclude an incorrect clinical diagnosis.
10. Unexplained Abnormalities on Liver Test Results
Liver biopsy is often used in the investigation of persistent abnormal liver enzymes but this must be taken in context, tempered by the results of other routine investigations along with the clinical picture. Liver biopsy provides an accurate diagnosis in >90% of patients with unexplained abnormalities on liver test results. The most common findings on liver biopsy in such cases include non-specific steatosis, NASH or congestion.
Some authors have questioned the utility of liver biopsy in the etiologic diagnosis of biochemical liver abnormalities of unknown cause. In one study, liver biopsy modified the therapeutic approach only in the three patients with hepatic tuberculosis.[12] Liver biopsy confirmed ultrasonographic findings of steatosis and differentiated bland steatosis from NASH, but did not influence the therapeutic approach.[12] Most patients with normal findings on ultrasonography had normal or near-normal biopsies.[12] The indication for liver biopsy should be individualized.
11. Research
Using liver biopsy in the context of research is controversial but has undoubtedly given invaluable information in the past in areas such as chronic hepatitis C and hepatitis B disease progression, studying the response to treatment and the development of new drugs. Liver biopsies should be performed in the context of a clinical trial and where approval has been given by the local research ethics committee. In circumstances where the patient will derive no potential benefit from the procedure, and will thus only accrue the risks of that procedure, the patient should be fully aware of this and give written and informed consent.
12. Non alcoholic fatty liver disease (NAFLD)
The initial clinical and laboratory assessment of a patient with suspected NAFLD should be determined by ASA, ALA, ALP (biochemical markers of liver injury and cholestasis) and liver functions (serum bilirubin, albumin, and prothrombin time). The next steps include presence of hepatitis C or any alternative clinical condition and estimate alcohol consumption. In absence of cirrhosis this is often sufficient for diagnosis. However diagnosis of steatohepatitis as apposed to fatty live alone, and its grade and stage can only be made precisely by a liver biopsy. The cost and risks of the biopsy are generally weighed against the value of the information obtained from the biopsy in estimating prognosis and guiding future management decisions.
13. Chronic viral hepatitis
The usefulness of liver biopsy in management of chronic viral hepatitis was questionable but with the emergence of new antiviral therapies there is no doubt of the value of histology in assessing patients that will be candidates for therapy and will likely benefit from treatment and assessing their response to it.
Chronic hepatitis C patients (with positive serum PCR), should undergo liver biopsy to be considered for antiviral therapy. Up to 50% of patients with active disease have a normal serum ALT, and performing a liver biopsy in these patients will allow an assessment of the grading of disease activity and staging of fibrosis and calculation of the Hepatitis Activity Index (a necroinflammatory-fibrosis scoring system). Unfortunately, histology of a single liver biopsy sample and the monitoring of aminotransferases are poor predictors of disease progression. Serial histology with biopsies taken every two or three years may be needed to assess disease progression and prognosis, especially in refractory cases.
Chronic hepatitis
Liver biopsy is indicated in hepatitis C virus (HCV) or hepatitis B when persistent, i.e., >6 months; when intermittent abnormalities in transaminase levels are observed; or when an alternative diagnosis (eg, alcoholic liver disease, nonalcoholic steatohepatitis [NASH], or hemochromatosis) is possible. Studies have demonstrated that >20% of HCV patients with normal serum alanine aminotransferase levels have advanced liver disease.
Follow-up biopsies may be helpful in assessing response to therapy and progression of disease. In HCV, liver biopsy impacts physician judgment with regard to antiviral therapy in several ways:
1. Likelihood of response to interferon: A decreased viral response is observed when diffuse fibrosis or cirrhosis is present.
2. Severity of infection: When the date of infection is relatively certain, the degree of fibrosis allows estimation of the rate of progression. Rapid progression increases the urgency for therapy, whereas with slower progression, therapy may be deferred.
3. Alternative diagnosis: Another cause of liver disease may be diagnosed in 4% of HCV patients.
4. Posttreatment biopsy: In settings other than clinical trials, posttreatment biopsy does not result in information sufficient to warrant the discomfort, risk, and cost.
