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Liver & intrahepatic bile ducts

General

Histology

Authors: Nicole Leonard, M.D., Kimberley J. Evason, M.D., Ph.D.

Editorial Board Member: Raul S. Gonzalez, M.D.

Deputy Editor-in-Chief: Catherine E. Hagen, M.D.

Last author update: 11 May 2021

Last staff update: 11 May 2021

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PubMed Search: Liver histology[TI] normal [TIAB]

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Table of Contents

Cite this page: Leonard N, Evason KJ. Histology. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/livernormalhistology.html. Accessed December 6th, 2022.

Definition / general

Liver is the largest solid organ and is located in the right upper quadrant of the abdomen

Essential features

Functional unit is the hepatic lobule, composed of hepatocyte plates surrounding a central vein with portal tracts at the periphery
Main cell type is the hepatocyte, which is critical for producing bile and for metabolizing drugs, proteins, fats, carbohydrates and vitamins
Biliary epithelial cells (cholangiocytes) line bile ducts, which transport and modify bile
Hepatic stellate cells, located in the space of Disse, store vitamin A and become activated and fibrogenic in response to injury
Dual blood flow from hepatic artery and portal vein passes through sinusoids and exits the liver via hepatic vein branches

Terminology

Hepatic: of or relating to the liver

Physiology

Drug metabolism
- Phase 1 reactions increase polarity and water solubility of compounds through oxidation, reduction and hydrolysis through the cytochrome p450 system
- Phase 2 reactions create less toxic byproducts through transferase reactions and conjugations
Lipid metabolism
- During prolonged fasting states, free fatty acids (FFAs) produced by lipolysis in adipose tissue are transported to the liver
- FFAs are beta-oxidized in liver to release ketone bodies to fuel the brain or formed into triglycerides for storage or transportation
Carbohydrate metabolism
- In the fed state, carbohydrates are stored as glycogen in the liver
- In the fasting state, this glycogen can be broken down for systemic use (glycogenolysis)
- Lactate, amino acids and glycerol can be converted into glucose (gluconeogenesis)
Protein metabolism
- Ingested proteins are broken down into amino acids to be used throughout the body
- Excess amino acids are oxidized for energy or converted into glucose, ketone bodies or fat
- Nitrogen waste products are converted to urea to be excreted in the urine
- Various proteins are synthesized, including albumin, coagulation factors and fibrinolytic components
Bile production (Compr Physiol 2013;3:1035)
- Bile salts are produced by hepatocytes from cholesterol and conjugated with glycine or taurine, secreted into canaliculi, modified by cholangiocytes and stored and further concentrated in the gallbladder
- Bile salts returning from the GI tract via the portal vein are actively transported into hepatocytes to be recycled
- Free bilirubin is taken up by hepatocytes, conjugated to glucuronic acid and secreted with bile
Vitamin metabolism
- Vitamin A storage (hepatic stellate cells)
- Vitamin D 25-hydroxylation
- Vitamins A, D, E and K absorption from intestine, which requires bile salts
- B vitamin uptake, storage and metabolism / conversion

Diagrams / tables

Images hosted on other servers:

Lobule and portal triad

Anatomy and functional segments

Clinical features

Metabolic differences among the zones of hepatic lobules influence hepatocytes’ susceptibility to viral infection, drug injury, nonalcoholic fatty liver disease and other insults (Exp Biol Med (Maywood) 2017;242:1605)

Laboratory

Aspartate transaminase (AST) and alanine transaminase (ALT) to evaluate potential hepatocyte damage
Albumin, coagulation factors, prothrombin time (PT) and partial thromboplastin time (PTT) to evaluate synthetic function
Alkaline phosphatase and bilirubin to evaluate the biliary system and excretion
Reference: CMAJ 2005;172:367

Gross description

Normal weight in adults is 1,400 - 1,600 grams (Am J Surg Pathol 1987;11:709)
Can be divided into 4 lobes: right, left, caudate and quadrate
Gallbladder (if present) is located on posterior surface of right lobe
Dual blood supply (hepatic artery and portal vein) enters at the hilum / porta hepatis on the inferior aspect
Peritoneum covers the superior, anterior and lateral surfaces
External surface is smooth and red-brown
Cut surface is firm and red-brown, with branches of portal vein, hepatic artery, bile ducts and hepatic vein seen throughout

Gross images

Contributed by Michelle Wilkinson, B.S., P.A. (ASCP)

Red-brown cut surface

Frozen section description

Frozen section may be done to evaluate potential donor livers
- Assess for large and small droplet steatosis, fibrosis and inflammation
- Sinusoids may appear prominent and mimic steatosis
- Submitting tissue sample in saline may introduce water artifact mimicking steatosis
Reference: J Clin Med Res 2011;3:191

Frozen section images

Contributed by Kimberley J. Evason, M.D., Ph.D.

