Difference between revisions of "Liver pathology"

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[[Image:Wątroba marska (Ultima Thule).jpg|thumb|right|Drawing of a [[cirrhosis|cirrhotic]] liver. (WC)]]
The '''liver''' is an organ [[pathologist]]s are seeing less of, as [[radiologist]]s (with multimodal imaging and triphasic CT scans) are pretty good at sorting-out many types of liver lesions.
The '''liver''' is an organ [[pathologist]]s are seeing less of, as [[radiologist]]s (with multimodal imaging and triphasic CT scans) are pretty good at sorting-out many types of liver lesions.


This article is an introduction to liver pathology. Liver neoplasms are dealt with in the ''[[liver neoplasms]]'' article.  Medical liver diseases (e.g. viral hepatitis) is dealt with in the ''[[medical liver disease]]'' article.
This article is an introduction to liver pathology. Liver neoplasms are dealt with in the ''[[liver neoplasms]]'' article.  Medical liver diseases (e.g. viral hepatitis) is dealt with in the ''[[medical liver disease]]'' article.
Liver biopsies are quite often non-specific, as the liver has the same appearance for many mechanisms of injury, especially when the injury is marked.
Almost every differential in liver pathology has "drugs" -- if it isn't clearly malignancy.


=Review of liver blood work=
=Review of liver blood work=
===Inflammation activity===
*This is covered in the ''[[Medical_liver_disease#Review_of_liver_blood_work|medical liver disease]]'' article.
*ALT.
*AST.


===Cholestatic markers===
=Normal liver=  
*ALP.
==Liver anatomy==
*GGT - used to assess whether the ALP is an "honest" value, elevated in cirrhosis.
The liver is divided into eight (Couinaud) segments:
*Segment I = caudate lobe.
*Segments II to VIII = clockwise from left upper lobe to left upper quadrant of the liver to the right of the inferior vena cava.
**Segment IV is divided into: IVa (superior) and IVb (inferior).


===Cirrhosis/decompensation===
Image:
*PLT - low is suggestive of dysfunction.
*[http://masterofmedicine.com/couinauds-liver-segments/ Couinaud segments (masterofmedicine.com)].
*INR - high is bad, unless anticoagulated.
 
===Viral===
*HBV DNA.
*HCV RNA.
*HBs Ag, HBs Ab, HBe Ag, HBe Ab.
*HCV Ab.
 
Others:
*[[EBV]].
*[[CMV]].
====Hepatitis B====
Meaning & utility of the various Hepatitis B tests:<ref>URL: [http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/hepatology/hepatitis-B/ http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/hepatology/hepatitis-B/]. Accessed on: 16 May 2011.</ref><ref name=lto_hepb>URL: [http://www.labtestsonline.org/understanding/analytes/hepatitis_b/test.html http://www.labtestsonline.org/understanding/analytes/hepatitis_b/test.html]. Accessed on: 16 May 2011.</ref>
{| class="wikitable" border="1"
! '''Test name'''
! '''Location'''
! '''Positive test'''
! '''Negative test'''
! '''Usual question'''
|-
| HBs Ag||Surface||Virus active||No active infection||Active infection?
|-
| HBs Ab||Surface||Exposed OR vaccinated||No exposure OR no vaccine OR loss of Ab||Immunization status?
|-
| HBe Ag||Virus core||Infect. w/ viral replication||No active infection||Active infect. w/ viral replication?
|-
| HBe Ab||Virus core||Exposed to virus||Infect. w/o antibody response OR not exposed||Immune response to infection?
|-
| HBV DNA||-||Active||Not active/no exposure||Viral load/how active?
|-
| HBc Ab||Virus core||Virus active/previous exposure||No exposure||Early active infection?
|}
Notes:
*''HBc Ab'' may test for acute (IgM) or chronic infection - dependent on specific antibody test; it is often used to look for early infection.<ref name=lto_hepb>URL: [http://www.labtestsonline.org/understanding/analytes/hepatitis_b/test.html http://www.labtestsonline.org/understanding/analytes/hepatitis_b/test.html]. Accessed on: 16 May 2011.</ref>
 
===Markers for rare liver diseases===
*Ceruloplasm - low think ''[[Wilson's disease]]''; typical value for Wilson's ~ 0.12 g/L.
**<0.20 g/L is a criteria for Wilson's disease.<ref name=pmid18556333>Diagnostic accuracy of serum ceruloplasmin in Wilson disease: determination of sensitivity and specificity by ROC curve analysis among ATP7B-genotyped subjects. Mak CM, Lam CW, Tam S. Clin Chem. 2008 Aug;54(8):1356-62. Epub 2008 Jun 12. PMID 18556333. URL: [http://www.clinchem.org/cgi/reprint/54/8/1356.pdf http://www.clinchem.org/cgi/reprint/54/8/1356.pdf]. Accessed on: 28 September 2009.</ref>
*Alpha-1 antitrypsin - if low think ''deficiency''.
 
===Hemosiderosis===
*Ferritin - high.
*Iron saturation - high.


Causes:
==Liver histology==
*Hemochromatosis.
*Hemolysis, chronic.
*Cirrhosis.
 
=Normal histology=
Liver has a dual blood supply:
Liver has a dual blood supply:
#Portal vein.
#Portal vein.
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**Artery.
**Artery.
**Vein; vein should be larger than the artery.
**Vein; vein should be larger than the artery.
**Bile duct - should have a lumen and be round.
**Bile duct - round, has a lumen - approximately the size of the artery.
***Cuboidal epithelium, central nucleus, lightly basophilic cytoplasm.
***Cuboidal epithelium, central nucleus, lightly basophilic cytoplasm.
***IHC: CK7 +ve.
***IHC: [[CK7]] +ve.
***Irregular bile ducts without a lumen are called ''bile ductules''; ''ductule'' implies a pathologic process.
***Irregular bile ducts without a lumen are called ''bile ductules''; ''ductule'' implies a pathologic process.
*Lobule - hepatocytes.  
*Lobule - hepatocytes.  
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**Cholestasis - absent/present.
**Cholestasis - absent/present.
**Presence of fibrosis?
**Presence of fibrosis?
***If a core biopsy is fragmented (on gross), think ''cirrhosis'',<ref>S. Fung. October 2007.</ref> as cirrhotic livers commonly cleave at the fibrous bands.
***If a core biopsy is fragmented (on gross), think ''cirrhosis'',<ref>Fung, S. October 2007.</ref> as cirrhotic livers commonly cleave at the fibrous bands.
***Grade the fibrosis.
***Grade the fibrosis.
*Central vein - has a ''collagen collar'' (seen on trichrome).
*Central vein - has a ''collagen collar'' (seen on trichrome).
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**Clinical correlate: ALP and GGT increased.
**Clinical correlate: ALP and GGT increased.
*Steatosis - fat.
*Steatosis - fat.
**Clinical correlate: obese patient, changes on medical imaging (increased radiolucency on CT).
**Clinical correlate: [[obese]] patient, changes on medical imaging (increased radiolucency on CT).


