Liver & Biliary Flashcards
A diagnosis of multifocal random hepatocellular necrosis and inflammation should prompt the clinician or diagnostician to search for a potential _____ cause.
Infectious
What compound can lead to the accumulation of glycogen in the liver of dogs?
Glucocorticoids
What portion of the hepatic lobule is most susceptible to hypoxic injury?
Centrilobular
Some cases of canine chronic hepatitis are associated with_____________.
Copper
A young dog with a ravenous appetite, decreased muscle mass and fetid feces should be screened for which condition?
Exocrine Pancreatic Insufficiency
(EPI)
What is the term for end-stage liver disease?
Cirrhosis
Categories of Liver Disease
- Congenital/Inherited
- Traumatic
- Circulatory
- Metabolic/Nutritional
- Inflammatory
- Toxic
- Neoplastic/Hyperplastic
- Gallbladder lesions
True/False
The liver, biliary system, and pancreas all originate from endodermal endothelium of the duodenum.
True
True/False
The hepatic artery provides ~70% of afferent blood flow to the liver.
False
Portal vein supplies most blood flow to the liver
True/False
Blood in the liver flows from portal triads to central veins, while bile flows in the opposite direction.
True
Which species lack a gallbladder?
Horse, rat, elephant
How much does the liver weigh in carnivores?
3-4% bodyweight
How much does the liver weigh in small ruminants and pigs?
1-2% bodyweight
How much does the liver weigh in large herbivores?
1% bodyweight
The hepatic lobule consists of:
- central vein at center
- portal triads at periphery
- canaliculi draining bile
- centrilobar, midzonal, periportal regions
The hepatic acinus contains
- portal triad at the center
- central veins at the periphery
- canaliculi draining bile
- Zone 1 - Periportal region, HIGH oxygen, nutrients, toxins
- Zone 2 - Midzonal region
- Zone 3 - Centrilobular, LOW oxygen & nutrients, site of earliest fat storage & glycogen
- Cells in the liver arranged in plates
- 2 cells thick with canaliculi between and sinusoids at lateral surface
- Cytosolic and membrane bound enzymes are what are measured for signs of liver damage
Hepatocytes
What are the cytosolic leakage enzymes from hepatocytes?
- Alanine Aminotransferase (ALT) - liver specific in dogs/cats
- Aspartate Aminotransferase (AST) - Liver & muscle
- Sorbitol Dehydrogenase (SDH) - Liver specific large animals
What are the membrane-bound induced enzymes from hepatocytes?
- Alkaline Phosphatase (ALP) - dogs/cats
- Gammaglutamyl Transpeptide (GGT) - Liver and biliary
- Fixed macrophages in liver sinusoids
- Phagocytosis
- Innate immune system
- Contain iron and lipofuscin
- Macrophage foci and pigment granulomas common - indicate hepatocellular turnover
Kupffer Cells
- Hepatic lipocytes between sinusoids and hepatocytes in space of Disse
- Vitamin A metabolism
- Important in fibrosis - can develop into myofibroblasts
Stellate Cells
Ito Cells
- Stem cell precursors to biliary and hepatic epithelium
- Located at edge of portal region in the limiting plate
Oval Cells
Dysfunction of protein synthesis in the liver leads to
Edema, ascites, bleeding disorders
Dysfunction of bile metabolism & transport and bilirubin metabolism leads to
Photosensitization, hyperbilirubinemia
Dysfunction of liver drug metabolism leads to
Toxicities
Dysfunction of liver’s ability to convert NHS (ammonia) to NH4 (ammonium) and other toxins into safe metabolites leads to
Hepatoencephalopathy
Dysfunction of the liver’s storage of lipid and carbohydrate leads to
Hepatic Lipidosis
Causes of Hyperbilirubinemia
- Prehepatic - hemolysis, increased unconjugated bilirubin initially
- Hepatic - liver disease, increased both conjugated & unconjugated bilirubin
- Posthepatic - biliary obstruction, increased conjugated bilirubin
Can be primary or secondary cause of lesions on sun-exposed, poorly pigmented skin
Primary (Type 1)
* Liver incapable of excreting photodynamic compound
* Can result from ingestion of St. John’s Wort (Hypericum perforatum)
Congenital (Type 2)
* Hereditary defect in heme metabolism
Secondary (Hepatogenous, Type 3)
* Follows cholestasis in herbivores
* Accumulation of phylloerythrin (chlorophyll catabolite) or other photodynamic compound
Photosensitization
Reactions to Liver Injury
- Hydropic or vacuolar degeneration
- Glycogen accumulation
- Fatty change / lipidosis
- Storage disorders
- Necrosis
- Inflammation
- Bile stasis
- Reversible swelling of hepatocytes
- Excess water enters due to inactivation of membrane sodium pump
- May lead to necrosis
Hepatocellular Swelling / Vacuolar / Hydropic Degeneration
- Reversible hepatocyte swelling with clear cytoplasm
- Usually midzonal but can be diffuse, zonal, or individual cells
- Liver appears swollen, orange-red color
- Physiologic in neonates
- Occurs ONLY in dogs as result of glucocorticoids
- NOT associated with necrosis
Glycogen Accumulation
Steroid Hepatophathy
True/False
Steroid hepatopathy is frequently seen in cats.
