Difference between revisions of "Liver pathology"

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=Biopsy=
=Biopsy=
===Adequacy===
==Stains==
Liver biopsy specimens should be:<ref>{{Ref MacSween|418}}</ref>
*The stains orders (initially) are dependent on the clinical history.
*2.0 cm in length and contain 11-15 portal tracts,
*#Anything with "tumour", "mass", or "query metastasis": 3 H&E 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.
*#Everything else is assumed to be "medical".
 
===Components===
Specimen, procedure:<br>
Diagnosis.
<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:
Medical liver biopsy stains:
*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.
*[[PAS]].
*[[PAS]].
**Useful for microvesicular steatosis.
**Useful for microvesicular steatosis.
Line 196: Line 180:
*Reticulin - demonstrates architecture.
*Reticulin - demonstrates architecture.


Additional stains:<ref name=ap27may09/>
===Additional stains/IHC===
Non-standard stains:
*[[Oil red O]].
**Useful for steatosis, not commonly done.
 
Common IHC:<ref name=ap27may09/>
*CK7 - bile ducts, and bile ductules +ve.
*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.
===Medical liver adequacy===
Liver biopsy specimens should be:<ref>{{Ref MacSween|418}}</ref>
*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:<br>
Diagnosis.
<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>


=Liver injury terms/histologic findings=
=Liver injury terms/histologic findings=

Revision as of 23:25, 19 January 2012

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.

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

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.

Other

  • Bilirubin.
    • Direct (AKA conjugated).
    • Indirect (AKA unconjugated).

A short DDx of elevated:[1]

  • Indirect:
    • Gilbert syndrome.
    • Crigler-Najjar syndrome type 1.
    • Crigler-Najjar syndrome type 2.
  • Direct:
    • Rotor syndrome.
    • Dubin-Johnson syndomre.

Viral hepatitis

  • HBV DNA.
  • HCV RNA.
  • HBs Ag, HBs Ab, HBe Ag, HBe Ab.
  • HCV Ab.

Others:

Hepatitis B

Meaning & utility of the various Hepatitis B tests:[2][3]

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.[3]

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

Hemosiderosis

  • Ferritin - high.
  • Iron saturation - high.

Causes:

  • Hemochromatosis.
  • Hemolysis, chronic.
  • Cirrhosis.

Medical imaging

Blood flow:[5]

  • Hepatopedal flow = normal portal vein flow.
  • Hepatofugal flow = reversed portal vein flow.

Interventional measurements

Wedged to free hepatic venous pressure:[6]

  • Normal = 1-4 mmHg.
    • Elevated in portal hypertension.

Normal 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[7] and likely has the following arrangements of hepatic sinusoids:[8]

  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 - should have a lumen and be round.
      • 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,[9] 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.

Biopsy

Stains

  • The stains orders (initially) are dependent on the clinical history.
    1. Anything with "tumour", "mass", or "query metastasis": 3 H&E stains.
    2. Everything else is assumed to be "medical".

Medical liver biopsy stains:

  • 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:[11]

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

Additional stains/IHC

Non-standard stains:

  • Oil red O.
    • Useful for steatosis, not commonly done.

Common IHC:[11]

  • 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.

Medical liver adequacy

Liver biopsy specimens should be:[12]

  • 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:

  • The term "acute" is infrequently used in liver pathology.
  • In the liver: neutrophils is not acute -- unlike most elsewhere in the body.[13]

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.[14]

Notes:

  • The term is used only in conjunction with steatohepatitis.
  • Feathery degeneration is the term used in the context of non-fatty disease.[15]

Images:

Ground glass hepatocytes

  • Eosinophilic dull/hazy, somewhat irregular cytoplasm.
    • Ground glass[16] = 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.[17]
  • 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.[18]

Classification:[19]

  • 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[20] and based on an animal model.[21]

Micrographs of GGHs:

Mallory bodies

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

Appearance:

  • "Twisted rope" appearance.[22]
  • 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):[23]

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:

Acidophilic body

  • Seen in ASH and NASH.[24]

Appearance:

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

Image:

Notes:

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

Councilman bodies

Appearance:

  • Eosinophilic globule.
  • Usu. surrounded by lymphocytes.