<!--
<!--
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**Clinical correlate: non-specific.
**Clinical correlate: non-specific.
*Congestive - dilation of portal venules, perisinusoidal fibrosis/zone III fibrosis.
*Congestive - dilation of portal venules, perisinusoidal fibrosis/zone III fibrosis.
**Clinical correlates: heart failure, imaging finding (portal vein thrombosis), medications.
**Clinical correlates: heart failure, imaging finding (portal vein [[thrombosis]]), medications.
*Ischemic - [[necrosis]].
*Ischemic - [[necrosis]].
**Clinical correlate - shock, known [[atherosclerosis]], known cirrhosis.
**Clinical correlate - shock, known [[atherosclerosis]], known cirrhosis.
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**Clinical correlate: toxin ingestion.
**Clinical correlate: toxin ingestion.


=Biopsy=
=Stains=
===Adequacy===
*The stains ordered (initially) are dependent on the clinical history.
Liver biopsy specimens should be:<ref>{{Ref MacSween|418}}</ref>
*#Anything with "tumour", "mass", or "query metastasis" in the clinical history is "tumour".
*2.0 cm in length and contain 11-15 portal tracts,
*#*Stains:
*The core should be deeper than 1.0 cm from the liver capsule; specimens close to the capsule may lead to over grading of fibrosis.
*#**3 H&E.
*#Everything else is assumed to be "medical".
*#*Stains:
*#**PAS-D - to detect mucin.
*#**PAS - marks glycogen and mucin; useful for microvesicular steatosis
*#**Trichrome - to detect fibrosis/cirrhosis.
*#***Mallory trichrome: red = hepatocytes, blue/black = nuclei, green = fibrosis.
*#**Reticulin - demonstrates architecture.
*#**Iron stain.
*#***Grading (0-4): 0 = none, 1: only at high power, 2: at medium power, 3: at lowest power, 4: seen without microscope.
*#****One should comment on location, i.e. macrophage (Kupffer cell) vs. periportal hepatocytes vs. centrilobular hepatocytes vs. bile ducts vs. endothelial cells.


===Components===
===Additional stains/IHC===
Specimen, procedure:<br>
Non-standard stains:
Diagnosis.
*[[Oil red O]].
<br>
The diagnosis usually contains grading and staging information, e.g. ''activity 2 /4, Laennec fibrosis stage 1 /4''.
 
In the context of medical liver disease:
*Grade = inflammation/activity.
*Stage = severity of fibrosis/architectural changes.
 
Notes:
*The term "acute" is infrequently used in liver pathology.
*In the liver: neutrophils ''is not'' acute -- unlike most elsewhere in the body.<ref>OA. September 2009.</ref>
 
=Stains=
*[[Oil red O]]  
**Useful for steatosis, not commonly done.
**Useful for steatosis, not commonly done.
*[[PAS]].
*[[HPS]].
**Useful for microvesicular steatosis.
**Similar to trichrome.
*[[Trichrome]].
**Useful for fibrosis/cirrhosis; components of trichrome: red = hepatocytes, blue/black = nuclei, green = fibrosis.
***[[Movat's stain]] is ''not'' favoured by hepatic pathologists.<ref>MG. 29 July 2009.</ref>
*Iron stain.
**Grading (0-4): 0 = none, 1: only at high power, 2: at medium power, 3: at lowest power, 4: seen without microscope.
**Should comment on location, i.e. macrophage (Kupffer cell) vs. periportal hepatocytes vs. centrilobular hepatocytes vs. bile ducts vs. endothelial cells.


===Liver stains - standard at one hospital===
Common IHC:<ref name=ap27may2009>Pollet, A. 27 May 2009.</ref>
IHC panel/special stains:<ref name=ap27may09>AP. 27 May 2009.</ref>
*[[CK7]] - bile ducts, and bile ductules +ve.
*PAS-D - to detect mucin.
*PAS - to detect glycogen and mucin.
*Trichrome - to detect fibrosis/cirrhosis.
*Reticulin - demonstrates architecture.
 
Additional stains:<ref name=ap27may09/>
*CK7 - bile ducts, and bile ductules +ve.
*CD34 - should be -ve in normal liver.
*CD34 - should be -ve in normal liver.
**CD34 marks endothelial cells - these are not present in a healthy liver lobule.
**CD34 marks endothelial cells - these are not present in a healthy liver lobule.
=Liver biopsy=
==Medical liver biopsy adequacy==
*This is covered in the ''[[Medical_liver_disease#Medical_liver_biopsy_adequacy|medical liver disease]]'' article.
==Reporting==
{{Main|Pathology reports}}
*This is covered in the ''[[Medical_liver_disease#Reporting|medical liver disease]]'' article.


=Liver injury terms/histologic findings=
=Liver injury terms/histologic findings=
==="Ballooning degeneration"===
===Bile duct injury===
*Central nucleus.
*Non-specific finding.
**"Fat cells" have peripheral nucleus.
**Seen in a number of conditions, e.g. autoimmune hepatitis, primary biliary cirrhosis, viral hepatitis.
*Cytoplasm cleared with "whisps" or cobbwebs.
*Large relative to normal hepatocyte.
**2-3X normal size.<ref>MG. 16 September 2009.</ref>


Notes:
Microscopic:
*The term is used only in conjunction with ''[[steatohepatitis]]''.
*Abnormal epithelium:
*''Feathery degeneration'' is the term used in the context of non-fatty disease.<ref>MG. 17 September 2009.</ref>
**Nuclei ''not'' round.
**Cytoplasmic eosinophilia.
*Intraepithelial lymphocytes.


