Liver Pathology Flashcards
1
Q
What does a Normal liver look like?
A
2
Q
What are the major structural components of the liver?
A
- Connective tissue capsule, trabeculae and reticular network forms the framework for hepatic architecture
- Sinusoids and hepatic cords
- Biliary tree
3
Q
What are major cells of the liver?
A
- Hepatocytes
- Kupffer cells
- Stellate cells
- Endothelial cells
- Biliary epithelium
4
Q
What is a hepatic lobule?
A
- An anatomic unit with the central vein at the center of the lobule and portal triads at the periphery
5
Q
What is a hepatic acinus?
A
- A functional unit with the central axis bridging between portal areas (1) with the outer part of the acinus around the central vein (3)
6
Q
Describe hepatocytes
A
- Account for approximately 80% of total liver mass
- Arranged in branching, single-cell plates between sinusoids
- Numerous microvilli on the surface facing the sinusoid
- Contain numerous intracellular organelles
7
Q
What are the functions of hepatocytes?
A
- Responsible for most of the synthetic secretory, storage, detoxification, and metabolic functions of the liver
- Produce and secrete bile into the bile canaliculi
8
Q
Describe Kupffer cells and their functions
A
- Member of the mononuclear phagocyte system
- Mobile macrophages located within the sinusoids
- Phagocytose immune complexes and particulate matter (senescent RBC, bacteria, etc) in the sinusoids
- Produce pro-inflammatory and anti-inflammatory cytokines to contribute to innate immunity
- Pro-inflammatory products (TNF-alpha) can activate hepatic stellate cells to create collagen
9
Q
What are the hepatic stellate (Ito) cells
A
- Located in the Space of Disse
- Store Vit A
- During hepatic injury:
- convert to a myofibroblast phenotype and produce collagen and other ECM components to promote hepatic fibrosis
10
Q
What is Sinusoidal Endothelium?
A
- Second most common cell in the liver
- 15-20% of all cells, only 3% of liver mass
- Contain numerous fenestrae
- They lack a well organized basement membrane
- Discontinuous capillary allows intimate contact with blood components and hepatocytes
- Facilitate exchanges between plasma and hepatocytes
11
Q
How is blood supplied to the liver?
A
- Liver has a dual blood supply
- Hepatic artery (O2)
- Portal vein (high nutrient blood)
- Blood flow is from the portal triad to the central vein
- Discontinuous capillary with fenestrated endothelium allows intimate contact with blood components and hepatocytes
12
Q
How does the liver produce lymph?
A
- Fluid from the hepatic interstitium flows into the space of Disse then to the portal interstitium to the portal lymphatics
- The fluid is derived from the blood as well as products of hepatocytes, hepatic stellate cells and Kupffer cells
- The liver accounts for 50% of lymph that enters the thoracic duct
- The role of lymphatics in disease is poorly understood
- obesity, lipidosis, hypercholesterolemia, lipoprotein-associated diseases
13
Q
What is the pathway of bile from the hepatocytes?
A
- Bile is transported from the hepatocyte through a progressively enlarging duct system for secretion into the small intestine
- Bile canaliculi
- Intrahepatic bile ductules (Canals of Hering)
- Intralobular bile ducts (portal triads)
- Intralobular ducts (joint into intralobar ducts then lobar)
- Lobar ducts
- Extrahepatic (common) bile duct
14
Q
What is Bile made up of?
A
- Water
- Bile salts
- Bilirubin
- Cholesterol
- Fatty acids
- Lecithin
15
Q
How many liver lobes do the different species have?
A
- Dogs/Cats 6
- Left lateral, left medial, quadrate, right medial, right lateral, caudate
- Mice/Rats 4
- Left, middle, right, caudate
- Horse 5
- right, quadrate, left medial, left lateral, caudate
- Bovine and humans 4
- right, caudate, left, quadrate
- Elephant and avian 2
- left, right
- Pigs 5
- left medial, left lateral, right medial, right lateral, caudate
16
Q
What species do NOT have a gallbladder?
A
- Equines - horses, mules, etc
- Cervids - white-tailed deer….
- exception is musk deer
- Camels
- Rats
- Elephants
- Giraffes
- often present in neonates
- Rhinoceroses
- Doves, pigeons, ostriches, and some psittacines
- most avian species have gall bladders
- others
17
Q
What is the function of the Liver?
