Pathology of the Liver and Biliary Tract 1 Normal Liver ...people.upei.ca/smartinson/LIVER_LECT_1_SAM_2017.pdf · Normal Liver; Hepatic Injury, Response, and Failure Shannon Martinson,

Pathology of the Liver and Biliary Tract – 1 Normal Liver; Hepatic Injury, Response, and Failure

Shannon Martinson, August 2017 http://people.upei.ca/smartinson/

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OUTLINE

Normal anatomy & function

Hepatobiliary injury and responses

Manifestations of hepatic failure

Developmental anomalies and miscellaneous lesions

Circulatory disturbances

Metabolic & nutritional disturbances

Infectious diseases of the liver (hepatitis)

Toxin-induced liver diseases

Diseases of uncertain cause

Proliferative lesions of the liver

Diseases of the gallbladder and bile ducts

INTRODUCTION - GENERAL CONSIDERATIONS

• Largest visceral organ • Size

• Carnivores 3-4% body weight • Omnivores 2% body weight • Herbivores 1% body weight

• 25% cardiac output • 2/3 via portal vein • 1/3 via hepatic artery

• Functions: multiple • Injurious agents: myriads • Clinical signs: variable

• The traditional structural unit is the hepatic lobule:

• Hexagonal structure 1-2 mm wide

• Central vein at the centre

• Portal triads at the periphery

• Bile ducts (BD)

• Branches of portal vein (PV)

• Hepatic artery (HA)

• Nerves and lymphatics

• Limiting plate

INTRODUCTION - NORMAL ANATOMY

Hepatic lobule

http://audilab.bmed.mcgill.ca/HA/HAimage/dig_fig_66.jpg

http://audilab.bmed.mcgill.ca/HA/HAimage/dig_fig_66.jpg


Hepatic artery

Portal vein

Portal triad

Bile duct


Robbins and Cotran Pathologic Basis of Disease (2010), 8th ed., Elsevier

Hepatic acinus

Limiting plate

Portal triad

centroacinar

Pathologic Basis of Veterinary Disease (2006), 4th ed., Mosby-Elsevier, chapter 8


Hepatic acinus

intermediate periacinar

Acinus = the functional unit

Hepatic acinus Acinus = the functional unit


Pathologic Basis of Veterinary Disease (Elsevier 2017), 6th ed., chapter 8

• Periportal hepatocytes are the most resistant to hypoxia and toxic insult

• Centrilobular hepatocytes are the most vulnerable

Pathologic Basis of Veterinary Disease (2012), 5th ed., Mosby-Elsevier, chapter 8


Hepatic sinusoids

Robbins and Cotran Pathologic Basis of Disease (2010), 8th ed., Elsevier, Inc. chaper 18

• Hepatocytes are arranged in cords separated by sinusoids

INTRODUCTION - NORMAL FUNCTION

Bilirubin metabolism

Bile acid metabolism

Carbohydrate metabolism

Lipid metabolism

Xenobiotic metabolism

Protein Synthesis

Immune function

• Clinical Signs of Liver Disease • Similar regardless of the cause • Occur :

• If functional reserve and regenerative capacity are overwhelmed

• If there is impaired bile flow • Often see icterus, ascites, hepatomegaly

• Liver lesions • Location and type are important • Histopathology is essential for diagnosis

HEPATOBILIARY INJURY AND RESPONSES

Methods of evaluating the liver include • Imaging • Serum biochemistry • FNA (US guided) • Liver biopsy (US guided or exploratory) • Necropsy

1. Hematogenous

2. Retrograde through biliary & pancreatic ducts

3. Direct extension through liver capsule


Portals of entry of injurious agents

1

2

3


Patterns of Hepatocellular Degeneration and Necrosis

• Centrilobular

• Midzonal

• Periportal

• Bridging

• Massive

Zonal

• Single cell necrosis

• Multifocal necrosis

Random



• Single cell necrosis

• Multifocal necrosis

Random

Often due to infectious disease process



• Centrilobular

• Midzonal

• Periportal

• Bridging

• Massive

Zonal

Often due to metabolic or toxic injury


Centrilobular necrosis*

Pathologic Basis of Veterinary Disease (2012), 5th ed., Mosby-Elsevier


Common causes: Anemia, Right heart failure, hypoxia

• Centrilobular hepatocytes receive the least amount of oxygen and have the greatest MFO function