Images:
===Bile duct hamartoma===
*[http://commons.wikimedia.org/wiki/File:Ballooning_degeneration_high_mag_cropped.jpg Ballooning degeneration (WC)].
*[[AKA]] ''Meyenburg complex'' and ''von Meyenburg complex''.
*[http://www.uthscsa.edu/hscnews/EnlargePicture.asp?PicName=LiverBeforeTreatment_BODY.jpg Ballooning degeneration (uthscsa.edu)].
*Classically associated with ''polycystic kidney disease'' (see ''[[Medical_liver_disease#Polycystic_kidney_disease_and_the_liver|medical liver disease]]'').
*[http://library.med.utah.edu/WebPath/LIVEHTML/LIVER039.html Ballooning degeneration (med.utah.edu)].
*May be seen in a normal liver - incidental finding at autopsy in 0.5-5.6% of cases.<ref name=pmid19018981>Hepatic von Meyenburg complex: a trigger of severe portal hypertension. Yoshida S, Kurokohchi K, Ueno T, Yoshino M, Shimada M, Masaki T. Liver Int. 2009 Apr;29(4):614-5. Epub 2008 Oct 14. PMID 19018981. URL: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2711260 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2711260]. Accessed on: 28 September 2009.</ref>
*Appearance on ultrasound<ref name=pmid17287178>Bile duct hamartomas--the von Meyenburg complex. Salles VJ, Marotta A, Netto JM, Speranzini MB, Martins MR. Hepatobiliary Pancreat Dis Int. 2007 Feb;6(1):108-9. PMID 17287178.</ref> and CT (hypodense)<ref name=pmid19294869>[The von Meyenburg complex] Schwab SA, Bautz W, Uder M, Kuefner MA. Rontgenpraxis. 2008;56(6):241-4. German. PMID 19294869.</ref> - similar to metastases.


==="Ground glass" hepatocytes===
Microscopic:<ref>{{Ref MacSween|176}}</ref>
*Eosinophilic dull/hazy, somewhat irregular cytoplasm.
*Many bile ducts (tubular structures with cuboidal epithelium).
**Ground glass<ref>URL: [http://en.wikipedia.org/wiki/Ground_glass http://en.wikipedia.org/wiki/Ground_glass]. Accessed on: 7 June 2010.</ref> = glass with a rough/flat finish; glass that is translucent and has a matte finish.
*Surrounded by a fibrous stroma.
***The term is frequently used in radiology to describe hazy radiodense areas in the lung.<ref>URL: [http://www.healthsystem.virginia.edu/internet/radiology/educ/groundglass.cfm http://www.healthsystem.virginia.edu/internet/radiology/educ/groundglass.cfm]. Accessed on: 7 June 2010.</ref>
*Usually suggests '''chronic''' [[HBV]] infection.  
**Pattern NOT seen in acute HBV.
**Caused by virion particles.


DDx:  
Note:
*Pseudo-Lafora bodies in patients on disulfiram (anatabuse) - rare.
*'''Not''' related to ''[[bile duct adenoma]]''.


====Classification====
====Images====
*GGHs are not routinely classified.  
<gallery>
Image:Von_Meyenburg_complex_low_mag.jpg | Von Meyenburg complex - bile duct hamartoma (WC)
Image:Bile_duct_hamartoma_intermed_mag.jpg | Bile duct hamartoma - intermed. mag. (WC)
Image:Von_Meyenburg_complex_liver.jpg | Von Meyenburg complex / bile duct hamartoma (WC)
</gallery>
www:
*[http://radiographics.rsna.org/content/25/3/659/F7.expansion.html Bile duct hamartoma - gross image (rsna.org)].
*[http://radiographics.rsna.org/content/25/3/659/F8.expansion.html Bile duct hamartoma (rsna.org)].


Notes:
===Isolated hepatic artery===
*Several different types of GGHs are recognized.<ref name=pmid14633616>Wang HC, Wu HC, Chen CF, Fausto N, Lei HY, Su IJ. Different types of ground glass hepatocytes in chronic hepatitis B virus infection contain specific pre-S mutants that may induce endoplasmic reticulum stress. Am J Pathol. 2003 Dec;163(6):2441-9. PMID 14633616. Available at: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=14633616 http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=14633616]. Accessed on: September 11, 2009.</ref>
*The hepatic artery branches within the liver should always be found together with a vein and bile duct.


Classification:<ref>Wang HC, Wu HC, Chen CF, Fausto N, Lei HY, Su IJ. Different types of ground glass hepatocytes in chronic hepatitis B virus infection contain specific pre-S mutants that may induce endoplasmic reticulum stress. Am J Pathol. 2003 Dec;163(6):2441-9. PMID 14633616. Available at: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1892360&rendertype=figure&id=f1
DDx:
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1892360&rendertype=figure&id=f1]. Accessed on: 17 September 2009.</ref>
*[[Focal nodular hyperplasia]].
*Type I ground glass hepatocytes (GGHs).
*[[Hepatic adenoma]].
**Weak Pre-S2 positive immunostaining; morphology: GGHs scattered singly.
*[[Hepatocellular carcinoma]].  
*Type II GGHs.
**Pre-S2 negative immunostaining; morphology: GGHs in clusters.


There is some suggestion that type II GGHs predispose to [[HCC]], based on data in children<ref name=pmid19719772>Pre-S2 deletion mutants of hepatitis B virus could have an important role in hepatocarcinogenesis in Asian children. Abe K, Thung SN, Wu HC, Tran TT, Le Hoang P, Truong KD, Inui A, Jang JJ, Su IJ. Cancer Sci. 2009 Aug 6. [Epub ahead of print] PMID 19719772.</ref> and based on an animal model.<ref name=pmid18505413>Ground glass hepatocytes contain pre-S mutants and represent preneoplastic lesions in chronic hepatitis B virus infection. Su IJ, Wang HC, Wu HC, Huang WY. J Gastroenterol Hepatol. 2008 Aug;23(8 Pt 1):1169-74. Epub 2008 May 26. Review. PMID 18505413.</ref>
===Ballooning degeneration===
{{Main|Ballooning degeneration}}


Micrographs of GGHs:
===Ground glass hepatocytes===
*[http://commons.wikimedia.org/wiki/File:Ground_glass_hepatocytes_high_mag_cropped.jpg Ground glass hepatocyte (WC)].
{{Main|Ground glass hepatocyte}}
*[http://www.consultantlive.com/aids/article/1145619/1363027 Ground glass hepatocytes (consultantlive.com)].
*[http://www.biomedcentral.com/1471-230X/5/36/figure/F1 Ground glass hepatocytes (biomedcentral.com)].
*[http://pathology.osu.edu/paxit/deptbase/Paxit/Images/10534/PAXIT052.JPG Ground glass hepatocyte (pathology.osu.edu)].


===Mallory bodies===
===Mallory bodies===
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Notes:
Notes:
*Previously thought to indicate alcoholic liver disease; they are more common in alcohol.
*Previously thought to indicate [[alcoholic liver disease]]; they are more common in [[alcohol]].