Frozen section portal tract

Frozen section central zone

Microscopic (histologic) description

Main liver cell types
- Hepatocytes
  - Arranged in plates 1 - 2 cells thick
  - Polygonal cells with round, centrally located nuclei and abundant eosinophilic cytoplasm with fine basophilic granules; can be pleomorphic and multinucleated
  - May contain fat vacuoles, glycogen or lipofuscin pigment
- Cholangiocytes (bile duct epithelial cells)
  - Line bile ductules and bile ducts
  - Cuboidal epithelial cells with round, centrally located nuclei
- Kupffer cells
  - Located in the sinusoids
  - Mononuclear, phagocytic cells (macrophages) that respond to cell injury
  - Bean shaped nucleus with abundant cytoplasm and star shaped cytoplasmic extensions
- Stellate cells
  - Located in the space of Disse (not normally seen on H&E)
  - Become activated in response to cell injury and differentiate into myofibroblasts
  - Store fat and vitamin A (Physiol Rev 2008;88:125)
- Endothelial cells
  - Line sinusoids as well as blood vessels
  - Indistinct cytoplasm and small, elongated nuclei
Important microscopic features
- Limiting plate: formed by hepatocytes joining together to form a distinct row around portal tracts
- Bile canaliculi: intercellular space formed by adjacent hepatocytes (often not well visualized in normal liver unless distended)
- Sinusoids
  - These separate cords of hepatocytes
  - Lined by endothelial cells and Kupffer cells
- Space of Disse: space between endothelial cells and hepatocytes (not well visualized on H&E)
- Central hepatic veins: lined by endothelium; lack valves
- Portal triad / portal tract:
  - Hepatic artery: lined by endothelium and a thin muscular layer, approximately the same diameter as a bile duct
  - Portal vein: lined by endothelium
  - Bile duct: lined by cuboidal epithelium, approximately the same diameter as a hepatic artery
  - Not every normal portal tract will always show an artery, vein and bile duct; some will show multiple artery or duct faces (Hepatology 1998;28:323)
  - Lymphatics: not normally seen on H&E
  - May contain few lymphocytes, macrophages, mast cells and eosinophils
  - Tend to be more fibrotic in subcapsular zone
2 concepts for describing microscopic architecture
- Acinus: functional unit centered around portal triad to include surrounding central veins
- Lobule: functional unit centered around central vein to include surrounding portal triads
  - Periportal zone / zone 1
    - Higher content of oxygen and nutrients
    - Highest metabolic activity
    - Least susceptible to ischemia and toxic injury
  - Midlobular zone / zone 2
  - Centrilobular zone / zone 3
    - Most susceptible to ischemia and toxic injury

Microscopic (histologic) images

Contributed by Kimberley J. Evason, M.D., Ph.D.

Lobule

Trichrome

Portal tract

PASD

Trichrome large portal tract

Hepatocytes and sinusoids

Central vein

Canaliculi

Reticulin

Kupffer cells

Iron

Cytology description

Hepatocytes
- Polygonal to round cells with abundant dense granular to vacuolated cytoplasm and round, centrally located nuclei with prominent nucleoli
- Arranged singly in 2 dimensional clusters or trabeculae 2 - 3 cell layers thick
Cholangiocytes (bile duct epithelial cells)
- Cuboidal to columnar cells with scant pale cytoplasm and small, round nuclei with inconspicuous nucleoli
- Arranged in picket fences with nuclear palisading or monolayered honeycomb sheets
Endothelial cells: rarely seen
Kupffer cells: rarely seen
Reference: Cytojournal 2005;2:7

Cytology images

Contributed by Kimberley J. Evason, M.D., Ph.D.

Benign hepatocytes, Diff-Quik

Benign hepatocytes, Pap

Positive stains

Hepatocytes: HepPar1, CAM5.2, CD10 (bile canaliculi), polyclonal CEA (bile canaliculi) (Manual of Surgical Pathology 2006;71)
Cholangiocytes: CK7, CK19, AE1 / AE3
Kupffer cells: CD68
Routine stains:
- Trichrome: highlights collagen fibers to assess and stage fibrosis
- Reticulin: highlights reticulin fibers to assess hepatic plates for expansion or collapse
- Periodic acid-Schiff (PAS): highlights glycogen
- Periodic acid-Schiff with diastase (PASD):
  - Highlights the basement membrane of bile ducts and ductules
  - Stains abnormal alpha-1 antitrypsin globules in hepatocytes in the setting of alpha-1 antitrypsin deficiency
- Iron: aids in evaluating iron deposits in hepatocytes and Kupffer cells

Negative stains

Hepatocytes: CK7, CK19
Cholangiocytes: HepPar1 (J Hepatobiliary Pancreat Sci 2012;19:289)

Electron microscopy description

Kupffer cells, endothelial cells, hepatic stellate cells, sinusoids, bile canaliculi, the space of Disse and intracellular components like mitochondria may be visualized with electron microscopy
Limited use diagnostically except in the evaluation of some metabolic disorders
References: World J Gastroenterol 2010;16:2851, Compr Physiol 2013;3:1035

Electron microscopy images

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