DDx:[25]

  • Viral hepatitis.
  • Yellow fever.
  • Others.

Notes:

  • Some sources say acidophilic body = councilman body,[26] others dispute this.[27][28]

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[29] 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.[30]
  • 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.
      • 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.[31] This can be considered a modification of the Batts-Ludwig system,[32] which does not split Stage 4 into 4A, 4B and 4C.

Laennec fibrosis (stage):[33]

  • 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:[34]

  • 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.[35]
  • Ishak[29] developed a 6-stage system (for research purposes).

Cirrhosis

  • Cirrhosis is stage 4 (Laennec).
    • The formal Robbins definitions is:[36] (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.[37]
  • In NAFLD portal-to-portal fibrosis (septal/bridging fibrosis) tends to be more common than perivenular fibrosis.[38]

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:

  1. Microvesicular steatosis.
    • Rare.
    • Nucleus is central.[39]
  2. Macrovesicular steatosis.
    • Common.
    • Nucleus is eccentric.

Microvescicular is considered potentially life threatening.[40]

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

  • Mild <33%, moderate >33% & <66%, marked >66%.[41]

Notes:

  • It is considered technically incorrect to say the liver, in steatosis/steatohepatitis, contains adipocytes; they are lipid-laden hepatocytes,[42] despite that:
    • Histologically, these cells look like adipocytes.
    • Lipid-laden hepatocytes have gene activations suggestive of adipogenic-like transformation.[43]
  • Donor livers with more fat = worse outcome.[44]
    • One cut-point is 30% -- more than 30% and the liver is undesirable for transplantation.[45]

Microvesicular steatosis

Microvesicular steatosis DDx:[46]

  • 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:[47]

  • 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.[48]

Centrilobular predominant (zone III) - DOA:[48]

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

Image: Centrilobular steatosis (WC).

Periportal predominant (zone I) - TAPES:[48]

  • Total parenteral nutrition (TPN).
  • AIDS.
  • Phosphorus poisoning.
  • Exogenous steroids.
  • Starvation.

Notes:

  • HCV genotype 3 is reported to cause periportal steatosis.[49]

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 hereditary hemochromatosis.

Histologic findings of large-duct obstruction:[50]

  1. Perivenular bilirubinostasis.
  2. Portal tract edema & inflammation (neutrophils & macrophages).
  3. Large bile plugs.
  4. Bile duct proliferation.[51][52]

Small-duct obstruction:

  • Abnormal liver plate architecture. (???)

Image: Cholestasis (WC).

Brown/yellow cytoplasmic inclusions

Comparison of brown/yellow cytoplasmic inclusions:[53]

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.[54]
  • Appearance on ultrasound[55] and CT (hypodense)[56] - similar to metastases.

Microscopic:[57]

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

Images:

Diseases

The liver is an organ of many medical diseases.

Liver lesions

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):[58]

Cystic liver lesions

Radiologic DDx:[59]

  • 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. 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. 441. ISBN 978-1416054542.
  2. URL: http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/hepatology/hepatitis-B/. Accessed on: 16 May 2011.
  3. 3.0 3.1 URL: http://www.labtestsonline.org/understanding/analytes/hepatitis_b/test.html. Accessed on: 16 May 2011.
  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.
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  7. 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.
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  9. S. Fung. October 2007.
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  11. 11.0 11.1 AP. 27 May 2009.
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  14. MG. 16 September 2009.
  15. MG. 17 September 2009.
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  21. 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.
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  24. 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.
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  31. 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
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  33. URL: http://www.pulsus.com/cddw2000/abs/080.htm. Accessed on: 9 December 2010.
  34. OA. 10 September 2009.
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  36. 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.
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