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.

Liver biopsies are quite often non-specific, as the liver isn't very sophisticated; it has the same appearance for many mechanisms of injury.

Almost every differential in liver pathology has "drugs" -- if it isn't clearly malignancy.

Liver neoplasms are dealt with in the liver neoplasms article.

Review of liver blood work

Inflammation activity

  • ALT.
  • AST.

Cholestatic markers

  • ALP.
  • GGT - used to assess whether the ALP is an "honest" value, elevated in cirrhosis.

Cirrhosis/decompensation

  • PLT - low is suggestive of dysfunction.
  • 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:[1][2]

Location Positive test Negative test Usual question
HBs Ag Surface Virus active No active infect. Active infection?
HBs Ab Surface Exposed OR vaccinated No exposure OR no vacc. OR loss of Ab Immunization status?
HBe Ag Virus core Infect. w/o immune response No active infect. Active infect. w/o immune response?
HBe Ab Virus core Exposed to virus Infect. w/o immune response OR not exposed Immune response to infect.?
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.[3]

Weird stuff

  • 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.[4]
  • Alpha-1 antitrypsin - if low think deficiency.

Hemosiderosis

  • Ferritin - high.
  • Iron saturation - high.

Causes:

  • Hemochromatosis.
  • Hemolysis, chronic.
  • Cirrhosis.

Structural approach

Examine:

  • Portal triad normal.
    • Artery.
    • Vein; vein should be larger than the artery.
    • Bile duct - should have a lumen and be round.
      • Cuboidal epithelium, central nucleus, lightly basophilic cytoplasm.
      • IHC: CK7+.
      • 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,[5] 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.
    • Clinical correlate - shock, known atherosclerosis, known cirrhosis.
  • Mass - cellular atypia or architectural abnormality.
    • Clinical correlate: mass on imaging.
  • Toxic - almost anything.
    • Clinical correlate: toxin ingestion.

Biopsy

Adequacy

Liver biopsy specimens should be:[6]

  • 2.0 cm in length and contain 11-15 portal tracts,
  • 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.

Components

Specimen, procedure:
Diagnosis.
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:

  • "Acute" is infrequently used in liver pathology.
  • In the liver: PMNs != acute -- unlike elsewhere in the body.[7]

Stains

  • Oil red O
    • Useful for steatosis, not commonly done.
  • PAS.
    • Useful for microvesicular steatosis.
  • Trichrome.
    • Useful for fibrosis/cirrhosis; components of trichrome: red = hepatocytes, blue/black = nuclei, green = fibrosis.
  • 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

IHC panel/special stains:[9]

  • PAS-D - to detect mucin.
  • PAS - to detect glycogen and mucin.
  • Trichrome - to detect fibrosis/cirrhosis.
  • Reticulin - demonstrates architecture.

Additional stains:[9]

  • 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 injury terms/histologic findings

"Ballooning degeneration"

  • Central nucleus.
    • "Fat cells" have peripheral nucleus.
  • Cytoplasm cleared with "whisps" or cobbwebs.
  • Large relative to normal hepatocyte.
    • 2-3X normal size.[10]

Note:

  • The term is used only in conjunction with steatohepatitis.
  • Feathery degeneration is the term used in the context of non-fatty disease.[11]

Micrograph:

"Ground glass" hepatocytes

  • Eosinophilic dull/hazy, somewhat irregular cytoplasm.
    • Ground glass[12] = 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.[13]
  • 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

  • Several different types of GGHs are recongnized.[14]

Classification:[15]

  • 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[16] and based on an animal model.[17]

Micrographs of GGHs:

"Mallory bodies"

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

Appearance:

  • "Twisted rope" appearance.[18]
  • Eosinophilic.
  • Green on trichrome.
  • Associations:
    • Often have PMNs around 'em.
    • Often seen in hepatocytes undergoing ballooning degeneration.

Notes:

  • Previously thought to indicate alcoholic liver disease; they are more common in alcohol.

Prevalence in common liver diseases (based on one study):[19]

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 %

Micrographs:

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[20] 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

  • May be referred to as piecemeal necrosis.[21]
  • Non-specific finding, i.e. seen in several conditions - e.g. viral hepatitis, autoimmune hepatitis.

Features:

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

Micrograph:

Fibrosis

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

TGH uses Laennec fibrosis; named after French chest physician.[22]

Laennec fibrosis (grade):[23]

  • Stage 0 - no fibrosis,
  • Stage 1 - minimal fibrosis - no fibrous septa, no "portal expansion", i.e. no enlargement of portal area.
  • 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.

Laennec fibrosis (grade) - simplified version:[24]

  • Stage 0 - nil.
  • Stage 1 - irregular (fibrotic) portal area.
  • Stage 2 - portal expansion.
  • Stage 3 - incomplete nodules.
  • Stage 4 - complete nodules.

Notes:

  • Many different grading schemes exist. Laennec is closely related to the Metavir scheme - which also asigns a score of 0-IV.
  • There is a review by Theise focused on viral hepatitis.[25]
  • Ishak[20] developed a 6-stage system (for research purposes).