Role of Liver Biopsy in Chronic Hepatitis C:
The main reasons for performing a liver biopsy includes current status of the liver injury and identifies features to start therapy. It also reveals advanced fibrosis or cirrhosis that necessitates screening for hepatocellular carcinoma. Though biopsy is used for the grade and stage of liver injury, it can also used for knowing histological progression regarding a disease.
According to the recommendations given by AASLD, a liver biopsy should be considered in patients with chronic hepatitis C infection if the patient and health care provider wish information regarding fibrosis stage for prognostic purpose or to make a decision regarding treatment(Class IIa, Level B) Although available noninvasive tests may be useful in defining the presence or absence of advanced fibrosis I persons with chronic hepatitis C infection , but it should not replace the liver biopsy in routine clinical picture( Class IIb, Level C)
Acute hepatitis: The majority of cases of acute icteric hepatitis are diagnosed using viral serology. Liver biopsy in this setting is generally not indicated; however, autoimmune hepatitis may have an acute presentation, and early biopsy to establish the diagnosis may improve outcome.
Autoimmune hepatitis: Autoimmune hepatitis is a selfperpetuating hepatocellular inflammation characterized histologically by the presence of periportal hepatitis. Diagnosis requires the absence of viral markers, alcohol consumption, use of hepatotoxic medications, and biliary lesions. Liver biopsy is essential to establish the diagnosis and determine patient prognosis. The presence of cirrhosis in a liver biopsy specimen indicates a poor prognosis. Biopsy may also be useful in evaluating therapeutic response to steroids or immunosuppressive agents.
Ischemic hepatitis: Ischemic hepatitis with very high aminotransferase values is usually preceded by hypotension, hypoxemia, or both. This may be a manifestation of multiorgan failure and portends a poor prognosis. If the patient survives, aminotransferase levels normalize rapidly, generally within a few days. Liver biopsy is usually not necessary to establish the diagnosis.
Alcoholic liver disease : - If the patient history includes excessive ethanol consumption, biopsy is unnecessary. If biopsy is performed, the most common histologic features are steatosis, ballooning degeneration of hepatocytes, hyaline (apoptotic) bodies, neutrophil inflammation, and pericellular
fibrosis.
Contraindications
Liver biopsy is a safe procedure when performed by experienced operators. Froehlich et al[13] noted a lower complication rate for physicians who performed more than 50 biopsies a year. Prior ultrasonographic localization of the biopsy site may decrease the rate of complications for physicians who perform infrequent liver biopsies. “Blind” liver biopsies should be performed by experienced gastroenterologists, hepatologists, or transplantation surgeons.[14] Contraindications to percutaneous liver biopsy are relatively few, but identifying contraindications is important to avoid the major complications associated with the procedure. Contraindications to liver biopsy include the following:
Absolute [15]
Uncooperative patient
History of unexplained bleeding
Bleeding tendency*
Prothrombin time >4 seconds more than control, (INR) greater than 1.6
Thrombocytopenia, Platelets <60,000/mm3
Prolonged bleeding time (10 min)
NSAID use within last 7 to 10 days
Unavailability of blood transfusion support
Suspected hemangioma or other vascular tumor
Inability to identify an adequate biopsy site by percussion and/or ultrasound
Suspected echinococcal cysts in the liver
Relative[15]
Morbid obesity (transjugular route preferred)
Ascites (transjugular route preferred)
Hemophilia
Infection in right pleural cavity
Infection below right hemidiaphragm
Suspected hemangioma
Suspected echinococcal infection
(* Although these criteria are considered absolute contraindications by most hepatologists, they can be corrected by transfusions of platelets or fresh-frozen plasma and are therefore not truly absolute.)
† Use of aspirin within 7-10 days is an absolute contraindication to liver biopsy. Use of other NSAIDS within the previous 3 days is generally an absolute contraindication.