Prevalence in common liver diseases (based on one study):<ref name=pmid7927209>Jensen K, Gluud C. The Mallory body: morphological, clinical and experimental studies (Part 1 of a literature survey). Hepatology. 1994 Oct;20(4 Pt 1):1061-77. Review. PMID 7927209.</ref>
Prevalence in common liver diseases (based on one study):<ref name=pmid7927209>Jensen K, Gluud C. The Mallory body: morphological, clinical and experimental studies (Part 1 of a literature survey). Hepatology. 1994 Oct;20(4 Pt 1):1061-77. Review. PMID 7927209.</ref>
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|}
|}


Micrographs:
====Images====
*[http://commons.wikimedia.org/wiki/File:Mallory_body_high_mag_cropped.jpg Mallory body (WC)].
<gallery>
Image:Mallory_body_high_mag_cropped.jpg | Mallory body. (WC/Nephron)
</gallery>
www:
*[http://en.wikipedia.org/wiki/File:CDC_mallory_bodies.jpg Mallory bodies - CDC/WP (WP)].
*[http://en.wikipedia.org/wiki/File:CDC_mallory_bodies.jpg Mallory bodies - CDC/WP (WP)].
*[http://www.nature.com/modpathol/journal/v20/n1s/fig_tab/3800682f6.html Mallory bodies - Mod. Pathol. (nature.com)].
*[http://www.nature.com/modpathol/journal/v20/n1s/fig_tab/3800682f6.html Mallory bodies - Mod. Pathol. (nature.com)].
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***Small, shrunken, pale staining.
***Small, shrunken, pale staining.
**Eosinophilic cytoplasm.
**Eosinophilic cytoplasm.
Image:
*[http://commons.wikimedia.org/wiki/File:Ballooning_degeneration_high_mag_cropped.jpg Councilman body - high mag. (WC)].


Notes:
Notes:
*[[AKA]] ''Councilman-like bodies''; see ''notes'' in ''Councilman bodies'' below.
*[[AKA]] ''Councilman-like bodies''; see ''notes'' in ''Councilman bodies'' below.
====Image====
<gallery>
Image:Ballooning_degeneration_high_mag_cropped.jpg | Councilman body - high mag. (WC)
</gallery>


===Councilman bodies===
===Councilman bodies===
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====Interface hepatitis====
====Interface hepatitis====
*May be referred to as ''piecemeal necrosis''.<ref name=aop>Atlas of Pathology. URL: [http://www.pathologyatlas.ro/viral-chronic-moderate-hepatitis.php http://www.pathologyatlas.ro/viral-chronic-moderate-hepatitis.php]. Accessed on: September 1, 2009.</ref>
*May be referred to as ''piecemeal necrosis''.<ref name=aop>Atlas of Pathology. URL: [http://www.pathologyatlas.ro/viral-chronic-moderate-hepatitis.php http://www.pathologyatlas.ro/viral-chronic-moderate-hepatitis.php]. Accessed on: September 1, 2009.</ref>
*Non-specific finding, i.e. seen in several conditions - e.g. viral hepatitis, autoimmune hepatitis.
*Non-specific finding, i.e. seen in several conditions - e.g. [[viral hepatitis]], [[autoimmune hepatitis]].


Features:
Features:
*Inflammation disrupts the "limiting plate", i.e. there is disruption of the hepatocytes that separate the portal tracts from the lobules.
*Inflammation disrupts the "limiting plate", i.e. there is disruption of the hepatocytes that separate the portal tracts from the lobules.


Micrograph:
=====Images=====
*[http://www.pathologyatlas.ro/viral-chronic-moderate-hepatitis.php Interface hepatitis (pathologyatlas.ro)]
<gallery>
Image: Interface hepatitis -- high mag.jpg | IH (mild) - high mag. (WC)
Image: Interface hepatitis -- very high mag.jpg | IH (mild) - very high mag. (WC)
</gallery>
www:
*[http://www.pathologyatlas.ro/viral-chronic-moderate-hepatitis.php Interface hepatitis (pathologyatlas.ro)].
*[http://www.nature.com/modpathol/journal/v20/n1s/fig_tab/3800693f1.html#figure-title Interface hepatitis (nature.com)].<ref name=pmid17486049>{{cite journal |author=Theise ND |title=Liver biopsy assessment in chronic viral hepatitis: a personal, practical approach |journal=Mod. Pathol. |volume=20 Suppl 1 |issue= |pages=S3-14 |year=2007 |month=February |pmid=17486049 |doi=10.1038/modpathol.3800693 |url=http://www.nature.com/modpathol/journal/v20/n1s/full/3800693a.html}}</ref>


===Fibrosis===
===Liver fibrosis===
*More collagen than there should be.
*More collagen than there should be.
*Assessment of fibrosis is based on the trichrome stain.
*Assessment of fibrosis is based on the trichrome stain.
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===Cirrhosis===
===Cirrhosis===
*Cirrhosis ''is'' stage 4 (Laennec).
{{Main|Cirrhosis}}
**The formal Robbins definitions is:<ref name=Ref_PCPBoD8_439>{{Ref PCPBoD8|439}}</ref> (1) bridging fibrosis, (2) nodule formation, and (3) disruption of the hepatic architecture.
*The etiology of late stage fibrosis (cirrhosis), may be impossible to determine.
*Perisinusoidal fibrosis may suggest congestive hepatopathy.<ref>OA. September 15, 2009.</ref>
*In NAFLD portal-to-portal fibrosis (septal/bridging fibrosis) tends to be more common than perivenular fibrosis.<ref name=pmid14991537>Pathologic features associated with fibrosis in nonalcoholic fatty liver disease. Gramlich T, Kleiner DE, McCullough AJ, Matteoni CA, Boparai N, Younossi ZM. Hum Pathol. 2004 Feb;35(2):196-9. PMID 14991537.</ref>


Cirrhosis can be divided (in gross pathology) into:
===Steatosis===
*Micronodular cirrhosis - classically due to alcohol.
{{Main|Steatosis}}
**Uniform, diffuse.
*Macronodular cirrhosis - classically due to viral hepatitis.
**Irregular.
 
Images:
*[http://www.meddean.luc.edu/lumen/MedEd/orfpath/cirhosis.htm Cirrhosis - macronodular & micronodular (meddean.luc.edu)].
*[http://commons.wikimedia.org/wiki/File:Cirrhosis_high_mag.jpg Cirrhotic liver - trichrome stain (WC)].
 
===Steatosis of the liver===
Can be divided into:
#Microvesicular steatosis.
#*Rare.
#*Nucleus is central.<ref>STC. 6 December 2010.</ref>
#Macrovesicular steatosis.
#*Common.
#*Nucleus is eccentric.
 
