A Systematic Review of the Quality of Liver Biopsy Specimens
 |
|
|
|
|
|
|
|
|
 |
 |
 |
 |
 |
 |
 |
 |
|
Background
The liver is the master of metabolism. It synthesizes many of the bodies proteins, is involved in digestion of proteins, carbohydrates, and fats, and detoxifies the body, eliminating it into the bile. The liver and gallbladder are intimately connected by a series of bile ducts. These bile ducts drain to the small intestine eventually joining up with the pancreatic duct. The liver biopsy may be either a tissue core biopsy or a radiologically directed fine needle aspiration biopsy. In this latter technique, a needle is directed into a mass lesion of the liver, a small sample is aspirated, smeared onto a microscope slide, stained, and analyzed under a microscope by the pathologist.. Very often a diagnosis can immediately be rendered.
Alagille Syndrome
Alcoholic Hepatitis
Ampulla of Vater Carcinoma
Budd-Chiari Syndrome (Hepatic Vein Thrombosis)
Cirrhosis
Desmoplastic Nested Spindle Cell Tumor of the Liver
Extrahepatic Biliary Atresia
Focal Nodular Hyperplasia
Gallbladder Cancer
Gallbladder-Chronic Cholecystis
Hemochromatosis
HepatitisHepatitis, Chronic
Hepatitis, Neonatal (Giant cell)
Intraductal Papillary Neoplasia of the Liver
Liver Cancer and Tumors
Nodular Regenerative Hyperplasia
Nonalcoholic Fatty Liver Disease (Nonalcoholic steatohepatitis)
Sclerosing CholangitisOUTLINE
Gross Appearance and Clinical Variants Histopathological Features and Variants Special Stains/
Immunohistochemistry/
Electron MicroscopyCommonly Used Terms Internet Links
HISTOPATHOLOGY CHARACTERIZATION GENERAL
EvangelosCholongitasMD
Characteristics for an optimal liver biopsy specimen were recently defined as 20 to 25 mm long and/or containing more than 11 complete portal tracts (CPTs).
A systematic review of percutaneous liver biopsy (PLB) and transjugular liver biopsy (TJLB) series yielded only 32 PLB studies in which these characteristics were evaluated: mean ± SD length, 17.7 ± 5.8 mm and number of CPTs, 7.5 ± 3.4; and 15 TJLB studies: mean ± SD length, 13.5 ± 4.5 mm and number of CPTs, 6.8 ± 2.3. Studies of sampling heterogeneity and intraobserver and interobserver variability also used inadequate specimens by present standards. Only 11 (5.3%) of 207 therapeutic studies for chronic hepatitis B and C documented length and/or number of CPTs. Of the current 12 studies evaluating noninvasive fibrosis tests, only 8 documented length or number of CPTs, and only 1 documented length and number of CPTs.
New studies are needed based on adequate liver biopsy samples to provide reliable estimation of grading and staging in chronic liver disease.VARIANTS SMOOTH MUSCLE IN EXTRAHEPATIC BILE DUCT Smooth Muscle Distribution in the Extrahepatic Bile Duct
Histologic and Immunohistochemical Studies of 122 CasesSeung-Mo Hong, M.D.; Gyeong Hoon Kang, M.D.; Han Young Lee, M.D.; Jae Y. Ro, M.D., Ph.D.
From the Departments of Pathology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea (S.-M.H., G.H.K.); The University of Texas M.D. Anderson Cancer Center, Houston, Texas (J.Y.R.), U.S.A.; and Department of Forensic Pathology, National Institute of Scientific Investigation, Seoul, Korea (H.Y.L.).
Am J Surg Pathol 2000;24:660-667 Abstract quote The distribution of smooth muscle fibers in the extrahepatic bile duct (EBD) wall is not well characterized.
We analyzed 101 consecutive Whipple's operation specimens and 21 autopsy specimens for the pattern of smooth muscle distribution in EBD using the Masson-trichrome stain and the desmin immunohistochemical stain.