False
Occurs ONLY in dogs
- Reversible accumulation of triglycerides / fatty acids in vacuoles in hepatocyte cytoplasm
- Associated with negative energy balance (anorexia, pregnancy, lactation, metabolic disease)
- Can lead to necrosis
Hepatic Lipidosis
Fatty Change / Steatosis
Sources of Fatty Acids
- Excessive dietary intake of FA or increased mobilization of FA (most common)
- Excessive FA synthesis (excessive carbohydrate intake)
- Decreased oxidation of FA (hepatocyte dysfunction)
- Decreased apoprotein synthesis and decreased lipoprotein export
- Decreased lipoprotein secretion (hepatocyte dysfunction)
Canine breeds with copper-associated hepatopathy
- Bedlington Terrier - mutation in copper transport proteins
- West Highland Terrier, Dalmation - familial association
- Doberman Pinscher, Labrador, Cocker Spaniel - breed predisposition
- can occur in any breed though
What is the granular accumulation inside of these hepatocytes that commonly leads to hepattopathy/hepatitis in dogs?
Copper
Patterns of hepatocellular necrosis
- Multifocal random - infectious
- Massive - toxins, nutritional
-
Zonal - toxins, hypoxia
- Centrilobular (Zone 3) - hypoxia, indirect toxins
- Midzonal (Zone 2) - rare, specific toxins
- Periportal (Zone 1) - direct toxins
Inflammation of hepatic parenchyma
Hepatitis
Inflammation of bile ducts / ductules
Cholangitis
Inflammation of hepatic parenchyma & bile ducts
Cholangiohepatitis
True/False
Inflammation of liver can be primary and lead to necrosis, fibrosis, and bile duct hyperplasia.
True
True/False
Inflammation of the liver can be secondary to necrosis and also contribute to ongoing necrosis, fibrosis, and bile duct hyperplasia.
True
Inflammation of gall bladder
Cholecystitis
Inflammation of large / common bile ducts
Choledochitis
True/False
Tyzzer’s Disease is an example of acute hepatitis.
True
- Stasis of bile in canaliculi or bile ducts
- Can be intra- extra/post-hepatic
- Can result from toxins, inflammation, obstruction
- Subsequently develop hyperbilirubinemia (postheapatic)
Bile Stasis / Cholestasis
How much of the liver can be removed before liver dysfunction occurs?
75%
True/False
The liver can regenerate as much as 20% of its mass and will function if the connective tissue framework remains intact.
False
Live can regenerat up to 80% of its mass!
True/False
Most liver regeneration occurs in the centrilobular regions.
False
Regeneration in portal regions - higher nutrients & stem cell capacity
True/False
Most liver regeneration occurs in the centrilobular regions.
