Liver pathology

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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)

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

  • Eosinophilic dull/hazy, somewhat irregular cytoplasm.
    • Ground glass[9] = glass with a rough/flat finish; glass that is translucent and has a matte finish.
      • The term is frequently used in radiology to describe hazy radiodense areas in the lung.[10]
  • Usually suggests chronic HBV infection.
    • Pattern NOT seen in acute HBV.
    • Caused by virion particles.

DDx:

  • Pseudo-Lafora bodies in patients on disulfiram (anatabuse) - rare.

Classification

  • GGHs are not routinely classified.

Notes:

  • Several different types of GGHs are recognized.[11]

Classification:[12]

  • Type I ground glass hepatocytes (GGHs).
    • Weak Pre-S2 positive immunostaining; morphology: GGHs scattered singly.
  • 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[13] and based on an animal model.[14]

Micrographs of GGHs:

  • Ground glass hepatocytes. (WC/Nephron)

  • Ground glass hepatocyte. (WC/Nephron)

www:

Mallory bodies

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

Appearance:

  • "Twisted rope" appearance.[15]
  • 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):[16]

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.[17]

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:[18]

  • Viral hepatitis.
  • Yellow fever.
  • Others.

Notes:

  • Some sources say acidophilic body = councilman body,[19] others dispute this.[20][21]

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[22] 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.[25] This can be considered a modification of the Batts-Ludwig system,[26] which does not split Stage 4 into 4A, 4B and 4C.

Laennec fibrosis (stage):[27]

  • 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:[28]

  • 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.[24]
  • Ishak[22] developed a 6-stage system (for research purposes).

Cirrhosis

  • Cirrhosis is stage 4 (Laennec).
    • The formal Robbins definitions is:[29] (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.[30]
  • In NAFLD portal-to-portal fibrosis (septal/bridging fibrosis) tends to be more common than perivenular fibrosis.[31]
  • The classic teaching is that cirrhosis is irreversible; however, there is increasing evidence that it regresses.[32][33][34]

Special types:

Gross

Cirrhosis can be divided (in gross pathology) into:

  • Micronodular cirrhosis - classically due to alcohol.
    • Uniform, diffuse.
  • Macronodular cirrhosis - classically due to viral hepatitis.
    • Irregular.

Images:

  • Cirrhotic liver - trichrome stain. (WC/Nephron)

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):[35]

Cystic liver lesions

Radiologic DDx:[36]

  • 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. ↑ URL: http://en.wikipedia.org/wiki/Ground_glass. Accessed on: 7 June 2010.
  10. ↑ URL: http://www.healthsystem.virginia.edu/internet/radiology/educ/groundglass.cfm. Accessed on: 7 June 2010.
  11. ↑ 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. Accessed on: September 11, 2009.
  12. ↑ 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 http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1892360&rendertype=figure&id=f1]. Accessed on: 17 September 2009.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ OA. September 9, 2009.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ URL: http://www.tissueculturemicroscopy.com/degenerations-and-certain-infiltrations.html. Accessed on: 1 February 2011.
  19. ↑ URL: http://medical-dictionary.thefreedictionary.com/cytosegresome+formations. Accessed on: 1 February 2011.
  20. ↑ URL: http://www.tissueculturemicroscopy.com/degenerations-and-certain-infiltrations.html. Accessed on: 1 February 2011.
  21. ↑ URL: http://books.google.com/books?id=MrLfdTZl1dEC&pg=PA62#v=onepage&q&f=false. Accessed on: 1 February 2011.
  22. ↑ 22.0 22.1 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.
  23. ↑ Atlas of Pathology. URL: http://www.pathologyatlas.ro/viral-chronic-moderate-hepatitis.php. Accessed on: September 1, 2009.
  24. ↑ 24.0 24.1 Theise, ND. (Feb 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. Cite error: Invalid <ref> tag; name "pmid17486049" defined multiple times with different content
  25. ↑ 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
  26. ↑ Batts KP, Ludwig J (December 1995). "Chronic hepatitis. An update on terminology and reporting". Am. J. Surg. Pathol. 19 (12): 1409–17. PMID 7503362.
  27. ↑ URL: http://www.pulsus.com/cddw2000/abs/080.htm. Accessed on: 9 December 2010.
  28. ↑ OA. 10 September 2009.
  29. ↑ Mitchell, Richard; Kumar, Vinay; Fausto, Nelson; Abbas, Abul K.; Aster, Jon (2011). Pocket Companion to Robbins & Cotran Pathologic Basis of Disease (8th ed.). Elsevier Saunders. pp. 439. ISBN 978-1416054542.
  30. ↑ OA. September 15, 2009.
  31. ↑ 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.
  32. ↑ Wanless, IR.; Nakashima, E.; Sherman, M. (Nov 2000). "Regression of human cirrhosis. Morphologic features and the genesis of incomplete septal cirrhosis.". Arch Pathol Lab Med 124 (11): 1599-607. doi:10.1043/0003-9985(2000)1241599:ROHC2.0.CO;2. PMID 11079009.
  33. ↑ Kim, SU.; Park, JY.; Kim, do Y.; Ahn, SH.; Choi, EH.; Seok, JY.; Lee, JM.; Park, YN. et al. (2010). "Non-invasive assessment of changes in liver fibrosis via liver stiffness measurement in patients with chronic hepatitis B: impact of antiviral treatment on fibrosis regression.". Hepatol Int 4 (4): 673-80. doi:10.1007/s12072-010-9201-7. PMID 21286337.
  34. ↑ Casado, JL.; Quereda, C.; Moreno, A.; Pérez-Elías, MJ.; Martí-Belda, P.; Moreno, S. (Dec 2013). "Regression of liver fibrosis is progressive after sustained virological response to HCV therapy in patients with hepatitis C and HIV coinfection.". J Viral Hepat 20 (12): 829-37. doi:10.1111/jvh.12108. PMID 24304452.
  35. ↑ 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.
  36. ↑ 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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