A
- Plays a central role in metabolism
- Synthesis and metabolism of proteins, lipids, and carbohydrates
- Storage of nutrients
- Conjugation and detoxification reactions
- Immune functions
- Waste product excretion
- Bile synthesis of secretion
18
Q
What nutrient synthesis, storage, and metabolism functions does the liver have?
A
- Glucose metabolism
- Degradation of plasma lipids and synthesis/storage/oxidation of fatty acids
- Production of most plasma proteins
- Production of cholesterol and lipoproteins
- Nutrient storage
- Glycogen and lipids
19
Q
What are the conjugation and detoxification functions of the Liver?
A
- Xenobiotic biotransformation and excretion
- Phase I reactions
- Convert toxins into less (sometimes more) harmful intermediate compounds
- Cytochrome P-450 enzymes
- Convert toxins into less (sometimes more) harmful intermediate compounds
- Phase II reactions
- Convert Phase I products into water soluble products for excretion
- Conjugation reactions (glucuronidation, sulfation, gluthathione, and AA conjugations)
- Convert Phase I products into water soluble products for excretion
20
Q
What are the immune functions of the liver?
A
- Remove foreign material from blood
- Kupffer cells
- Hepatocyte protein synthesis
- Inflammation (acute phase proteins) and innate immunity and signaling pathways
21
Q
How is Bile synthesized in the liver?
A
- Bilirubin is derived from hemoglobin and other heme proteins
- Bilirubin is taken up by hepatocytes, conjugated to glucuronic acid to become water soluble and less toxic and excreted through the biliary system
- Bile acids are produced by hepatocytes and efficiently recycled by the enterohepatic circulation
- Bile acids are essential for digestion and absorption of lipids and fat-soluble vitamins
- Excretion of waste products and metabolites
22
Q
How is liver dysfunction determined?
A
- The liver has alarge functional reserve capacity
- Clinical evidence of disease may initially be absent
- There are a wide variety of clinical assays to use to evaluate liver function
- Liver enzymes:
- Gamma-glutamyl transpeptidase (GGT)
- Alkaline phosphatase (ALP)
- Alanine transminase (ALT)
- Aspartate transaminase (AST)
- Bilirubin, bile products, albumin, total protein
- Prothrombin time
- Liver enzymes:
23
Q
What are the clinical signs of hepatic disease?
A
- Icterus
- Photosensitization
- Encephalopathy
- Hemorrhage
- Edema
- GI distrubances
- Untrhiftiness
24
Q
What is Icterus?
A
- Excess bilirubin (hyperbilirubinemia) results in yellow discoloration of tissue
- Causes:
- Overproduction
- hemolysis or excessive RBC degradation
- Hepatocyte injury
- decreased uptake, conjugation, or secretion of bilirubin
- Decreased bile flow (cholestais)
- Intrahepatic (bile canaliculi)
- Extrahepatic (bile ducts/gall bladder
- Overproduction
25
Q
What is photosensitization?
A
- Activation of pigments by UV light causes erythema, hair loss, and dermal necrosis
- Type 1 - increased ingestion of photodynamic pigments
- Type 2 - abnormal metabolism of photodynamic pigments
- Type 3 - decreased secretion of photodynamic pigments
26
Q
How does liver disease lead to encephalopathy?
A
- Accumulation of ammonia, toxic products and neurotransmitter-like substances cause neurologic dysfunction
- These substances are normally excreted by the liver
- Accumulation can be due to decreased metabolism by the liver or vascular shunting past the liver
- Signs ranged from depression to convulsions
27
Q
How does liver disease lead to hemorrhage?
A
- All clotting factors are produced by the liver
- Factor VIII is on e possible exception
- With severe hepatic injury, decreased production can result in defective secondary hemostasis
28
Q
How does liver disease lead to edema?
A
- Albumin, produced mainly by the liver, regulates plasma osmotic pressure
- Hypoalbuminemia results in fluid imbalance and edema
29
Q
How does liver disease cause GI distrubances?
A
- Decreased bile secretion will disrupt digestion
- Decreased bile acids decrease fat and fat-soluble vitamin absorption
30
Q
How does liver disease result in unthriftiness?