Cirrhosis

  • Cirrhosis is Grade 4 Laennec.
  • The etiology of late stage fibrosis (cirrhosis), may be impossible to determine.
  • Perisinusoidal fibrosis may suggest congestive hepatopathy.[26]
  • In NAFLD portal-to-portal fibrosis (septal/bridging fibrosis) tends to be more common than perivenular fibrosis.[27]

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:

Steatosis of the liver

Can be divided into:

  • Microvesicular steatosis, and
  • Macrovesicular steatosis.

Microvescicular is considered to be potentially life threatening.[28]

Quantity of fat is usually given as a percentage and graded mild, moderate, or marked.

  • Mild <33%, moderate >33% & <66%, severe >66%.[29]

Notes:

  • It is considered technically incorrect to say the liver, in steatosis/steatohepatitis, contains adipocytes; they are lipid-laden hepatocytes,[30] despite that:
    • Histologically, these cells look like adipocytes.
    • Lipid-laden hepatocytes have gene activations suggestive of adipogenic-like transformation.[31]

Microvesicular steatosis

Microvesicular steatosis DDx:[32]

  • 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:[33]

  • Tetracycline,
  • Reye's syndrome, and
  • Fatty liver of pregnancy.

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.[34]

Centrilobular predominant (zone III) - DOA:[34]

  • Diabetes mellitus.
  • Obesity, non-alcoholic steatohepatitis (NASH).
  • Alcoholic liver disease, alcoholic steatohepatitis (ASH).

Image: Centrilobular steatosis (WC).

Periportal predominant (zone I) - TAPES:[34]

  • TPN.
  • AIDS.
  • Phosphorus poisoning.
  • Exogenous steroids.
  • Starvation.

Notes:

  • HCV genotype 3 is reported to cause periportal steatosis.[35]

Image: Periportal steatosis (WC).

Cholestasis

Appearance of bile:

  • 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 something or other.

Large-duct obstruction:[36]

  1. Perivenular bilirubinostasis.
  2. Portal tract edema & inflammation (neutrophils & macrophages).
  3. Large bile plugs.

Small-duct obstruction:

  • Ductules. ???

Brown/yellow cytoplasmic inclusions

Comparison of brown/yellow cytoplasmic inclusions:[37]

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, 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.[38]

Microscopic:[39]

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

Images:

Notes:

  • Appearance on ultrasound[40] and CT (hypodense)[41] - similar to metastases.

Diseases

Main article: Medical liver disease

The liver is an organ of many diseases.

Malignant 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):[42]

Cystic liver lesions

Radiologic DDx:[43]

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

See also

References

  1. ↑ http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/hepatology/hepatitis-B/
  2. ↑ http://www.labtestsonline.org/understanding/analytes/hepatitis_b/test.html
  3. ↑ http://www.labtestsonline.org/understanding/analytes/hepatitis_b/test.html
  4. ↑ 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. Accessed on: 28 September 2009.
  5. ↑ S. Fung. October 2007.
  6. ↑ MacSween's Pathology of the Liver. 5th Ed. P.418.
  7. ↑ OA. September 2009.
  8. ↑ MG. 29 July 2009.
  9. ↑ 9.0 9.1 AP 27 May 2009.
  10. ↑ MG. 16 September 2009.
  11. ↑ MG. 17 September 2009.
  12. ↑ [1]
  13. ↑ http://www.healthsystem.virginia.edu/internet/radiology/educ/groundglass.cfm
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ OA. September 9, 2009.
  19. ↑ 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.
  20. ↑ 20.0 20.1 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.
  21. ↑ Atlas of Pathology. URL: http://www.pathologyatlas.ro/viral-chronic-moderate-hepatitis.php. Accessed on: September 1, 2009.
  22. ↑ 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
  23. ↑ http://www.pulsus.com/cddw2000/abs/080.htm
  24. ↑ OA. 10 September 2009.
  25. ↑ 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.
  26. ↑ OA. September 15, 2009.
  27. ↑ 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.
  28. ↑ Steatosis. pathconsultddx.com. URL: http://www.pathconsultddx.com/pathCon/diagnosis?pii=S1559-8675%2806%2970840-3. Accessed on: 2 Sep 2009.
  29. ↑ MG. September 17, 2009.
  30. ↑ MG. September 2009.
  31. ↑ URL: http://www.jci.org/articles/view/20513/version/1. Accessed on: 23 September 2009.
  32. ↑ PMID 2177300
  33. ↑ http://www.mailman.srv.ualberta.ca/pipermail/patho-l/1996-June/001788.html
  34. ↑ 34.0 34.1 34.2 Steatosis. pathconsultddx.com. URL: http://www.pathconsultddx.com/pathCon/diagnosis?pii=S1559-8675%2806%2970840-3. Accessed on: 2 Sep 2009.
  35. ↑ 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. Accessed on: September 9, 2009.
  36. ↑ MacSween 5th Ed. P.565.
  37. ↑ MG. September 2009.
  38. ↑ 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.
  39. ↑ MacSween 5th Ed. P.176.
  40. ↑ 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.
  41. ↑ [The von Meyenburg complex] Schwab SA, Bautz W, Uder M, Kuefner MA. Rontgenpraxis. 2008;56(6):241-4. German. PMID 19294869.
  42. ↑ TN 07 DM16.
  43. ↑ http://radiographics.rsnajnls.org/cgi/content/abstract/21/4/895
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