Zonal


Midzonal necrosis Periportal necrosis



• Caused by toxins that don’t require activation by metabolism

Zonal



Bridging necrosis (central to central) Massive necrosis


Zonal

• Acute hepatitis

• Chronic hepatitis

• Cholangitis

• Cholangiohepatitis


Patterns of Hepatic Inflammation


General Responses of Liver to Injury

• Nature of the response depends on duration and severity of damage

• Clinical signs don’t occur until there is a 75% loss of functional reserve • Liver enzymes can be

elevated earlier

Regeneration of Parenchyma

Replacement by Fibrosis

Biliary Hyperplasia

• Very good regenerative ability

• Hepatocytes and Oval (stem) cell proliferation

• For optimal regeneration (without scarring) the following are necessary:

• Intact reticulin framework

• Good blood supply

• Patent bile ducts to drain bile



1. Regeneration

Pathologic Basis of Veterinary Disease (2006) 4th ed., Mosby-Elsevier, chapter 8



1. Regeneration

• If chronic / ongoing damage • Nodular proliferations with scarring

Pathologic Basis of Veterinary Disease (2006) 4th ed., Mosby-Elsevier, ch 8 Image: Dr A Lopez

• Increased amount of connective tissue within the liver • Ito (stellate) cells • Significance is dependent upon effects on normal hepatic function, blood and biliary flow

Images - Pathologic Basis of Veterinary Disease (2006), 4th ed., Mosby-Elsevier



2. Fibrosis



2. Fibrosis

Biliary Fibrosis

Multifocal Fibrosis

Patterns of Fibrosis • Focal/multifocal fibrosis • Diffuse hepatic fibrosis • Biliary fibrosis

Diffuse Fibrosis

Patterns of Fibrosis • Focal/multifocal fibrosis • Diffuse hepatic fibrosis • Biliary fibrosis



2. Fibrosis

Multifocal Fibrosis

Biliary Fibrosis

Image: Dr A Lopez

• Nonspecific

• Bile drainage obstruction

• Often seen in chronic hepatotoxicity

• Pyrrolizidine alkaloids

• Aflatoxins

• Can occur quickly in young animals

• An attempt to regenerate hepatocytes?

Proliferation of new bile ducts within the portal areas



3. Biliary hyperplasia

• Final irreversible result of hepatic disease • Distortion of the architecture

• Cause cannot be determined

• Characterized by 3 components*:

1. Nodular regeneration

2. Fibrosis

3. Bile duct hyperplasia


End-Stage Liver - Cirrhosis

• Final irreversible result of hepatic disease • Distortion of the architecture

• Cause cannot be determined

• Characterized by 3 components:

1. Nodular regeneration

2. Fibrosis

3. Bile duct hyperplasia

Cirrhotic liver, Masson trichrome stain



• Several possible causes: • Chronic toxicity

• Chronic cholangitis

• Biliary obstruction

• Right sided heart failure

• Inherited metabolic disease

• Chronic hepatitis

• Idiopathic

Cirrhotic liver, Masson trichrome stain



• Liver failure is a clinical syndrome that occurs when there is inadequate liver function

• It indicates massive reduction of the amount of liver cells or a loss of function

• Greater than 2/3 loss

• Result of either acute or chronic liver damage

MANIFESTATIONS OF LIVER FAILURE

1. Hepatic encephalopathy

2. Disturbances of bile flow & icterus

3. Metabolic disturbances

4. Vascular and hemodynamic alterations

5. Cutaneous lesions

6. Impaired immune functions

Consequences of hepatic failure differ somewhat among domestic species. They include:

Liver Failure

• Signs are variable and nonspecific: • Depression, aimless wandering, head

pressing, behavioural changes • Central blindness • Mania, convulsions

• Many possible underlying causes: • Acute liver disease:

• Horses and ruminants

• Portosystemic shunts • Dogs and cats

• Chronic liver disease • Any species

Hepatic Encephalopathy


vet.uga.edu

video

http://vet.uga.edu/ivcvm/courses/vpat5215/digestive/week03/liverpath/he.htm

https://www.youtube.com/watch?v=6Rv_D5MDQl4

Hepatic Encephalopathy


• Blood accumulation of neurotoxic substances bypassing the liver and reaching the brain

• Clinical signs are more severe after feeding

Pathogenesis

• Main substance is ammonia

• Other factors:

• +/- Imbalance of inhibitory & excitatory amino acid neurotransmitters

• +/- Increased brain concentration of benzodiazepines

Neurotoxic substances

www.nadis.org.uk/bulletins/nervous-diseases-in-cattle.aspx

Disturbances of Bile Flow


• Elevation of bilirubin in the blood

• >2 mg/dL leads to icterus Hyperbilirubinemia • Abnormal accumulation of bile within the liver (intrahepatic), extrahepatic

bile ducts or within the gall bladder Cholestasis

• Yellow discolouration of tissues and body fluids due to hyperbilirubinemia Icterus (Jaundice)



• Overproduction of bilirubin

• Intravascular hemolysis in particular

Pre-hepatic Icterus

• Decreased uptake, conjugation or secretion of bilirubin

• Due to hepatocellular injury

Hepatic Icterus

• Reduced outflow of bile within the canaliculi, extrahepatic bile ducts or gallbladder

• Due to a blockage within the duct system

Post-hepatic Icterus

Diagnosis of icterus and cholestasis:

Gross

• Generalized yellowish discoloration

• Yellowish/greenish brown liver

Histo

• Bile in canaliculi & hepatocytes

Clinical chemistry

• ↑ blood levels of

• Bilirubin

• Cholesterol

• Bile acids



Robbins and Cotran Pathologic Basis of Disease (2010), 8th ed., Elsevier, Inc. ch 18

Hemorrhagic diathesis

• ↓ synthesis of clotting factors

• ↓ clearance of products of clotting (FDP)

• ↓ platelet function

• ↓ absorption of vitamin K (2, 7, 9, 10)

• Disseminated intravascular coagulation (DIC)

Intravascular hemolysis

• Mainly in horses

Hypoalbuminemia

• ↓ Production

• Loss in ascites or GIT due to portal hypertension

Metabolic Disturbances


Portal hypertension

• Due to impedence of blood flow from portal vein to heart – often from hepatic fibrosis

Acquired portosystemic shunts

• Due to portal hypertension

• Multiple vascular channels open between portal vein and systemic circulation

• Allows blood to bypass the liver

Ascites (dogs and cats)

• Due to:

• Portal hypertension

• ↓ colloid osmotic pressure

• Retention of sodium and water (hyperaldosteronism)

Vascular and Hemodynamic Alterations


Acquired PSS

Hepatogenous photosensitization (2⁰)

• Normally chlorophyll is broken down in the rumen → phylloerythrin → conjugated and excreted into bile

• Phylloerythrin is photodynamic

• With hepatic disease or biliary obstruction, phylloerythrin builds up in the blood

Cutaneous Lesions


• Injury to skin resulting from activation of photodynamic pigments by UV light (290 – 400 nm) Photosensitization

• Oxidative damage • Hair loss, erythema

and necrosis • Icterus

• Rare disease in dogs

• Crusting, erosions & scaling at mucocutaneous junctions and footpads

Pathologic Basis of Veterinary Disease (2006),4th ed., Mosby-Elsevier, ch 8

Cutaneous Lesions


Hepatocutaneous Syndrome

• Honeycomb pattern (US) • Hyperechoic network (areas of parenchymal collapse)

• Hypoechoic zones (regenerative nodules)

• Nodular liver parenchyma

• Diffuse vacuolar change

• Regenerative nodules

Cutaneous Lesions


Hepatocutaneous Syndrome

Documents

Pathology of the Liver and Biliary Tract 1 Normal Liver ...people.upei.ca/smartinson/LIVER_LECT_1_SAM_2017.pdf · Normal Liver; Hepatic Injury, Response, and Failure Shannon Martinson,