A
- Chronic liver dysfunction results in weight loss and poor conditions
- Hypoalbuminemia
- Altered fat and protein metabolism
- Altered digestion
31
Q
What are examples of acute hepatic disease?
A
- Icterus
- GI abnormalities
32
Q
What are examples of chronic hepatic disease?
A
- Weight loss
- Unthriftines
33
Q
What are the Pathological Processes that affect the liver?
A
- Cell adaptation and injury
- Tissue injury
- Vascular disturbances
- Inflammation
- Immunopathology
- Developmental
- Metabolic
- Neoplasia
34
Q
What is Regenerative hyperplasia?
A
- Hepatocytes can rapidly transition for G0 to G1
- Localized or a single episode of extensive damage can return to normal morphology by compensatory hyperplasia if the structural framework is intact
- If the structural framework is damaged: hyperplasia occurs in a nodular morphology (regenerative nodules)
- usually in combination with hepatic fibrosis
35
Q
What is hepatocyte Nodular hyperplasia?
A
- Most common in older dogs
- Rarely associated with hepatic dysfunction
- Normal hepatic framework is infringed upon by hyperplastic hepatocytes
- There is no fibrosis associated with the nodules
- Hyperplastic nodules have reduced function
- Blood and bile flow within nodules is abnormal
36
Q
What is hepatocyte cirrhosis?
A
- Regenerative hyperplasia + fibrosis
- “End-stage liver”
- An irreversible, final outcome of a variety of progressive hepatic diseases (toxicity, chronic inflammation, biliary disease)
- Morphology is severely distorted
- Associated with signs of hepatic failure
37
Q
What is cholangiolar hyperplasia (“ductular reaction”)
A
- Hyperplasia of progenitor cell around the portal triads than can differentiate into either hepatocytes of bile duct epithelium
- A non-specific response to various diseases, including toxicity, cholestasis, and hypoxia
- Morphologically these form multiple duct-like structures in the portal area
38
Q
What is hepatocyte atrophy?
A
- Most common in hepatocytes that have lost normal vascular and nutrient supply
- Acquired portosystemic shunts due to hepatic fibrosis
- Starvation after all body nutrient stores are depleted
- Hepatocytes are smaller and may be reduced in number
- The liver is smaller than normal
- Remember that a small liver in a neonatal animal is most likely a developmental problem7
- Hypoplasia
- Remember that a small liver in a neonatal animal is most likely a developmental problem7
39
Q
What are the common causes of hepatocyte injury?
A
-
Chemicals
- Xenobiotics (toxins), endogenous and exogenous substances
-
Nutrients
- Too few (hypoxia)
- Too many (lipidosis)
-
Infectious agents
- Bacterial
- Viral
- Fungal
40
Q
What are the Mechanisms for Hepatocyte injury?
A
-
Loss of membrane integrity
- Cell membranes breakdown and loose the ability to segregate reactions within the cell
- Free radicals
- Phospholipases
- Direct membrane injury
- Cell membranes breakdown and loose the ability to segregate reactions within the cell
-
Loss of ability to produce energy
- ATP is insufficient to support cell functions
- Oxidative phosphorylation and glycolysis
- ATP is insufficient to support cell functions
-
Genetic damage
- functional changes induced by a mutation
41
Q
What are the morphologic features of injured hepatocytes?
A
- Sublethal Injury: (potentially reversible)
- Cell swelling
- Intracellular accumulations
- Neoplastic transformation
- Lethal injury:
- Apoptosis
- Necrosis (oncotic death)
42
Q
What is happening in the image?
A
cell swelling
43
Q
What is happening in the image?
A
lipidosis
44
Q
What is happening in the image?
A
- Cell swelling and lipidosis
- Often concurrent - reflecting a gradient of injury
48
Q
What are the causes of hepatocyte Apoptosis?
A
- Physiologic:
- maintenance of homeostasis
- Pathologic:
-
Unrepaired DNA damage
- damaged or transformed cells
- Heat
-
Hypoxia
- Mitochondrial injury
- Viral infection
- Physical pressure
-
Unrepaired DNA damage
49
Q
What are the causes of hepatocyte necrosis?