1. Uncooperative patient
At the time of biopsy, it is essential for the patients to be cooperative and must be able to hold their breath and remain still during the procedure. An untoward movement when the biopsy needle is in the hepatic parenchyma can result in laceration of the liver and/or capsule which can lead to intrahepatic and/or intra-peritoneal hemorrhage. Sedation should be considered for such patients, and short-acting benzodiazepianes like lorazepam, midazolam can be used to allay anxiety and fear, with no increased risk.[16] When absolutely necessary, the biopsy may be performed under general anesthesia in uncooperative patients in whom the benefit of obtaining liver histology outweighs the risks of the procedure
2. Extrahepatic cholestasis and cholangitis
Cholestasis due to extrahepatic biliary obstruction is usually stated as a contraindication to liver biopsy due to the risk of bile leakage with subsequent biliary peritonitis, septic shock, and death.[17] With the availability of current hepato-biliary imaging techniques (ERCP, MRCP), the indication for liver biopsy and its benefits in biliary obstruction have decreased significantly and it should only be performed in these cases when there is doubt about the diagnosis and the benefit of knowing liver histology outweighs the risk. The transjugular approach is preferred under these circumstances to minimize the risk biliary peritonitis.[18]
3. Impaired coagulation.
There are widely divergent opinions about the values at which abnormal coagulation indexes become contraindications to percutaneous liver biopsy. There are number of studies that show that the degree of bleeding from the liver puncture site bears no correlation to peripheral blood coagulation parameters, when these parameters are modestly increased.[19,20] Some of these investigators have postulated that this discrepancy in liver bleeding time may be due to the inherent elasticity of the biopsy track collapsing down after the core has been taken, together with the high local concentrations of clotting factors within the hepatic parenchyma.[21] It should, however, be borne in mind that during a blind percutaneous liver biopsy, the liver is not the only structure to be punctured and the skin and subcutaneous tissues (and occasionally other organs) can bleed. Thus, peripheral indexes of clotting must still be taken into consideration. In the absence of factor concentrate inhibitors, liver biopsy is safe if the clotting abnormalities are corrected before and for 24 hours after biopsy.[22,23]
a. Prothrombin time
Several large studies have failed to show an increased risk of bleeding associated with a prolongation of the prothrombin time of four seconds above control values.[19,21,24] The largest retrospective study of percutaneous liver biopsy to date failed to show any correlation between a prolongation of prothrombin time by seven seconds over control values and the occurrence of hemorrhagic complications.[25] By contrast, a number of other studies, however, have corroborated the widely held belief that a coagulopathy predisposes the patient to hemorrhage after percutaneous liver biopsy.[26] A study in UK showed that bleeding was commoner if the international normalized ratio (INR) was raised, with 3.3% of the bleeds occurring when the INR was between 1.3 and 1.5, and 7.1% occurring when the INR was >1.5.[27] This suggests that about 90% of the bleeds occurred in patients with an INR<1.3 and reinforces the fact that having a normal INR or prothrombin time is no reassurance that the patient will not bleed after the procedure.
b. Thrombocytopenia
The level at which thrombocytopenia becomes a contraindication to percutaneous liver biopsy is uncertain from published data. One authority[28] proposes a platelet count above 100,000/mm3, whereas other groups such as the Mayo Clinic regard counts as low as 56,000/mm3 to be safe[24] Most recognized UK texts require that the platelet count be above 80,000/cubic mm[29] whereas a survey of most US centers showed a preference for platelet counts above 50,000/cubic mm[30] One study of 87 patients found that those patients with a platelet count below 60,000/mm3 were significantly more likely to bleed after percutaneous liver biopsy than those with platelet counts above this value.[31] The evidence for a cut off value remains scanty and takes no account of the function of the platelets.