The patterns were categorized as continuous, interrupted, scattered, and no muscle layer. EBDs were divided into lower, middle, and upper portions, and the distribution pattern of smooth muscle fibers was analyzed separately in each portion. Because most surgically resected specimens contained the middle and lower EBDs with only a portion of the upper EBD, only the length of the middle and lower EBDs (common bile duct, CBD) was measured. The mean length of CBD in surgically resected specimens was 6.4 ± 1.4 cm (men, 6.6 ± 1.3 cm; women, 6.1 ± 1.5 cm). The mean length of CBD in autopsy specimens was 6.8 ± 1.0 cm. The predominant patterns of the lower third of the EBD were interrupted (49%) and continuous (43%). The predominant patterns of the middle third of the EBD were scattered (63%) and interrupted (23%). Those of the upper third of the EBD were no muscle fiber (58%) and scattered (39%). In conclusion, different patterns of smooth muscle distribution were observed in different portions of the EBD. Because scattered muscle fibers or no muscle fibers were the main features of the upper third of the EBD, understanding of this pattern may be helpful for assessment of the depth of invasion or staging of carcinoma of the upper third of the EBD.
STEATOSIS QUANTIFICATION
- Semiquantitative evaluation overestimates the degree of steatosis in liver biopsies: a comparison to stereological point counting.
Franzen LE, Ekstedt M, Kechagias S, Bodin L.
1Department of Pathology, Clinical Research Centre, University Hospital, Orebro, Sweden.
Mod Pathol. 2005 Jul;18(7):912-6. Abstract quote
The degree of steatosis in liver biopsies is usually assessed by a morphological semiquantitative approach in which the histopathologist uses a four-graded scale: 0-3 or none, slight, moderate and severe. Scores 1-3 are considered to correspond to fat deposition in <33, 33-66 and >66% of the hepatocytes.
There is a considerable inter- and intra-individual variation in such scoring methods and a more standardized and quantitative approach is preferable. In the present study, we compare the semiquantitative technique with the stereological point counting method in the assessment of hepatic steatosis. A total of 75 archived liver needle biopsies were used. They were selected according to the original routine diagnosis of slight, moderate or severe steatosis. In all, 10 randomly selected images from each biopsy were digitized into a computer, a point grid lattice was superimposed and the number of hits on fat globules was counted. A pathologist scored the specimens in a four-graded scale as described above. The mean liver biopsy area (volume) with fat in hepatocytes was 2.2% for grade 1, 9.2% for grade 2 and 23.1% for grade 3. The kappa value for the semiquantitative estimates was 0.71 for the unweigthed kappa and 0.87 for weighted kappa. The intraclass correlation coefficient (ICC) was 0.99 for images counted twice and 0.95 when two sets of images were captured from the same biopsy. These ICCs indicate excellent agreement and above that of the semiquantitative estimates.
In conclusion, the area/volume of fat content of the hepatocytes is greatly overemphasized in semiquantitative estimation. Furthermore, the point counting technique has a better reproducibility than visual evaluation and should be preferred in estimates of liver steatosis in scientific studies and in clinical contexts when the amount of steatosis is important for treatment and prognosis, such as liver transplantation.TRANSPLANTED LIVER Activation of hepatic stellate cells in liver tissue of patients with fulminant liver failure after treatment with bioartificial liver
Lydia M. Petrovic, MD
Nicolas Arkadopoulos, MD
Achilles A. Demetriou, MDHum Pathol 2002;32:1371-1375. Abstract quote
We studied the explanted livers from 12 patients with fulminant hepatic failure who were treated with a bioartificial liver and subsequently underwent orthotopic liver transplantation and from 18 patients who underwent orthotopic liver transplantation without previous treatment.
Ten normal livers were used as controls. In addition to morphologic evaluation, an immunohistochemical analysis was performed with the monoclonal antibodies for -smooth muscle actin and proliferation marker Ki-67. The expression of these markers was graded semiquantitatively from 0 to 3+ in a blinded fashion. The zonal distribution of activated hepatic stellate cells was also evaluated. In all cases, the hepatic stellate cells were activated and expressed -smooth muscle actin. In all patients with submassive or massive liver cell necrosis, the distribution of activated hepatic stellate cells was predominantly in zone 1 of the acinus (periportal area).
In contrast, in cases with early nodular regeneration and no significant fibrosis, the activated hepatic stellate cells were distributed throughout the liver parenchyma, involving zones 2 and 3 of the acinus. Expression of the proliferation marker Ki-67 was graded 3+ in all patients treated with the bioartificial liver who had orthotopic liver transplantation and 2+ in patients who underwent orthotopic liver transplantation only.