Microvescicular is considered to be potentially life threatening.<ref>Steatosis. pathconsultddx.com. URL: [http://www.pathconsultddx.com/pathCon/diagnosis?pii=S1559-8675%2806%2970840-3 http://www.pathconsultddx.com/pathCon/diagnosis?pii=S1559-8675%2806%2970840-3]. Accessed on: 2 Sep 2009.</ref>
 
Quantity of fat is usually given as a percentage and graded ''mild'', ''moderate'', or ''marked''.
*Mild <33%, moderate >33% & <66%, marked >66%.<ref>MG. September 17, 2009.</ref>
 
Notes:
*It is considered technically incorrect to say the liver, in steatosis/steatohepatitis, contains ''adipocytes''; they are ''lipid-laden hepatocytes'',<ref>MG. September 2009.</ref> despite that:
**Histologically, these cells look like adipocytes.
**Lipid-laden hepatocytes have gene activations suggestive of adipogenic-like transformation.<ref>URL: [http://www.jci.org/articles/view/20513/version/1 http://www.jci.org/articles/view/20513/version/1]. Accessed on: 23 September 2009.</ref>
*Donor livers with more fat = worse outcome.<ref name=pmid20644128>{{cite journal |author=Doyle MB, Vachharajani N, Wellen JR, ''et al.'' |title=Short- and long-term outcomes after steatotic liver transplantation |journal=Arch Surg |volume=145 |issue=7 |pages=653–60 |year=2010 |month=July |pmid=20644128 |doi=10.1001/archsurg.2010.119 |url=}}</ref>
**One cut-point is 30% -- more than 30% and the liver is undesirable for transplantation.<ref>STC. 6 December 2010.</ref>
 
====Microvesicular steatosis====
Microvesicular steatosis DDx:<ref name=pmid2177300>{{cite journal |author=Hautekeete ML, Degott C, Benhamou JP |title=Microvesicular steatosis of the liver |journal=Acta Clin Belg |volume=45 |issue=5 |pages=311–26 |year=1990 |pmid=2177300 |doi= |url=}}</ref>
*Acute fatty liver of pregnancy,
*Reye's syndrome.
*Drug toxicity:
**Sodium valproate toxicity.
**High-dose tetracycline toxicity.
*Jamaican vomiting sickness.
*Congenital defects of urea cycle enzymes.
 
Less common causes:
*Alcoholism.
*Hepatitis D.
*Weird stuff:
**Congenital defects of fatty acid beta oxidation,
**Cholesterol ester storage disease,
**Wolman disease and Alpers syndrome.
 
The classic causes of microvesicular steatosis are:<ref>[http://www.mailman.srv.ualberta.ca/pipermail/patho-l/1996-June/001788.html http://www.mailman.srv.ualberta.ca/pipermail/patho-l/1996-June/001788.html]</ref>
*Fatty liver of pregnancy.
*Aspirin (Reye's syndrome).
*Tetracycline.
It was once thought that all other causes of fatty liver produce macrovesicular steatosis.
 
====Macrovesicular steatosis====
Can sometimes be divided into ''centrilobular'' predominant and ''periportal'' predominant.<ref name=pcddx_steatosis>Steatosis. pathconsultddx.com. URL: [http://www.pathconsultddx.com/pathCon/diagnosis?pii=S1559-8675%2806%2970840-3 http://www.pathconsultddx.com/pathCon/diagnosis?pii=S1559-8675%2806%2970840-3]. Accessed on: 2 Sep 2009.</ref>
 
Centrilobular predominant (zone III) - ''DOA'':<ref name=pcddx_steatosis/>
*[[Diabetes mellitus]].
*Obesity, non-alcoholic steatohepatitis (NASH).
*Alcoholic liver disease, alcoholic steatohepatitis (ASH).
 
Image: [http://commons.wikimedia.org/wiki/File:Non-alcoholic_fatty_liver_disease1.jpg Centrilobular steatosis (WC)].
 
Periportal predominant (zone I) - ''TAPES'':<ref name=pcddx_steatosis/>
*Total parenteral nutrition (TPN).
*AIDS.
*Phosphorus poisoning.
*Exogenous steroids.
*[[Starvation]].
 
Notes:
*HCV genotype 3 is reported to cause periportal steatosis.<ref name=pmid16614743>Yoon EJ, Hu KQ. Hepatitis C virus (HCV) infection and hepatic steatosis. Int J Med Sci. 2006;3(2):53-6. Epub 2006 Apr 1. PMID 16614743. Avialable at: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1415843 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1415843]. Accessed on: September 9, 2009.</ref>
 
Image: [http://commons.wikimedia.org/wiki/File:Periportal_hepatosteatosis_intermed_mag.jpg Periportal steatosis (WC)].


===Cholestasis===
===Cholestasis===
Appearance of bile:
{{Main|Cholestasis}}
*Smooth/homogenous.
*Brown/yellow.
*Globule/droplet - that is larger than an iron granule.
 
Note:
*Iron in bile ducts or endothelial cell = non-specific, used to be thought to be specific for hereditary hemochromatosis.
 
Histologic findings of large-duct obstruction:<ref>{{Ref MacSween|565}}</ref>
#Perivenular bilirubinostasis.
#Portal tract edema & inflammation (neutrophils & macrophages).
#Large bile plugs.
#Bile duct proliferation.<ref name=pmid7439807>{{cite journal |author=Chapman RW, Arborgh BA, Rhodes JM, ''et al.'' |title=Primary sclerosing cholangitis: a review of its clinical features, cholangiography, and hepatic histology |journal=Gut |volume=21 |issue=10 |pages=870–7 |year=1980 |month=October |pmid=7439807 |pmc=1419383 |doi= |url=}}</ref><ref name=pmid14594129>{{cite journal |author=Leuschner U |title=Primary biliary cirrhosis--presentation and diagnosis |journal=Clin Liver Dis |volume=7 |issue=4 |pages=741–58 |year=2003 |month=November |pmid=14594129 |doi= |url=}}</ref>
 
Small-duct obstruction:
*Abnormal liver plate architecture. (???)
 
Image: [http://commons.wikimedia.org/wiki/File:Cholestasis_high_mag.jpg Cholestasis (WC)].
 