The effect on bleeding of thrombocytopenia due to hypersplenism compared with thrombocytopenia resulting from bone marrow failure has, to our knowledge, not been studied in detail. The absolute value of the platelet count may not be crucial in determining the risk of bleeding as it is well recognized that even those patients with normal prothrombin times and platelet counts can have severely deranged bleeding times. Nevertheless, for a percutaneous liver biopsy the minimum platelet count felt to be safe without the need for support is 60,000/mm3.
c. Platelet function/bleeding time
The practice of measuring bleeding time (BT) before liver biopsy is much more common in Asia compared with the USA (73 v 36%).[30] BT is seldom if ever measured in UK centers prior to liver biopsy even though the ingestion of aspirin and other non-steroidal anti-inflammatory drugs in the week prior to invasive intervention is a recognized contraindication by several authorities. There are to our knowledge, however, no convincing data to support this as a contraindication to percutaneous liver biopsy.
Patients with renal impairment usually have abnormalities of platelet function. According to one small study, patients with end stage renal failure on hemodialysis are at high risk (up to 50%) of hemorrhagic complications after percutaneous liver biopsy, independent of the BT.[32] This same study suggested that liver transplant recipients with a BT above 10 minutes (upper limit of normal) had a higher incidence of bleeding complications compared with those with a BT below 10 minutes.The sample size, however, is too small to allow any firm conclusions to be drawn.
Several other factors are likely to affect platelet function with or without affecting the BT. This fact, together with the considerable variation in results obtained between different operators, makes the use of BT as a measure of risk for hemorrhage difficult to interpret. One study was able to show that within a group of cirrhotic patients, those with abnormal BT (42%) were more likely to have significantly lower platelet counts, longer prothrombin times and higher blood urea and serum bilirubin than those with normal BT (58%). It also demonstrated that the bilirubin concentration as well as the platelet count were independently correlated with the BT (although the correlation for the latter was weak, and the raised serum bilirubin may well be just a surrogate marker for the severity of liver disease).[33]
4. Ascites
The presence of tense ascites is considered a contraindication to percutaneous liver biopsy, because of the increased difficulty of obtaining a satisfactory specimen due the distance between the abdominal wall and the liver, and also because of the possibility of lacerating the liver with risk of uncontrollable hemorrhage into the ascites. Despite the lack of evidence to support these logical reasoning, most authorities suggest other alternatives for obtaining a liver biopsy in a patient with tense ascites. This includes performing a total paracentesis prior to performing the percutaneous biopsy or performing an image guided biopsy, a transjugular liver biopsy, or a laparoscopic biopsy. There is some evidence to support the fact USG or CT guided liver biopsy in the presence of ascites does not increase the complication rate.[34,35]
5. Cystic lesions
Modern imaging techniques can often identify benign cystic lesions of the liver, thereby eliminating the need for biopsy in many cases. Cystic lesions within the liver may communicate with several structures including the biliary tree and therefore pose a risk of biliary peritonitis after biopsy. The cystic lesion quoted most often as a contraindication to percutaneous liver biopsy was the echinococcal cyst because of the risk of dissemination of the hydatid cysts throughout the abdomen, and the risk of anaphylaxis. Recent advances in the treatment of hydatid disease of the liver mean that this may no longer be so.[36] Aspiration of hydatid cysts with 19-22 gauge needles under ultrasound guidance has been shown to be safe and can be used both diagnostically[37] and therapeutically[38] for theinjection of hypertonic saline or 95% ethanol under albendazole cover.
6. Vascular lesions
Biopsies should not be performed on suspected liver hemangiomas. In addition, adenomas, hepatocellular carcinoma, and amyloidosis are also prone to bleeding.
7. Amyloidosis
The use of liver biopsy in the diagnosis of amyloid liver disease was first reported in 1928. Volwiler and Jones reported the first death from hemorrhage after amyloid liver biopsy.[39] which along with other reports of hemorrhage after liver biopsy in patients with amyloid have lead to the inclusion of amyloid liver disease in the list of contraindications to percutaneous liver biopsy.[39] One intraperitoneal bleed was reported in a small series of liver biopsies in amyloid liver disease in 18 patients, which was managed conservatively.[40] However, there are no large controlled trials to show an increased risk of hemorrhage after liver biopsy in amyloid liver disease. Stauffer and colleagues[40] decided that liver biopsy was a useful method in the establishment of the diagnosis of hepatic amyloid, and certainly in the context of the investigation of hepatomegaly of uncertain etiology this seems reasonable. However, if a diagnosis of amyloidosis had already been made or is strongly suspected, then a specific indication for performing a percutaneous liver biopsy is needed rather than for performing a more benign procedure such as a rectal biopsy.
