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Pattern-Based Approach to the Liver Biopsy

Updated: Sep 5, 2018

The following content was adapted from the 2012 USCAP short course: Pattern-based algorithms in diagnostic liver pathology presented by Dr. Romil Saxena and Dr. Neil D. Theise.

Assessment of liver architecture

Normal architecture:

  • Sheets of hepatocytes interrupted at uniform intervals by portal tract branches and hepatic venous tributaries of various sizes

  • Scarce fibrous tissue (if present, should surround the portal tracts and central veins)

Clues to alteration of architecture:

  • Portal tracts and central veins are not seen in the biopsy

  • Architecture is distorted by fibrous tissue.


Evaluate portal tracts & lobules to determine pattern of injury present

Following assessment of parenchymal architecture, examination of portal tracts and lobules usually leads one to identify the dominant pattern of injury.

The major patterns of liver injury include:

Portal infiltrates
Ductular reaction
Lobular injury

The algorithm below can be utilized to help determine which pattern is present.


Portal Cellular Infiltrates

"The BLUE portal tract"

The infiltrate may be limited to the portal tracts or extend beyond it to involve the limiting plate of hepatocytes at the interface with portal tracts (interface hepatitis, formerly referred to as piecemeal necrosis). There may be associated lobular inflammation with variable degrees of hepatocyte necrosis.

The old term is “ductular proliferation,” but this term focused too much on the epithelial, ductule-like cells in the reactions, excluding the equally important stromal, vascular, and inflammatory components that accompany them. The combination of these elements is what helps to define the disease states characterized by prominent ductular reactions.

Common Causes:

  • Inflammatory hepatitis (chronic viral hepatitis, autoimmune hepatitis, drug induced hepatitis)

  • Chronic biliary diseases (primary biliary cirrhosis, chronic biliary strictures)

  • Metabolic diseases (Wilson disease, alpha-1 antitrypsin deficiency)

  • Sarcoidosis

  • Neoplastic conditions (lymphomas/leukemias).

The character of the infiltrate, the pattern of involvement and associated findings (such as ductular reaction in chronic biliary diseases, intracytoplasmic globules in alpha-1 antitrypsin deficiency) provide clues to the diagnosis.


Ductular Reaction/Proliferation


Ductular reactions (DRs) are a mixed tissue reaction at the interface of portal tract or septal stroma and the hepatic parenchyma. The hepatobiliary epithelial cells in DRs are now recognized as most often representing a stem/progenitor cell response to bile duct or hepatocyte injury and derive from the most important stem cell niche for the liver, the canal of Hering, where the hepatocyte canalicular system meets the smallest branches of the biliary tree. However, in some cases, less frequently, there may also be biliary metaplasia of hepatocytes at the interface as well, and thus represent a degenerative rather than a regenerative process.

If DRs are prominent at low power the differential diagnosis is usually simple, particularly if there is appropriate clinical history to go along with the biopsy, surgical or autopsy liver tissue being examined. These may be divided into acute vs. chronic injuries and biliary vs. hepatocellular tract injuries.

Biliary Tract Disorders presenting with DR

  • Obstruction (stricture, biliary atresia)

  • Primary biliary cirrhosis (PBC)

  • Primary sclerosing cholangitis (PSC)

  • PFIC

  • Alagille

  • Ascending cholangitis

Non-biliary disorders presenting with DR:

  • Neonatal hepatitis

  • Viral hepatitis

  • Alpha-1 antitrypsin

  • Budd-Chiari

  • Sepsis

  • Alcohol induced liver disease

  • Drug induced hepatitis


Lobular Injury


When the lower power view of a biopsy specimen shows portal tracts in normal distribution, but a “busy lobule,” the causes are diverse and an eye for subtlety is required. There is usually an amazing amount of diagnostic data contained in the fine detail that will require significant time analyzing the high power view of the tissue, the rare times when it is the high power examination that is the most telling for evaluating liver disease.

Common causes of lobular injury:

  • Inflammation :Acute hepatitis

  • Metabolic processes: Fatty change, Steatosis, Storage material

  • Vascular diseases: Sickle cell disease, Veno-occlusive, Cardiac decompensation, Budd-Chiari

  • Infiltrative processes: Malignant/neoplastic, Amyloid

  • Pigment deposition: Hemosiderosis, Dubin-Johnson, Cholestasis (drug induced, graft vs. host, chronic rejection)




Steatosis or accumulation of fat is commonly seen in liver biopsies. Since fat dissolves out during paraffin processing of tissues, its presence is seen as empty vacuoles of various sizes.

The fat vacuoles may appear as:

  1. Large intracytoplasmic lipid vacuoles that enlarges the hepatocyte in which they reside and push the nucleus against the cell membrane (Macrovesicular steatosis).

  2. Multiple small vacuoles that indent but do not displace the nucleus (microvesicular steatosis).

  3. Medium sized vacuoles which are similar to those of macrovesicular steatosis except that they are smaller and do not enlarge the cell. These are referred to variably medium droplet fat or small-droplet fat; the latter term may cause confusion with microvesicular steatosis.

The pattern of fat accumulation and accompanying histological findings provide clue to the differential diagnosis.

The commonest conditions which display a steatotic pattern of liver injury are:


  • Alcohol-induced liver disease (ALD)

  • Wilson disease

  • Drug-induced liver injury (amiodarone, methotrexate, anti-HIV agents)

  • Viral infections (hepatitis C virus, human immunodeficiency virus)

Metabolic diseases can cause fat accumulation due to defective fat utilization or protein/caloric deprivation due to malabsorption of dietary avoidance. Accumulation of fat occurs easily in children and infants in temporary states of caloric deprivation. Metabolic diseases most often associated with fat accumulation are:

  • Cystic fibrosis

  • Galactosemia

  • Hereditary fructose intolerance

  • Glycogen storage disease I and III

  • Urea cycle defects

  • Fatty oxidation defects

  • Mitochondriopathies


Near-Normal Appearance

"THE CALM (but not quiet) LIVER"

Etiologies associated with no changes:

  • OTC (Ornithine Transcarbamylase deficiency)

  • Primary hyperoxaluria

  • Urea cycle defects

Etiologies causing subtle changes:

  • Gaucher's

  • Resolving hepatitis

  • Wilson's disease

  • Canalicular cholestasis

  • Veno-occlusive disease

  • Sickle cell disease

  • Compression from adjacent mass

  • Nodular regenerative hyperplasia

  • Hepatocellular adenoma