Centrilobular histopathologic changes in liver transplant biopsies.Khettry U, Backer A, Ayata G, Lewis WD, Jenkins RL, Gordon FD.
Departments of Pathology, Surgery and Medicine, Lahey Clinic Medical Center, Burlington, MA; Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA; and Harvard Medical School, Boston, MA.
Hum Pathol 2002 Mar;33(3):270-6 Abstract quote We evaluated centrilobular histologic changes seen on post-orthotopic liver transplantation (OLT) biopsies to refine the pathologic diagnosis by systematic study of morphologic and clinical data with possible identification of prognostic criteria.
A total of 110 biopsies with zone 3 pathology from 59 patients were reviewed and correlated with clinical findings. Within the first 6 months post-OLT (group I), 39 of 47 patients had combinations of centrilobular hepatocytic dropout, ballooning, and cholestasis on single or multiple biopsies attributed to perioperative ischemic/perfusion injury; 12 of 39 patients with all 3 features present had increased incidence of biliary complications and sepsis and decreased 1-year patient and graft survival; 17 of 39 patients with 2 of the 3 features had increased biliary complications but not decreased 1-year survival; and the remaining 8 of 47 patients had central venulitis associated with acute cellular rejection. After 6 months post-OLT (group II), 14 patients, including 2 from group I, had biopsies with centrilobular pathology; 8 of 14 had central venulitis related to rejection (acute, 4; chronic, 4), and fibrosis was seen in 8 (rejection, 6; cardiac problems, 2). In conclusion, combinations of centrilobular hepatocytic ballooning, dropout, and cholestasis are seen in association with reversible or irreversible ischemic/perfusion damage in the early post-OLT period.
The presence of all 3 features is associated with a poor outcome. Central venulitis as a feature of acute/chronic rejection is seen at any time post-OLT and is not a predictor of poor graft/patient survival.
SPECIAL STAINS/
IMMUNO-HISTOCHEMISTRY/
OTHERCHARACTERIZATION IMMUNO-HISTOCHEMISTRY Identification of mitochondria in liver biopsies. A study by immunohistochemistry, immunogold and Western blot analysis.
Foschini MP, Macchia S, Losi L, Dei Tos AP, Pasquinelli G, Di Tommaso L, Del Duca S, Roncaroli F, Dal Monte PR.
Department of Radiology and Anatomic Pathology, Ospedale Bellaria, University of Bologna, Italy.
Virchows Arch 1998 Sep;433(3):267-73 Abstract quote
Hepatocytes are rich in mitochondria, which play an important role in hepatic metabolism. In certain pathologic conditions (most often alcoholic liver disease) mitochondria became enlarged; nevertheless, even in these conditions they are hardly detectable on light microscopy. Recently an antimitochondrial antibody (mAM), which recognizes a 60-kDa protein, has been characterized.
The purpose of the present study was to study immunoreactivity of this antibody in a series of liver biopsies. We studied 146 liver biopsies using an mAM. In 8 cases an ultrastructural study was also done, and in 2 cases Western blot analysis was performed.
Cases were divided as follows: alcoholic liver disease (ALD, 31); steatosis (8); nonalcoholic steatohepatitis (NASH, 1); hepatitis C virus (HCV)-related hepatitis (83); hepatitis B virus (HBV)-related hepatitis (6); primary biliary cirrhosis (1); sclerosing cholangitis (1); haemosiderosis (1); sarcoidosis (1); alpha-1-antitrypsin deficiency (1); nonspecific findings (12). All the patients were investigated for alcohol or drug abuse, pharmacological treatment, hyperlipidaemia, hypercholesterolaemia and diabetes. Immunoreactivity was diffuse in cases of ALD, NASH and steatosis, and in patients with drug abuse.
Electron microscopic immunogold and Western blot analysis confirmed that in the conditions examined the protein recognized by the mAM showed greater expression. Immunohistochemical staining was helpful in demonstrating a toxic or a metabolic insult even in cases in which the histological picture was blurred by viral infection.
BILIARY EPITHELIAL TREFOIL PEPTIDE
Biliary epithelial trefoil peptide expression is increased in biliary diseases.Srivatsa G, Giraud AS, Ulaganathan M, Yeomans ND, Dow C, Nicoll AJ.
Department of Medicine, University of Melbourne at Western Hospital, Footscray, Victoria, Australia, Department of Pathology, University of Melbourne at Western Hospital, Footscray, Victoria, Australia.