8. Local infection
Infection in the right lung, pleural space, or peritoneal cavity may cause infectious organisms to be carried into the liver by the biopsy needle, with potential risk of causing infectious hepatitis or hepatic abscess.
Complications
Although the liver has a rich vascular supply, complications associated with percutaneous liver biopsy are rare, but are potentially fatal. The majority (60%) of complications occur within the first 2 hours, and 96% of complications occur during the first 24 hours after the procedure.[25,41] Potentially fatal complications generally occur within the first 6 hours, which is the reason for the standard 6-hour postbiopsy monitoring period. Approximately 2% (1-3%) of patients undergoing biopsy require hospitalization for the management of complications after a liver biopsy, especially if the procedure was performed with a Tru-cut biopsy needle. Vasovagal episode, hypotension and pain are the most common reasons for admission.[14,42]
Complications of percutaneous liver biopsy43
· Pain (0.056-22%)
· Pleuritic
· Peritoneal
· Diaphragmatic
· Hemorrhage
· Intraperitoneal (0.03-0.7%)
· Intrahepatic and/or subcapsular (0.059-23%)
· Hemobilia (0.059-0.2%)
· Bile peritonitis (0.03-0.22%)
· Bacteremia
· Sepsis (0.088%) and abscess formation
· Pneumothorax and/or pleural effusion (0.08-0.28%)
· Hemothorax (0.18-0.49%)
· Arteriovenous fistula (5.4%)
· Subcutaneous emphysema (0.014%)
· Anesthetic reaction (0.029%)
· Needle break (0.02-0.059%)
· Biopsy of other organs
· Lung (0.001-0.014%)
· Gallbladder (0.034-0.117%)
· Kidney (0.09-0.029%)
· Colon (0.003-0.044%)
· Mortality (0.008-0.3%)
1. Pain
Pain occurs in approximately 30- 50% of patients undergoing a liver biopsy. Immediately after the procedure, patients report localized discomfort at the biopsy site or mild, dull ache in the right upper quadrant. This typically is relatively short in duration, lasting less than 2 hours, and often responds to analgesics.[44] Approximately one fourth of patients have pain referred to the right shoulder, but is easily controlled with acetaminophen or mild narcotic analgesics. Unrelenting, severe abdominal pain is alarming, possibly indicating a more serious complication such as intraperitoneal bleeding or peritonitis.
2. Hemorrhage
Bleeding is another complication which is potentially lethal. Presentations include subcapsular or parenchymal hematoma, free intraperitoneal hemorrhage or hemobilia. Although very rare, clinically significant intraperitoneal hemorrhage is the most common fatal complication of percutaneous liver biopsy. Peritoneal hemorrhage may result from laceration of the liver caused by deep inspiration or patient movement during the biopsy, or may result from penetration of distended veins, aberrant arteries or branch of the hepatic artery or portal vein. It commonly manifests within the first 2-3 hours after the Procedure[25,45] although it has been reported to present as long as 24 hours post-procedure. Late hemorrhage is associated with a poor outcome. The overall rate of occurrence of peritoneal hemorrhage is around 0.3%. Older age, multiple needle passes (>3), and the presence of cirrhosis or hepatic malignancy have been described to be associated with increased risk of free intraperitoneal hemorrhage complicating liver biopsy.[25,42]
Abdominal pain and persistent hemodynamic instability, presenting as tachycardia and hypotension, are typical of significant bleeding. Early diagnosis via ultrasonography or CT is preferred. Findings of free intraperitoneal fluid on ultrasonography or CT should be correlated with the clinical assessment of the patient.[46] If hemorrhage is suspected, immediate arrangements for blood, platelets, and plasma should be made, and an angiographer and surgeon should be alerted early in the process to facilitate rapid intervention if needed.