====Brown/yellow cytoplasmic inclusions====
Comparison of brown/yellow cytoplasmic inclusions:<ref>MG. September 2009.</ref>
{| class="wikitable" border="1"
!
! '''Colour'''
! '''Granularity'''
! '''Refractile'''
! '''Usual location'''
! '''Association'''
|-
| Iron||Brown||Coarse granules||Yes - shinny||Periportal (zone I)||Hemolysis, hereditary hemochromatosis
|-
| Bile||Brown - coffee stained||Not granular||No - dull||Portal||Duct injury/obstruction
|-
| Lipofuscin||Yellow||Fine granules||No||Centrilobular (zone III)||Advanced age
|-
|}
 
===Bile duct hamartoma===
*[[AKA]] ''Meyenburg complex'' and ''von Meyenburg complex''.
*Classically associated with ''polycystic kidney disease'' (see ''[[medical liver disease]]'').
*May be seen in a normal liver - incidental finding at autopsy in 0.5-5.6% of cases.<ref name=pmid19018981>Hepatic von Meyenburg complex: a trigger of severe portal hypertension. Yoshida S, Kurokohchi K, Ueno T, Yoshino M, Shimada M, Masaki T. Liver Int. 2009 Apr;29(4):614-5. Epub 2008 Oct 14. PMID 19018981. URL: [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2711260 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2711260]. Accessed on: 28 September 2009.</ref>
*Appearance on ultrasound<ref name=pmid17287178>Bile duct hamartomas--the von Meyenburg complex. Salles VJ, Marotta A, Netto JM, Speranzini MB, Martins MR. Hepatobiliary Pancreat Dis Int. 2007 Feb;6(1):108-9. PMID 17287178.</ref> and CT (hypodense)<ref name=pmid19294869>[The von Meyenburg complex] Schwab SA, Bautz W, Uder M, Kuefner MA. Rontgenpraxis. 2008;56(6):241-4. German. PMID 19294869.</ref> - similar to metastases.
 
Microscopic:<ref>{{Ref MacSween|176}}</ref>
*Many bile ducts (tubular structures with cuboidal epithelium).
*Surrounded by a fibrous stroma.
 
Images:
*[http://commons.wikimedia.org/wiki/File:Von_Meyenburg_complex_low_mag.jpg Von Meyenburg complex - bile duct hamartoma (WC)].
*[http://commons.wikimedia.org/wiki/File:Bile_duct_hamartoma_intermed_mag.jpg Bile duct hamartoma - intermed. mag. (WC)].


=Diseases=
=Diseases=
Line 500: Line 324:


==Liver mass DDx (simple)==
==Liver mass DDx (simple)==
Basic DDx of a liver mass (5 Hs):<ref>Toronto Notes 2007. DM16.</ref>
Basic DDx of a liver mass (5 Hs):<ref name=Ref_TN2007>{{Ref TN2007|DM16}}</ref>
*Hepatocellular carcinoma (HCC).
*[[Hepatocellular carcinoma]] (HCC).
*[[Hydatid cyst]].
*[[Hydatid cyst]].
**Images: [http://pathmicro.med.sc.edu/parasitology/hydatid-hist1.jpg Hydatid cyst (med.sc.edu)] [http://www.atlas.or.kr/atlas/include/viewImg.html?uid=645 Hydatid cyst (atlas.or.kr)] [http://cal.vet.upenn.edu/projects/paraav/images/lab7-14.jpg]
**Images: [http://pathmicro.med.sc.edu/parasitology/hydatid-hist1.jpg Hydatid cyst (med.sc.edu)] [http://www.atlas.or.kr/atlas/include/viewImg.html?uid=645 Hydatid cyst (atlas.or.kr)] [http://cal.vet.upenn.edu/projects/paraav/images/lab7-14.jpg]
*Hemangioma.
*[[Liver hemangioma]].
**Images: [http://www.pathguy.com/lectures/cavernous_hemangioma.jpg Hemangioma (pathguy.com)] [http://www.ikp.unibe.ch/lab2/Hemang.jpg Hemangioma (ikp.unibe.ch)]
**Images: [http://www.pathguy.com/lectures/cavernous_hemangioma.jpg Hemangioma (pathguy.com)] [http://www.ikp.unibe.ch/lab2/Hemang.jpg Hemangioma (ikp.unibe.ch)]
*[[Hepatic adenoma]].
*[[Hepatic adenoma]].
Line 514: Line 338:
*Autosomal dominant polycystic liver disease.
*Autosomal dominant polycystic liver disease.
*Biliary hamartoma.
*Biliary hamartoma.
*Caroli disease.
*[[Caroli disease]].
*Undifferentiated embryonal sarcoma.
*Undifferentiated embryonal sarcoma.
*Biliary cystadenoma.  
*Biliary cystadenoma.  
*Cystadenocarcinoma.
*Cystadenocarcinoma.
*Cystic mets.
*Cystic metastasis.
*Pyogenic and amebic abscesses.
*Pyogenic and amebic abscesses.
*Intrahepatic hydatid cyst.
*Intrahepatic [[hydatid cyst]].
*Extrapancreatic pseudocyst.
*Extrapancreatic pseudocyst.
*Biloma.
*Biloma.

Latest revision as of 21:29, 23 June 2018

The liver is an organ pathologists are seeing less of, as radiologists (with multimodal imaging and triphasic CT scans) are pretty good at sorting-out many types of liver lesions.

Drawing of a cirrhotic liver. (WC)

This article is an introduction to liver pathology. Liver neoplasms are dealt with in the liver neoplasms article. Medical liver diseases (e.g. viral hepatitis) is dealt with in the medical liver disease article.

Review of liver blood work

Normal liver

Liver anatomy

The liver is divided into eight (Couinaud) segments:

  • Segment I = caudate lobe.
  • Segments II to VIII = clockwise from left upper lobe to left upper quadrant of the liver to the right of the inferior vena cava.
    • Segment IV is divided into: IVa (superior) and IVb (inferior).

Image:

Liver histology

Liver has a dual blood supply:

  1. Portal vein.
  2. Hepatic artery.
    • The arterial flow is increased in cirrhosis.

Blood most likely flows through several hepatic lobules on one transit through the liver[1] and likely has the following arrangements of hepatic sinusoids:[2]

  1. Direct sinusoids - short flow path, no detours.
  2. Branching sinusoids - direct connection between inlet and outlet; however, have branch points for detours.
  3. Interconnecting sinusoids - connect branching sinusoids.

Structural approach

Examine:

  • Portal triad normal.
    • Artery.
    • Vein; vein should be larger than the artery.
    • Bile duct - round, has a lumen - approximately the size of the artery.
      • Cuboidal epithelium, central nucleus, lightly basophilic cytoplasm.
      • IHC: CK7 +ve.
      • Irregular bile ducts without a lumen are called bile ductules; ductule implies a pathologic process.
  • Lobule - hepatocytes.
    • What zone has the defect?
    • Cholestasis - absent/present.
    • Presence of fibrosis?
      • If a core biopsy is fragmented (on gross), think cirrhosis,[3] as cirrhotic livers commonly cleave at the fibrous bands.
      • Grade the fibrosis.
  • Central vein - has a collagen collar (seen on trichrome).

Pattern approach

 
 
 
 
Common liver
injury patterns
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis
 
Biliary
 
Steatosis

Hallmarks:

  • Hepatitis - portal inflammation, lobular inflammation, interface hepatitis (inflammation at the portal-lobule interface).
    • Clinical correlate: AST and ALT increased.
  • Biliary - inflammation confined to the portal tract, cholestasis.
    • Clinical correlate: ALP and GGT increased.
  • Steatosis - fat.
    • Clinical correlate: obese patient, changes on medical imaging (increased radiolucency on CT).
 