Histopathology 2002 Mar;40(3):261-8 Abstract quote Biliary epithelial trefoil peptide expression is increased in biliary diseases
Aims: Maintenance of the cellular integrity of the biliary epithelium may involve the production of mucins and mucin-associated peptides. In the luminal gastrointestinal tract, mucins and the mucin-associated trefoil peptides (TFF) are integral to cytoprotection and cellular repair of the mucosa.
Methods and results: Samples of normal and diseased human liver tissue were examined using histological and immunohistochemical techniques, for the expression of TFF and mucins. Bile ducts were classified as small, medium or large depending upon the number of biliary epithelial cells. TFF expression was demonstrated in biliary epithelial cells of both normal and diseased liver tissue. TFF expression was greatest in the large bile ducts. In normal liver tissue, expression of at least one TFF was demonstrated in 2-7% of small bile ducts, 5-31% of medium bile ducts and 31-85% of large bile ducts. Seventy-seven percent of large bile ducts secreted mucins and all three TFF concurrently, compared with 3% of medium bile ducts and no small bile ducts. Biliary disease resulted in an increased expression of TFF1 and TFF3 in the medium bile ducts.
Conclusions: The biliary epithelial cells in normal and diseased human liver tissue express TFF, particularly in the larger bile ducts. TFF expression may be up-regulated or induced in biliary diseases as a response to injury, as is seen in epithelial damage elsewhere in the gastrointestinal tract.
FIBRILLIN-1
Abnormal hepatic expression of fibrillin-1 in children with cholestasis.Lamireau T, Dubuisson L, Lepreux S, Bioulac-Sage P, Fabre M, Rosenbaum J, Desmouliere A.
Groupe de Recherches pour l'Etude du Foie, Universite Victor Segalen, Bordeaux, France.
Am J Surg Pathol 2002 May;26(5):637-46 Abstract quote Fibrillin-1, one of the main constituents of microfibrils, is present in normal adult liver and overexpressed in fibrotic area around cirrhotic nodules and hepatocellular carcinoma.
In this work fibrillin-1 expression was studied by immunohistochemistry in liver samples from children with various cholestatic diseases corresponding to paucity of intrahepatic bile ducts, biliary atresia, congenital hepatic fibrosis, Byler's disease, mitochondrial cytopathy, sclerosing cholangitis, or choledochal cyst. As controls, histologically normal liver samples were used. In control liver, as in adult, fibrillin-1 was expressed in vessel walls, sinusoids, and portal connective tissue, particularly at the interface with the limiting hepatocytic plate and close to the basement membrane of bile ducts.
In paucity of intrahepatic bile ducts without fibrosis, the fibrillin-1 distribution was similar to controls. In cholestatic diseases associated with severe fibrosis, such as biliary atresia, congenital hepatic fibrosis, Byler's disease, mitochondrial cytopathy, or sclerosing cholangitis, an enhanced deposition of fibrillin-1 was observed in portal connective tissue and fibrous septa. The strong fibrillin-1 expression close to the basement membrane of biliary structures was lost in cholestatic diseases, except biliary atresia.
Finally, in normal and pathologic tissues, fibrillin-1 was co-localized with its putative receptor alphaVbeta3 in sinusoids but not around biliary structures.
HEPATOCYTE PARAFFIN
ANTIBODY 1
The diagnostic value of hepatocyte paraffin antibody 1 in differentiating hepatocellular neoplasms from nonhepatic tumors: a review.Lamps LW, Folpe AL.
Adv Anat Pathol 2003 Jan;10(1):39-43 Abstract quote Hepatocyte paraffin-1 (HepPar-1) is a recently developed monoclonal antibody that appears to identify an antigen unique to hepatocellular mitochondria.
This article reviews the use of this new antibody in the differential diagnosis of primary hepatocellular neoplasms, cholangiocarcinomas, and carcinomas metastatic to the liver.