Aggressive fluid management and blood and platelet transfusion, as indicated, may be sufficient in most cases to improve the patient’s hemodynamic status. If hemodynamic instability persists despite aggressive resuscitative measures, angiographic embolization or surgical exploration is indicated to stop the bleeding. Angiography with potential embolization is the preferred intervention in most cases.
Intrahepatic or subcapsular hematomas are the most common bleeding complication and have been noted on approximately 23% of ultrasound images obtained following biopsy. Most of these are clinically asymptomatic and are often incidental findings.[47] The rate of occurrence have been similar after either blind or laparoscopy-guided modalities, but incidence may be influenced by needle type and imaging technique. Symptomatic hematomas require imaging by ultrasound, CT or MRI to establish the diagnosis. Large intrahepatic hematomas may cause pain along with tachycardia,hypotension, and a delayed decrease in the hematocrit.[45] Conservative treatment of hematomas is generally sufficient. Rarely, large hematomas may cause biliary obstruction which would require angiographic embolization or surgical management.
The least common of the hemorrhagic complications is hemobilia, or bleeding into the bile duct associated with the classic triad of gastrointestinal bleeding, biliary colic, and jaundice.25 It is a rare complication of liver biopsy; one study of 68,276 biopsies reported only 4 instances of hemobilia.[25] Clinical presentation ranges from chronic anemia to rapid exsanguination. Hemobilia typically develops later than other complications. The average time to onset of symptoms is approximately five days after the biopsy, [48] but onset may occur earlier. Conservative treatment often is sufficient. However, if clinically significant hemobilia is present, angiography is the modality of choice because both diagnosis and intervention can be accomplished with a single procedure. 3. Transient bacteremia after percutaneous biopsy of a normal liver is a well recognized phenomenon and has been reported in 5.8 to 13.5% of patients after liver biopsy.[43] Although, such bacteremia is generally inconsequential, septicemia and shock can develop on rare occasions in patients with biliary obstruction and cholangitis. Currently, there are no recommendations for the routine use of prophylactic antibiotics in patients undergoing liver biopsy, including those with prosthetic valves or joints.[49]
4. Biliary peritonitis is another noteworthy complication, although rare. Severe abdominal pain and vasovagal hypotension herald its occurrence. Analgesics and fluid management usually are sufficient, but persistence of the condition may necessitate endoscopic retrograde cholangiopancreatography with stent placement Other rare complications of percutaneous liver biopsy include biliary ascites, bile pleuritis, bile peritonitis, pneumothorax, hemothorax, subcutaneous emphysema, pneumoperitoneum, pneumoscrotum, subphrenic abscess, carcinoid crisis, anaphylaxis after biopsy of an echinococcal cyst, pancreatitis due to hemobilia, breakage of the biopsy needle, and accidental biopsy of other organs.[25,45,50]
The mortality rate among patients after percutaneous liver biopsy is approximately 1 in 10,000 to 1 in 12,000,[45,24] and is highest among patients who undergo biopsies of malignant lesions.
Procedure
Preparation:
A detailed history and physical are essential elements to obtain prior to performing a liver biopsy. This history will provide the indication or any contraindications for this procedure. The physician should ask the patient about any personal or family history of bleeding disorders or prior episodes of prolonged bleeding after procedures or operations. A detailed medication list should be obtained, particularly focusing on medications interfering with coagulation such as warfarin, aspirin and nonsteroidal anti-inflammatory drugs. A complete list of allergies to medicine should be obtained, with particular attention being paid to adverse affects related to anesthetic agents.
The patient should be given information prior to the procedure with explicit instructions on what to expect and how to prepare for the examination. Any medications affecting coagulation should be discontinued preferably one week prior to the biopsy. Typically, overnight fasting is requested prior to the procedure. On occasion, just prior to the procedure, the operator may ask the patient to ingest a food with high fat content to stimulate gallbladder contraction to lower the risk of gallbladder perforation.