False
Regeneration in portal regions - higher nutrients & stem cell capacity
- Post-necrotic & post-inflammatory response with proliferation of fibroblasts and myofibroblasts (from Stellate Cells)
- Production of collagen
- Can result from necrosis, inflammation, hypoxia
- Almost always occurs with regeneration & bile duct hyperplasia
- Can lead to disruption of blood flow, portal hypertension, bile duct obstruction, chronic cholangitis (cats specifically)
Fibrosis
- Proliferation of bile duct epithelium in portal areas
- Can result from necrosis, inflammation, toxins, obsrtuction
- Non-specific reaction to injury
*
Bile Duct Hyperplasia / Biliary Hyperplasia
Describe end stage liver disease / cirrhosis.
Be specific!
Severe diffuse (bridging) hepatic fibrosis w/ nodular regeneration & bile duct hyperplasia
Hepatic Cirrhosis Sequelae
Portal hypertension
-> multiple portosystemic shunts
-> loss of hepatic function
-> insufficiency
-> failure (coagulopathies, hyperbilirubinemia, hepatoencephalopathy, edema, ascites, hypoproteinemia, photosensitization)
Congenital / Inherited Liver Diseases
- Hereditary Hyperbilirubinemia - rare, sheep
- Storage Diseases - rare
- Peritoneal-pericardial Diaphragmatic Hernia - displacement of liver into thorax, cats most often
- Vascular Shunts - common
- Biliary Anomalies - cysts, ductal malformations, multiple GBs
Circulatory Liver Diseases
- Congestion - right-side heart failure, caudal vena cava obstruction, acute (dilation) or chronic passive (atrophy & fibrosis; “nutmeg liver”)
- Porto-Systemic / Porto-Caval Shunt - intrahepatic (large breed dogs), extrahepatic (small breed dogs/other species), congenital or acquired, leads to hepatoencephalopathy, microhepatica in congenital shunts
- Portal Vein Hypoplasia - microvascular dysplasia, non-cirrhotic portal hypertension, telangiectasia (peliosis hepatitis)
- Portal Vein Thrombi - uncommon
- Infarcts - rare due to collateral blood supply
- Telangiectasia (Pelios Hepatis) - dilation of small sinusoids (incidental in cats, cattle, ferrets)
- Anomalous arteriovenous malformations - rare
What is the cause of “nutmeg liver”?
Chronic Passive Congestion
What liver pathology can lead to hepatoencephalopathy (e.g. hyperammonemia) & elevations in bile acids?
Porto-Systemic or Porto-Caval Shunts
True/False
Ascites does not develop with congenital shunts without another cause for portal hypertension or hypoalbuminemia. Ascites can be seen with acquired shunts.
True
Signs of congenital shunts
- small stature
- anesthetic intolerance
- behavior abnormalities
- head pressing
- seizures
- GI signs
- PU/PD
- ammonium biurate urolithiasis
- dysuria
Traumatic Liver Diseases
- Displacement
- Hematoma (blunt force)
- Lobar tosrion - often left lateral lobe, may not be traumatic
- Rupture (blunt or sharp trauma) - firm friable liver predisposed
- Atrophy of adjacent hepatocytes and dilation of sinusoids due to accumulation of eosinophilic material in space of Disse
- Material is usually SAA
- Associated with inflammatory conditions
- Predisposed breeds - Chinese Shar-Pei, Abyssinian, Siamese, Oriental breed cats)
- Spontaneous or biopsy-induced liver rupture can occur
Amyloidosis
Inflammatory / Infectious Liver Diseases
- Viral
- Bacterial
- Fungal
- Parasitic
Viral Liver Diseases
- Infectious Canine Hepatitis (adenovirus) - blue eyes from corneal edema
- Rift Valley Fever (phlebovirus) - ruminants
- Herpesviruses - equine, bovine, canine, psittacine
- Coronaviruses - FIP, mouse hepatitis virus
- Woodchuck Hepatitis Virus (hepadnovirus) - oncogenic potential
- Theiler’s Disease (equine parvovirus)
Bacterial Liver Diseases
- Clostridial Organisms - Tyzzer’s Disease (C. piliforme), Red Water/Bacillary Hemoglobinuria (C. hemolyticum), Black Disease/Infectious Necrotic Hepatitis (C. novyi)
- Bacterial Liver Abscesses - common in cattle (Salmonella, Fusobacterium necrophorum, Leptospirosis, Mycobacterium)
True/False
In fungal liver diseases, the entire animal is usually infected, not just the liver.