 
 
 
 
 
 
 
Uncommon liver
injury patterns
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infiltrative
 
Congestive
 
Ischemic
 
Mass
 
Toxic

Hallmarks:

  • Infiltrative - amyloid, monoclonal appearing lymphocytes.
    • Clinical correlate: non-specific.
  • Congestive - dilation of portal venules, perisinusoidal fibrosis/zone III fibrosis.
    • Clinical correlates: heart failure, imaging finding (portal vein thrombosis), medications.
  • Ischemic - necrosis.
  • Mass - cellular atypia or architectural abnormality.
    • Clinical correlate: mass on imaging.
  • Toxic - almost anything.
    • Clinical correlate: toxin ingestion.

Stains

  • The stains ordered (initially) are dependent on the clinical history.
    1. Anything with "tumour", "mass", or "query metastasis" in the clinical history is "tumour".
      • Stains:
        • 3 H&E.
    2. Everything else is assumed to be "medical".
      • Stains:
        • PAS-D - to detect mucin.
        • PAS - marks glycogen and mucin; useful for microvesicular steatosis
        • Trichrome - to detect fibrosis/cirrhosis.
          • Mallory trichrome: red = hepatocytes, blue/black = nuclei, green = fibrosis.
        • Reticulin - demonstrates architecture.
        • Iron stain.
          • Grading (0-4): 0 = none, 1: only at high power, 2: at medium power, 3: at lowest power, 4: seen without microscope.
            • One should comment on location, i.e. macrophage (Kupffer cell) vs. periportal hepatocytes vs. centrilobular hepatocytes vs. bile ducts vs. endothelial cells.

Additional stains/IHC

Non-standard stains:

  • Oil red O.
    • Useful for steatosis, not commonly done.
  • HPS.
    • Similar to trichrome.

Common IHC:[4]

  • CK7 - bile ducts, and bile ductules +ve.
  • CD34 - should be -ve in normal liver.
    • CD34 marks endothelial cells - these are not present in a healthy liver lobule.

Liver biopsy

Medical liver biopsy adequacy

Reporting

Main article: Pathology reports

Liver injury terms/histologic findings

Bile duct injury

  • Non-specific finding.
    • Seen in a number of conditions, e.g. autoimmune hepatitis, primary biliary cirrhosis, viral hepatitis.

Microscopic:

  • Abnormal epithelium:
    • Nuclei not round.
    • Cytoplasmic eosinophilia.
  • Intraepithelial lymphocytes.

Bile duct hamartoma

  • AKA Meyenburg complex and von Meyenburg complex.
  • Classically associated with polycystic kidney disease (see medical liver disease).
  • May be seen in a normal liver - incidental finding at autopsy in 0.5-5.6% of cases.[5]
  • Appearance on ultrasound[6] and CT (hypodense)[7] - similar to metastases.

Microscopic:[8]

  • Many bile ducts (tubular structures with cuboidal epithelium).
  • Surrounded by a fibrous stroma.

Note:

Images

  • Von Meyenburg complex - bile duct hamartoma (WC)

  • Bile duct hamartoma - intermed. mag. (WC)

  • Von Meyenburg complex / bile duct hamartoma (WC)

www:

Isolated hepatic artery

  • The hepatic artery branches within the liver should always be found together with a vein and bile duct.

DDx:

Ballooning degeneration

Main article: Ballooning degeneration

Ground glass hepatocytes

Main article: Ground glass hepatocyte

Mallory bodies

  • Cytoplasmic inclusion.
  • Represents: aggregation of denatured keratin filaments.

Appearance:

  • "Twisted rope" appearance.[9]
  • Eosinophilic.
  • Green on trichrome.
  • Associations:
    • Often have PMNs around 'em.
    • Often seen in hepatocytes undergoing ballooning degeneration.

Notes:

Prevalence in common liver diseases (based on one study):[10]

Disease Prevalence
Alcoholic hepatitis 65 %
Alcoholic cirrhosis 51 %
Wilson's disease 25 %
Primary biliary cirrhosis 24 %
Nonalcoholic cirrhosis 24 %
Hepatocellular carcinoma 23 %
Morbid obesity 8 %

Images

  • Mallory body. (WC/Nephron)

www:

Acidophilic body

  • Seen in ASH and NASH.[11]

Appearance:

  • Small (degenerative) hepatocyte with a:
    • Pyknotic nucleus.
      • Small, shrunken, pale staining.
    • Eosinophilic cytoplasm.

Notes:

  • AKA Councilman-like bodies; see notes in Councilman bodies below.

Image

  • Councilman body - high mag. (WC)

Councilman bodies

Appearance:

  • Eosinophilic globule.
  • Usu. surrounded by lymphocytes.

DDx:[12]

  • Viral hepatitis.
  • Yellow fever.
  • Others.

Notes:

  • Some sources say acidophilic body = councilman body,[13] others dispute this.[14][15]

Inflammation

  • Location and composition must be described, e.g. zone 1, lymphocytic infiltrate.

Grading

  • Inflammation is usually often scored (0-4; 0 = nil, 1 = mild, 2 = moderate, 3 = moderate/marked, 4 = marked).
  • The grade (usually) approximately corresponds to the transaminases.

Notes:

  • Ishak[16] grades inflammation based on activity in the:
    • Interface (0-4).
    • Confluent (zone III) necrosis (0-6).
    • Lobular necro-inflammation (0-4).
    • Portal inflammation. (0-4).

Interface hepatitis

Features:

  • Inflammation disrupts the "limiting plate", i.e. there is disruption of the hepatocytes that separate the portal tracts from the lobules.
Images

  • IH (mild) - high mag. (WC)

  • IH (mild) - very high mag. (WC)

www:

Liver fibrosis

  • More collagen than there should be.
  • Assessment of fibrosis is based on the trichrome stain.
    • Reticulin may be somewhat helpful.
      • The normal reticulin pattern is chicken wire-like; in early pre-cirrhosis (Grade 1-2) the chicken wire is collapsed/flattened.

The Toronto General Hospital uses the Laennec fibrosis system; named after the French chest physician.[19] This can be considered a modification of the Batts-Ludwig system,[20] which does not split Stage 4 into 4A, 4B and 4C.