Informed consent must be obtained by the physician from the patient or a designated conservator prior to the procedure. The physician should provide a detailed explanation about the risks and benefits of performing the biopsy. The physician should answer any questions the patient may have about the procedure itself and reassure the patient about the safety.
Equipment: The following equipment is necessary to have prior to performing the liver biopsy: signed informed consent, sterile gloves, a percutaneous liver biopsy device tray (which is available from multiple commercial medical device companies). Typically the device tray will include the following: an antiseptic skin preparation solution such as betadine, sterile gauze, sterile drape, 10 ml ampule of sterile saline solution, sterile surgical scapel, sterile core biopsy needle, 2 sterile injection needles (typically 21 and 25 gauge), formalin filled specimen container. Imaging equipment is not essential and may vary amongst institutions. However, we recommend ultrasound guidance and imaging prior to performing this procedure.
Timeout: Prior to the procedure beginning, a “timeout” should occur as final verification of correct patient, procedure, physician and site.
Patient Position: Upon entering the room, the patient should be positioned appropriately to allow optimal conditions for an adequate and safe biopsy. The patient should be in the supine position and up against the right edge of the bed. The patient’s right arm is then positioned behind his or her head. We then ask the patient to angle their hips and lower extremities toward the left. This positioning applies forces to rotate the liver against the right body wall and toward the entry point for the biopsy needle. The patient should be comfortable enough to maintain this position for several minutes. Lastly, the height of the patient’s stretcher should be adjusted to approximately the operator’s elbow level.
Inspection and marking: Once the patient is positioned appropriately, the operator should inspect and palpate the patient’s abdomen and liver edge. Percussion should be performed over the right upper quadrant in the midaxillary line. The percussion should focus on the intercostal spaces. The biopsy is typically performed in the 7th or 8th intercostal space, but location may vary. Percussion during inspiration and end expiration allows the operator to listen for lung resonance (during inspiration when the lungs are fully expanded and the diaphragm has shifted caudad) changing to liver dullness (after full exhalation when the lungs are collapsed and the diaphragm has shifted cephalad). The biopsy should be performed in an intercostal space which is dull to percussion at the end of exhalation. Instructing the patient to breathe in an appropriate manner to facilitate this process is key to a safe procedure.
The patient should be instructed to inhale, and then exhale slowly and completely. At the end of exhalation, the patient should hold their breath, which will allow the operator the time to perform the biopsy with the liver in the proper plane. Marking: Once an intercostal space has been chosen as a potential site, the patient should practice this breathing as the operator percusses the site to ensure appropriate dullness. A mark “X” is then placed on the biopsy site with a marking pen. The site should be marked on the superior border of the rib to avoid the neurovascular bundle which resides on the inferior border.
Ultrasound: At this juncture, ultrasound is used to verify the adequacy of the biopsy site. The gallbladder should be identified, if it has not been surgically removed, to ensure it is not in the plane of the impending biopsy. The patient is again instructed to inhale and fully exhale while the operator holds the ultrasound transducer at the designated biopsy site. At the end of exhalation, an adequate amount of liver parenchyma should be fully visible with no evidence of other organs in the biopsy plane. Doppler imaging can be applied to the field to ensure the absence of large blood vessels in this plane. One image of the liver parenchyma and one image of the parenchyma with doppler flow can be captured and saved for documentation.
Once adequate imaging of the liver has occurred, the operator should consider the directional plane of the biopsy needle. At the time of the biopsy, the needle should pass in the same directional plane as the ultrasound transducer signal. In an attempt to visualize this plane, we keep the transducer in place and use a flat edge to mark a line across the patient’s abdomen in this plane. The operator should be sure not to vary too much in the cranial/caudal or the anterior/posterior direction as this can lead to unnecessary injury.
Sterilization
After fully marking the entry for the biopsy site and the directional plane of the needle, the operator should begin the sterilizing process. A topical povidone-iodine solution antiseptic should be used for this process. The antiseptic should be applied first at the point of entry, and then continued in the surrounding area by moving out in concentric circles. For this component of the procedure, non sterile gloves may be worn.