True
Parasitic Liver Diseases
- Toxoplasma gondii
- Neospora caninum
- Eimeria stiedae - proliferative cholangitis in rabbits
- Ascaris suum - milk-spotted liver in pigs
- Cestodes - cysticerci & hydatid cysts in liver
- Fasciola - common in sheep and cattle, leave migration tunnels
Idiopathic Inflammatory Liver Diseases
- Theiler’s Disease / Serum Hepatitis - horses, likely equine parvovirus, “dish rag” liver
- Canine Chronic Hepatitis - often idiopathic, 1/3 copper associated
- Feline Chronic Cholangitis - cholangitis»hepatitis in cats, can be suppurative or lymphocytic, can be part of triaditis
- Acute Neutrophilic (Suppurative) Cholangitis - older cats, less common in dogs
True/False
The liver is not a common site for toxic injury.
False
VERY COMMON - ingested toxins reach the liver first!
True/False
Predictable toxins are dose-dependent, meaning there is a known threshold that will cause toxic effects.
True
e.g. CCl4
True/False
Idiosyncratic toxins are non-dose dependent, meaning a random animal in a population can be affected regardless of dose.
True
e.g. Phenobarbital
What is a direct toxin?
Substance that is directly toxic as ingested. Predominantly affects periportal region.
What is an indirect toxin?
Substance that has toxic metabolites. Affects region where metabolization occurs.
True/False
Toxin testing is relatively easy as you can simply order a broad-spectrum tox panel to determine the cause of liver injury.
False
-NO broad tox panel (hundreds of toxins)
-Requires THOROUGH history
Mechanisms of Hepatotoxicity
- DNA - alkylation (pyrrolizidine alkaloids), intercalation (cyclophosphamide)
- RNA - binding RNA polymerase (amonita mushroom), impaired transcription (aflatoxin)
- Lysosomes - inhibition of enzymes (locoweed)
- Cell Membrane Damage - free radicals (Vit E/Se:FA imbalance, CCl4)
- Canaliculi Damage
- Apoptosis Stimulation - mitochondrial damage
- Idiopathic - alcohol unknown
What is the necrosis pattern of CCL4?
Centrilobular Area
* metabolized to free radical by MFOs in SER
* highest concentration of MFOs in centrilobular area
What is the necrosis pattern of Allyl Alcohol?
Periportal Area
* metabolized by alcohol dehydrogenase on cytosol
* highest concentration of dehydrogensases in periportal area
What is the necrosis pattern of Ngaione?
Midzonal Area
* toxic intermediates metabolized by MFOs
* intermediates accumulate in midzonal area where there is an intermediate amount of MFOs
Nutritional/Metabolic Liver Diseases
- Hepatic Lipidosis
- Hepatosis Dietetica - acute necrosis in young rapidly growing pigs, Vit E/Se deficiency
- Copper Toxicity
Gallbladder Lesions
- Mucocele - idiopathic, may lead to obstruction, potential for rupture
- Cholelithiasis - inrequent in animals, may lead to obstruction
-
Cholecystitis - secondary to pressure necrosis/inflammation w/ obstruction or ascending bacterial infection
- Salmonella w/ fibrinous cholecystitis
- Clostridia w/ necrosis
Neoplastic Liver Diseases
- Adenoma - hepatocellular (uncommon in dogs), cholangiocellular (uncommon in cats)
- Carcinoma - hepatocellular (uncommon in dogs; infrequently metastatic), cholagiocellular (uncommon in dogs & cats; highly metastatic)
-
Metastatic or Multicentric tumors - more common than primary neoplasm
- hemangiosarcoma
- pancreatic ademocarcinoma
- pancreatic islet cell tumor
- histiocytic sarcoma
- mast cell tumor
- gastrointestinal adenocarcinoma
- splennic sarcoma
- adrenal carcinoma
- neuroendocrine tumors