A
- Unintentional and passive
- Caused by pathologic injury to the hepatocyte
- Hypoxia
- Toxins
- Infectious agents
- Many of the same factors that initiate apoptosis when the stimulus is mild, initiate necrosis when more severe
- Hepatocyte undergoes passive self-lysis
50
Q
What are the morphologic patterns of necrosis of injury?
A
-
Zonal (lobular)
- There is a repeating pattern of necrosis within the hepatic lobule - commonly due to toxins or hypoxia
- Common:
- Centrilobular
- Periportal
- Less Common:
- Paracentral- wedge-shaped area radiating out from the center
- Midzonal - Midway between portal and central
- Massive - An entire lobule is affected
-
Multifocal:
- Hepatocytes are affected randomly
- Commonly due to blood-borne infectious agents
51
Q
What is the centrilobular (periacinar) pattern of hepatic necrosis?
A
- Centrilobular hepatocytes are mainly affected
- Causes:
- Hypoxia
- Nutrient deficiency
- Toxins that are biotransformed into toxic intermediate compounds
52
Q
What is the periportal (Centriacinar) pattern of hepatic necrosis?
A
- Periportal hepatocytes are mainly affected
- Causes:
- Ascending biliary infections
- Toxins (direct-acting)
53
Q
What is the multifocal pattern of hepatic necrosis?
A
- Hepatocytes are affected randomly
- Causes:
- Blood-borne infectious agents
- Viruses often causes hepatic necrosis with variable amounts of inflammation
- Certain bacteria produce toxic substances or invade hepatocytes and can result in extensive necrosis
- Blood-borne infectious agents
56
Q
What causes Extracellular matrix injury?
A
- A reflection of damage to both cells and extracellular matrix
- Causes:
- Fibrosis
- Amyloidosis
- Calcification
57
Q
What is hepatic fibrosis?
A
- Fibrosis is a common manifestation of hepatic injury
- Causes of fibrosis include almost any (mainly recurring) insult:
- Cell injury
- Vascular disturbances
- Inflammation
- Mediation of fibrosis
- Hepatic stellate cells
- Located in the Space of Disse
- Myofibroblasts
- Located in connective tissue of portal areas and central veins
- Hepatic stellate cells
58
Q
What are the possible morphologies of hepatic fibrosis?
A
- Periportal - direct-acting toxins or biliary inflammation
- Centrilobular - Indirect-acting (biotransformed) toxins or hypoxia
- Bridging (Diffuse) - Progressive, ongoing fibrosis
- Fibrosis can significantly alter the ECM and hepatic architecture
59
Q
What is hepatic cirrhosis?
A
- Sometimes referred to as “end-stage liver”
- Morphologically these are characterized by fibrosis and regenerative hyperplastic nodules
- This is characteristic of severe chronic and progressive hepatic injury
61
Q
How does chronic passive congestion affect the heart?
A
- Right heart failure
- Initially there is centrilobular congestion
- Progressive hypoxia leads to centrilobular hepatocyte necrosis
- Chronically, there is centrilobular fibrosis and periportal pooling of blood
- Ascites can occur due to portal hypertension
- “nutmeg liver”
63
Q
What is liver inflammation?
A
- A wide variety of infectious agents and non-infectious reactions can induce inflammation
- Viruses, bacteria, fungi, parasites, immunologic responses
- The morphology of the inflammation often suggests cause
- Suppurative = bacterial
- Lymphocytic = viral
- Granulomatous = fungal or higher bacteria
71
Q
What are hepatic cysts?
A
- Often biliary origin
- In cats these often occur as part of polycycstic kidney disease
- Defective polycystin due to PKD-1 or PKD-2 gene mutations
- Most common in Persian cats
- Progressive renal disease
72
Q
What is hepatic hypoplasia?
A
- Most commonly due to vascular maldevelopment in the liver
- Microvascular dysplasia
- Congenital portosystemic shunts
73
Q
What is Microvascular dysplasia?
A
- Most prevalent in small breed dogs (Yorkshire and Cairn Terriers among others)
- Abnormal development of branches of the portal vein, with compensatory increase in hepatic arteries that take on a coiled appearance
- Clinical features/lesion are similar lesions to congenital portosystemic shunts
74
Q
What are congenital Portosystemic shunts?
