Liver pathology

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:

• 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:

• Epstein-Barr virus (EBV).
• Cytomegalovirus (CMV) - especially in the immune incompetent.

Hepatitis B

Meaning & utility of the various Hepatitis B tests:

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.
• Carriers of hepatitis B: HBs Ag +ve, HBs Ab -ve, HBc Ag -ve, HBc Ab +ve, HBe Ag -ve, HBe Ab +ve.

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.
• Alpha-1 antitrypsin - if low think deficiency.

Hemosiderosis

• Ferritin - high.
• Iron saturation - high.

Causes:

• Hemochromatosis.
• Hemolysis, chronic.
• Cirrhosis.

Medical imaging

Blood flow:

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

Interventional measurements

Wedged to free hepatic venous pressure:

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

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:

• Couinaud segments (masterofmedicine.com).

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 and likely has the following arrangements of hepatic sinusoids:

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, 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.

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:

• 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

Liver biopsy specimens should be:

• 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.

Reporting

Main article: Pathology reports

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.

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.
• Appearance on ultrasound and CT (hypodense) - similar to metastases.

Microscopic:

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

Note:

• Not related to bile duct adenoma.

Images:

• Bile duct hamartoma - gross image (rsna.org).
• Von Meyenburg complex - bile duct hamartoma (WC).
• Bile duct hamartoma - intermed. mag. (WC).
• Bile duct hamartoma (rsna.org).

Isolated hepatic artery

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

DDx:

• Focal nodular hyperplasia.
• Hepatic adenoma.
• Hepatocellular carcinoma.

Ballooning degeneration

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

Notes:

• The term is used only in conjunction with steatohepatitis.
• Feathery degeneration is the term used in the context of cholestasis.
  • It is usually periportal.

Images:

• Ballooning degeneration (WC).
• Ballooning degeneration (uthscsa.edu).
• Ballooning degeneration (med.utah.edu).

Ground glass hepatocytes

• Eosinophilic dull/hazy, somewhat irregular cytoplasm.
  • Ground glass = 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.
• 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.

Classification:

• 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 and based on an animal model.

Micrographs of GGHs:

• Ground glass hepatocyte (WC).
• Ground glass hepatocytes (consultantlive.com).
• Ground glass hepatocytes (biomedcentral.com).
• Ground glass hepatocyte (pathology.osu.edu).

Mallory bodies

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

Appearance:

• "Twisted rope" appearance.
• 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):

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:

• Mallory body (WC).
• Mallory bodies - CDC/WP (WP).
• Mallory bodies - Mod. Pathol. (nature.com).

Acidophilic body

• Seen in ASH and NASH.

Appearance:

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

Image:

• Councilman body - high mag. (WC).

Notes:

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

Councilman bodies

Appearance:

• Eosinophilic globule.
• Usu. surrounded by lymphocytes.

DDx:

• Viral hepatitis.
• Yellow fever.
• Others.

Notes:

• Some sources say acidophilic body = councilman body, others dispute this.

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 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.
• 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:

• Interface hepatitis (pathologyatlas.ro)

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

Laennec fibrosis (stage):

• 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:

• 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.
• Ishak developed a 6-stage system (for research purposes).

Cirrhosis

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

Special types:

• Garland cirrhosis (AKA holly leaf cirrhosis) - see primary biliary cirrhosis.

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:

• Cirrhosis - macronodular & micronodular (meddean.luc.edu).
• Cirrhotic liver - trichrome stain (WC).

Steatosis of the liver

Can be divided into:

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

Microvescicular is considered potentially life threatening.

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

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

Notes:

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

Microvesicular steatosis

Microvesicular steatosis DDx:

• 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:

• 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.

Centrilobular predominant (zone III) - DOA:

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

Image: Centrilobular steatosis (WC).

Periportal predominant (zone I) - TAPES:

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

Notes:

• HCV genotype 3 is reported to cause periportal steatosis.
• Donor livers with more macrovescicular steatosis = worse outcome.
  • More than 30% means the liver is undesirable for transplantation.

Image: Periportal steatosis (WC).

Cholestasis

General

Short DDx - by etiology:

• Congenital: Bile duct cyst, biliary atresia, liver cysts.
• Infectious: Worm.
• Tumour: pancreas, bile duct, liver.
• Endocrine: cholestasis of pregnancy.
• Trauma -> sepsis.
• Autoimmune: PSC, PBC.
• Toxins: alcohol -> cirrhosis.
• Everything else: drugs, e.g. NSAIDs.

Short DDx - structural:

• Obstruction - large duct:
  • Tumour.
  • Gallstone.
  • Worm.
  • PSC.
• Small duct - autoimmune:
  • PBC.
• Other:
  • Rx.
  • Toxins.
  • Cholestasis of pregnancy.

Microscopic

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.

Brown/yellow cytoplasmic inclusions

Comparison of brown/yellow cytoplasmic inclusions:

Finding	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

Large duct obstruction

Histologic findings of large-duct obstruction:

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

Note:

• Ductular reaction = increased number of ducts + neutrophils.

Small duct obstruction

Small-duct obstruction:

• Abnormal liver plate architecture. (???)

Images:

• Cholestasis (WC).
• Centrilobular cholestasis (humpath.com).

Sign out

LIVER, CORE BIOPSY:
- CENTRILOBULAR CHOLESTATSIS (MILD), SEE MICROSCOPIC DESCRIPTION AND COMMENT.
- NEGATIVE FOR FIBROSIS.

COMMENT:
There is no apparent feathery degeneration. There is no bile ductular proliferation. No
definite onion-skin lesions are identified.

The centrilobular distribution of the bile favours a large duct obstruction. Possible
causes include gallstones, other obstructing lesions, herbals and drugs.

Clinical and radiologic correlation is suggested.

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):

• Hepatocellular carcinoma (HCC).
• Hydatid cyst.
  • Images: Hydatid cyst (med.sc.edu) Hydatid cyst (atlas.or.kr) [1]
• Hemangioma.
  • Images: Hemangioma (pathguy.com) Hemangioma (ikp.unibe.ch)
• Hepatic adenoma.
• Hyperplasia, focal nodular.

Cystic liver lesions

Radiologic DDx:

• 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

• Pancreas.
• Gastrointestinal pathology.
• Liver neoplasms.
• Medical liver disease.