Laennec fibrosis (stage):[21]

  • Stage 0 - no fibrosis; "loose" strands of collagen - spaces between collagen bundles.
  • Stage 1 - minimal fibrosis - no fibrous septa, minimal "portal expansion".
  • Stage 2 - mild fibrosis; portal expansion, +/-delicate septa, +/-sinusoidal fibrosis.
  • Stage 3 - moderate fibrosis - several fibrous septa, not bridging.
  • Stage 4A - mild cirrhosis/definite or probable cirrhosis - delicate septa only, fragmentation with rounded fibrous septa.
  • Stage 4B - moderate cirrhosis - at least some broad septa.
  • Stage 4C - severe cirrhosis - large regions of "extinction", i.e. loss of normal parenchyma.

A simplified version:[22]

  • Stage 0 - nil; loose strands of collagen.
  • Stage 1 - portal expansion (minimal), no septa.
  • Stage 2 - portal expansion (mild), few thin septa.
  • Stage 3 - incomplete nodules.
  • Stage 4 - complete nodules.

Notes:

  • Many different staging schemes exist. Laennec is closely related to the Metavir scheme - which also assigns a score of 0-IV.
  • There is a review by Theise focused on viral hepatitis.[18]
  • Ishak[16] developed a 6-stage system (for research purposes).

Cirrhosis

Main article: Cirrhosis

Steatosis

Main article: Steatosis

Cholestasis

Main article: Cholestasis

Diseases

Main article: Medical liver disease

The liver is an organ of many medical diseases.

Liver lesions

Main article: Liver neoplasms

Includes pre-malignant lesions, i.e. dysplastic lesions, and malignant lesions, e.g. hepatocellular carcinoma (HCC).

Liver mass DDx (simple)

Basic DDx of a liver mass (5 Hs):[23]

Cystic liver lesions

Radiologic DDx:[24]

  • Bile duct cyst.
  • Autosomal dominant polycystic liver disease.
  • Biliary hamartoma.
  • Caroli disease.
  • Undifferentiated embryonal sarcoma.
  • Biliary cystadenoma.
  • Cystadenocarcinoma.
  • Cystic metastasis.
  • Pyogenic and amebic abscesses.
  • Intrahepatic hydatid cyst.
  • Extrapancreatic pseudocyst.
  • Biloma.
  • Intrahepatic hematoma.

See also

References

  1. ↑ Fine DR, Glasser D, Hildebrandt D, Esser J, Lurie RE, Chetty N (September 1995). "An anatomic and physiological model of hepatic vascular system". J. Appl. Physiol. 79 (3): 1008–26. PMID 8567497.
  2. ↑ Koo A, Liang IY, Cheng KK (October 1975). "The terminal hepatic microcirculation in the rat". Q J Exp Physiol Cogn Med Sci 60 (4): 261–6. PMID 1041797.
  3. ↑ Fung, S. October 2007.
  4. ↑ Pollet, A. 27 May 2009.
  5. ↑ Hepatic von Meyenburg complex: a trigger of severe portal hypertension. Yoshida S, Kurokohchi K, Ueno T, Yoshino M, Shimada M, Masaki T. Liver Int. 2009 Apr;29(4):614-5. Epub 2008 Oct 14. PMID 19018981. URL: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2711260. Accessed on: 28 September 2009.
  6. ↑ Bile duct hamartomas--the von Meyenburg complex. Salles VJ, Marotta A, Netto JM, Speranzini MB, Martins MR. Hepatobiliary Pancreat Dis Int. 2007 Feb;6(1):108-9. PMID 17287178.
  7. ↑ [The von Meyenburg complex] Schwab SA, Bautz W, Uder M, Kuefner MA. Rontgenpraxis. 2008;56(6):241-4. German. PMID 19294869.
  8. ↑ Burt, Alastair D.;Portmann, Bernard C.;Ferrell, Linda D. (2006). MacSween's Pathology of the Liver (5th ed.). Churchill Livingstone. pp. 176. ISBN 978-0-443-10012-3.
  9. ↑ OA. September 9, 2009.
  10. ↑ Jensen K, Gluud C. The Mallory body: morphological, clinical and experimental studies (Part 1 of a literature survey). Hepatology. 1994 Oct;20(4 Pt 1):1061-77. Review. PMID 7927209.
  11. ↑ Tiniakos DG (2009). "Liver biopsy in alcoholic and non-alcoholic steatohepatitis patients". Gastroenterol. Clin. Biol. 33 (10-11): 930–9. doi:10.1016/j.gcb.2009.05.009. PMID 19646834.
  12. ↑ URL: http://www.tissueculturemicroscopy.com/degenerations-and-certain-infiltrations.html. Accessed on: 1 February 2011.
  13. ↑ URL: http://medical-dictionary.thefreedictionary.com/cytosegresome+formations. Accessed on: 1 February 2011.
  14. ↑ URL: http://www.tissueculturemicroscopy.com/degenerations-and-certain-infiltrations.html. Accessed on: 1 February 2011.
  15. ↑ URL: http://books.google.com/books?id=MrLfdTZl1dEC&pg=PA62#v=onepage&q&f=false. Accessed on: 1 February 2011.
  16. ↑ 16.0 16.1 Ishak K, Baptista A, Bianchi L, et al. (June 1995). "Histological grading and staging of chronic hepatitis". J. Hepatol. 22 (6): 696-9. PMID 7560864.
  17. ↑ Atlas of Pathology. URL: http://www.pathologyatlas.ro/viral-chronic-moderate-hepatitis.php. Accessed on: September 1, 2009.
  18. ↑ 18.0 18.1 Theise ND (February 2007). "Liver biopsy assessment in chronic viral hepatitis: a personal, practical approach". Mod. Pathol. 20 Suppl 1: S3-14. doi:10.1038/modpathol.3800693. PMID 17486049. http://www.nature.com/modpathol/journal/v20/n1s/full/3800693a.html.
  19. ↑ Why does cirrhosis belong to Laennec? Duffin JM. CMAJ. 1987 Sep 1;137(5):393-6. PMID 3304599. URL: http://www.pubmedcentral.nih.gov/pagerender.fcgi?artid=1492806&pageindex=4
  20. ↑ Batts KP, Ludwig J (December 1995). "Chronic hepatitis. An update on terminology and reporting". Am. J. Surg. Pathol. 19 (12): 1409–17. PMID 7503362.
  21. ↑ URL: http://www.pulsus.com/cddw2000/abs/080.htm. Accessed on: 9 December 2010.
  22. ↑ OA. 10 September 2009.
  23. ↑ Greenwald, J.; Heng, M. (2007). Toronto Notes for Medical Students 2007 (2007 ed.). The Toronto Notes Inc. for Medical Students Inc.. pp. DM16. ISBN 978-0968592878.
  24. ↑ Mortelé, KJ.; Ros, PR.. "Cystic focal liver lesions in the adult: differential CT and MR imaging features.". Radiographics 21 (4): 895-910. PMID 11452064. http://radiographics.rsnajnls.org/cgi/content/abstract/21/4/895.
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