Once the area has been appropriately sterilized, the operator should open the cover to the biopsy tray and visually inspect the items to ensure that all of the items appear intact and are available. If all items appear intact, then the operator should place on a sterile gown, cap, mask with face shield and finally, sterile gloves. The sterile drape should then be placed on the patient, with the “X” marked biopsy site visible within the drape’s central opening. All exposed areas within the sterile drape opening should be completely covered with the topical antiseptic. If possible, the crease from the drape’s folding should align with the directional plane line of the biopsy. Sterile technique should be maintained throughout the entire procedure.
Anesthesia
Conscious sedation may be used for percutaneous liver biopsies. However, as previously stated, active patient participation is helpful to ensure the biopsy is performed during end expiration. In addition, the biopsy itself is performed so rapidly, that conscious sedation is rarely necessary. Therefore, we use primarily local anasthesia. Once the sterile drape is in place, local anasthetic should be used. 1 or 2% Lidocaine is aspirated into a syringe, and a 25 gauge needle is used to apply the medication to the dermal and subcuatenous tissue layers. The 25 gauge needle is then exchanged for a 21 or 22 gauge needle for deeper lidocaine injection. All tissue layers should be injected down to the capsule of the liver, and an adequate amount of lidocaine should be used to maximize local effect. Suction should be applied to the syringe prior to injection at each tissue layer. A small amount of blood may be seen within the syringe once the needle has reached the liver capsule and parenchyma. Once this is seen, the local anesthetic has been applied deep enough. Considerable effort should be made to provide adequate anasthetic to the portion of the capsule that will come in contact with the needle. This may be achieved by applying the deep layers of anasthesia during end expiration, or angling the anasthetic needle cephalad in anticipation of the motion that will occur with expiration.
Technique
Once adequate local anasthesia has been injected, palpation of this region should confirm positioning above the rib. A second syringe is then used to aspirate the provided sterile saline. The biopsy needle is then attached to the syringe. The needle must be attached securely. A loosely attached needle would negate the negative pressure essential during the biopsy.
A small, shallow incision is then made using the provided scalpel, allowing the biopsy needle to pass through the skin easily. The needle is introduced into the incision and slowly advanced toward the liver. The needle should passed through the anesthetized tract. Suction should be applied to the syringe as the needle passes through the tissue planes. There should be a popping sensation, with a lessening of resistance, as the needle passes through the peritoneum. A small amount of saline should then be flushed through the needle to expel any superficial tissue in the needle.
In final preparation for the biopsy, the operator should be sure the needle is aligned with the straight line drawn previously (which represented the direction displayed by the ultrasound transducer). In addition, the needle should be aligned and passed in a plane parallel to the floor. The operator should avoid passing the needle in a superior or posterior direction.
Suction is applied to the syringe. Some syringes have a locking mechanism to provide constant negative pressure. The patient is again asked to completely exhale and to hold their breath at end expiration. At this juncture, with constant suction being applied to the syringe, the needle is rapidly advanced into the liver and then withdrawn. The entire process of passing the needle should last no longer then approximately one second.
The needle is removed completely from the patient, and a gauze is applied with pressure to the biopsy site.
The biopsy specimen is now within the needle or syringe. The specimen can be removed from the syringe by pulling the plunger out the back of the syringe and emptying the contents into a formalin containing bottle. The specimen may also be removed by pushing the syringe contents back through the syringe and needle into the formalin containing bottle.
However, this in theory, may damage the specimen. If no specimen is obtained, the needle and syringe should be carefully examined again to ensure no problems exist. Another pass may be necessary. No more than three passes should be performed, as the risk of bleeding and other complications
increases significantly.
Post Procedure Monitoring:
Once an adequate specimen is obtained, a bandage should be applied to the biopsy site. The patient should be instructed to lay in the right lateral decubitus position for at least 2 hours.
Frequent vital signs should be monitored. The patient should be evaluated for any evidence of a complication. Post procedure monitoring should last at least 2 hours prior to discharge.
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