A
- Congenital shunts are due to vascular abnormalities that shunt blood past the liver
- Microvascular dysplasia is one component of portosystemic shunts
- Intra- or extra-hepatic vascular abnormalities are present
- Affects livers lack adequate nutrients and are hypoplastic and have inadequate functions
75
Q
What metabolic disturbances can occur with hepatic diseases?
A
- Alteration in hepatic metabolic function accompany most primary hepatic diseases and many secondary non-hepatic disease
-
Altered plasma protein production can influence various homeostatic processes
- Albumin - fluid balance and edema
- Coagulation factors - hemorrhage and hemostasis
- Acute phase proteins - inflammation
-
Bilirubin metabolism and bile flow influence digestion
- Bilirubin accumulates when there is excessive production (eg hemolysis) decreased hepatocyte function, or decreased biliary flow (cholestasis)
- Cholestasis can be intrahepatic (ex: hepatocyte injury or hemolysis) or extrahepatic (extrahepatic bile duct obstruction)
- Decreased bile acids results in lipid malabsorption/steatorrhea and deficiency of fat-soluble vitamins
-
Altered plasma protein production can influence various homeostatic processes
76
Q
What is hepatic lipidosis?
A
- Liver is central to fat metabolism and involves proteins, fats, carbohydrates, and energy
-
Metabolic imbalance can result in lipidosis
- Increased rate of fat entry to hepatocytes
- Decreased rate of lipoprotein formation within hepatocytes
- Decreased protein or energy (ATP)
- Increased carbohydrates
- Some degree of lipidosis accompanies many metabolic alterations
78
Q
What are some specific lipidosis syndromes?
A
- Feline fatty liver syndrome
- Bovine fatty liver syndrome/ketosis
- Hyperlipidemia of ponies
79
Q
What is going on with this cat?
A
feline fatty liver syndrome
82
Q
What is the morphology of glycogenosis?
A
- Morphologically, hepatocytes have a swollen, foamy appearance
- Due to excessive glycogen in the cytoplasm
- Distribution tends to be diffuse
- Cell swelling is a differential
- This is usually more localized or zonal
83
Q
What are the Mechanisms of Action of Hepatotoxicity?
A
- Direct injury to hepatocytes
- Membrane damage, or damage to membrane pumps
- Formation of toxic intermediate products
- The most common mechanism of injury
- Chemical agent is not toxic until biotransformed
- Lipid peroxidation
- Mitochondrial or plasma membranes
- Interference with metabolism
84
Q
What are the functional effects of Hepatotoxicity?
A
- Decreased protein and nucleic acid synthesis
- Enzyme inhibition
- Inhibition of mitosis
- Cell membrane dysfunction
- Carcinogenesis
- Idiosyncratic reactions
86
Q
What is the Morphology of hepatocyte injury due to Hepatotoxicity?
A
- Degeneration
- Hydropic change
- Lipidosis
- Necrosis or apoptosis
- Centrilobular necrosis is most common due to indirect acting toxins
- Periportal necrosis occurs with direct acting toxins
87
Q
What is the morphology of fibrosis caused by hepatotoxicity?
A
- Most common with recurrent injury
- Results in irreversible stromal damage
- It is a common feature of most hepatotoxins over time
98
Q
What is Hepatic adenoma?
A
- Benign neoplasm of hepatocytes
- Most common in young ruminants and old dogs
- Must be differentiated from nodular hyperplasia
99
Q
What is hepatocellular carcinoma?
A
- Most common primary hepatic neoplasm in dogs
- Locally invasive within the liver
- Some will metastasize to regional lymph nodes
100
Q
What is a Bile duct adenoma?
A
- Biliary cystadenomas
- Benign and cystic
- Most common primary hepatic neoplasm of cats
- Account for about half of primary tumors in cat livers
101
Q
What is a bile duct carcinoma?
A
- Cholangiocellular carcinoma
- Most common primary malignant liver neoplasm of cats
- Less common than hepatocellular carcinoma in dogs
- Metastasis is common to regional lymph nodes and by seeding of the peritoneal cavity
102
Q
What is going on in the picture?
A
Intestinal adenocarcinoma
103
Q
What is going on in this picture?
A
Hemangiosarcoma