Hepatocyte paraffin-1 appears to be the most sensitive and specific positive marker of hepatocellular differentiation, but like any immunohistochemical marker, should be interpreted only in the context of the overall clinicopathologic picture and as part of a panel of antibodies.ELECTRON MICROSCOPY Toxic Effects of Nucleoside Reverse Transcriptase Inhibitors on the Liver
Value of Electron Microscopy Analysis for the Diagnosis of Mitochondrial Cytopathy
Jean-Paul Duong Van Huyen, MD,1,4 Alain Landau, MD,2 Christophe Piketty, MD,3,4 Marie-France Bélair,4 Dominique Batisse, MD,3 Gustavo Gonzalez-Canali, MD,3 Laurence Weiss, MD, PhD,3,4 Raymond Jian, MD,2 Michel D. Kazatchkine, MD, PhD,3,4 and Patrick Bruneval, MDAm J Clin Pathol 2003;119:546-555 Abstract quote
Nucleoside reverse transcriptase inhibitors (NRTIs) induce mitochondrial toxic effects resulting in multiple organ disorders. Liver involvement has been associated mainly with severe lactic acidosis and massive steatosis. However, patients with HIV infection who are receiving antiretroviral treatment frequently have mildly abnormal liver test results that, to date, have not been linked unambiguously to the toxic effects of NRTIs.
Thirteen patients with HIV infection treated with NRTI-based regimens had low-grade abnormal liver test results associated with digestive and nonspecific general symptoms. Histologic examination of liver samples showed diffuse steatosis in only 6 cases and mild steatosis in the remaining cases, associated with megamitochondria, mild lobular inflammation and necrosis, Mallory bodies, and perisinusoidal fibrosis. In all cases, ultrastructural study disclosed mitochondrial abnormalities.
Our work demonstrates that NRTI-induced toxic effects in the liver may occur as indolent nonspecific disease with variable histologic features and emphasizes the diagnostic value of electron microscopy, particularly when diffuse steatosis is absent.The hepatic mitochondrial DNA depletion syndrome: ultrastructural changes in liver biopsies.
Mandel H, Hartman C, Berkowitz D, Elpeleg ON, Manov I, Iancu TC.
Metabolic Disease Unit, Rambam Medical Center, Israel.
Hepatology 2001 Oct;34(4 Pt 1):776-84 Abstract quote
Mitochondrial respiratory chain disorders are an established cause of liver failure in early childhood. In some patients, the levels of mitochondrial DNA are markedly reduced, a condition referred to as mtDNA depletion syndrome (MDS).
We report here on the ultrastructural changes in the livers of 10 infants with the hepatic form of this syndrome. All patients displayed progressive liver failure, neurological abnormalities, hypoglycemia, and lactic acidosis that warranted investigation of respiratory chain disorder in liver tissue, specifically expressing the disease. Decreased activity of respiratory chain complexes containing mtDNA-encoded subunits (complexes I, III, IV) was shown in 5 patients. Mitochondrial DNA depletion was confirmed by Southern blot analysis in the livers of 6 patients. We found hepatocytes filled with mitochondria having aspects of "oncocytic transformation," associated with numerous changes in shape, size, cristae, and matrix. The changes were virtually identical in all specimens. In many hepatocytes, microvesicular steatosis was the salient feature. Additional findings included cholestasis and focal cytoplasmic biliary necrosis (CBN), as well as cytosiderosis in hepatocytes and sinusoidal cells. In some hepatocytes the damage appeared extreme, but fibrosis was identified only in the few patients who died beyond 6 months of age.
Although individual ultrastructural findings are not specific, when taken together, they show a diagnostic pattern highly suggestive of a respiratory chain disorder. In the appropriate clinical context, these findings can direct the clinician towards the diagnosis of hepatic MDS.
Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.
Kupffer Cells-Scavenger cells of the liver, analagous to macrophages.
Prussian Blue-Name for the stain which turns a brilliant blue when iron is present.
Basic Principles of Disease
Learn the basic disease classifications of cancers, infections, and inflammation
Commonly Used Terms
This is a glossary of terms often found in a pathology report.Diagnostic Process
Learn how a pathologist makes a diagnosis using a microscopeSurgical Pathology Report
Examine an actual biopsy report to understand what each section meansSpecial Stains
Understand the tools the pathologist utilizes to aid in the diagnosisHow Accurate is My Report?
Pathologists actively oversee every area of the laboratory to ensure your report is accurateGot Path?
Recent teaching cases and lectures presented in conferences
Last Updated May 5, 2006
Send mail to The Doctor's Doctor with questions or comments about this web site.
Read the Medical Disclaimer.
Copyright © The Doctor's Doctor