Patterns of fibrosis Postnecrotic scarring “Milk spotted liver”, pig (multifocal fibrosis) “Milk spotted liver”, pig (multifocal fibrosis) • Single event of widespread hepatocellular necrosis hepatocellular necrosis followed by fibrosis Biliary fibrosis Focal/multifocal fibrosis Diffuse hepatic fibrosis (End-stage liver) Biliary fibrosis in chronic cholangitis due to Biliary fibrosis in chronic cholangitis due to Fasciola hepatica Fasciola hepatica, cow , cow
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Can occur quickly in young animalsSecondary to liver fibrosis An attempt to regenerate hepatocytes?hepatocytes?
Biliary duct hyperplasia (arrows) and fibrosis (F)Biliary duct hyperplasia (arrows) and fibrosis (F)
End-stage liver (Cirrhosis)Final irreversible result of different hepatic diseases characterized by• Nodular regeneration• Fibrosis• Bile duct hyperplasia
Liver architecture is veryLiver architecture is verydistorted so the initialpattern or cause can nolonger be determined
End stage liver IICirrhotic liver, dogCirrhotic liver, dog
Clinical syndrome that results from inadequate liver function
• It indicates massive reduction of the amount of liver
Clinical syndrome that results from inadequate liver function
cells or decrease in their functionality (when liver’s considerable reserve and regenerative capacity is overwhelmed or when biliary outflow is obstructed)overwhelmed or when biliary outflow is obstructed).
• Result of either acute or chronic liver damage• Not all functions lost at the same time
Manifestations of liver dysfunction and failure
Potential consequences of hepatic dysfunction and failure differ somewhat among domestic species. They include:1. Hepatic encephalopathy2. Disturbances of bile flow & icterus3 Metabolic disturbances3. Metabolic disturbances4. Vascular and hemodynamic alterations5. Cutaneous lesions6 I i d i f ti6. Impaired immune functions –detoxification & phagocytosis
Hepatic encephalopathyHepatic encephalopathyHepatic Coma
Signs varyDepression, behavioral
p
p ,changesMania, convulsions
Acute liver disease (HAcute liver disease (Horses and ruminants)Portosystemic shunts y
(Dogs and cats)Chronic liver disease (Any
animal)animal)
Pathogenesis of hepatic encephalopathy
Blood accumulation of neurotoxic substancesBlood accumulation of neurotoxic substances bypassing the liver and reaching the brain Requires shunting of >10-15% of portal bloodq g pMain substance is ammonia Clinical signs are more severe after feedingOther factors implicated are• Imbalance of inhibitory & excitatory amino acid
neurotransmittersneurotransmitters• Increased brain concentration of benzodiazepines
Disturbances of bile flowCholestasis and Icterus (Jaundice)
Cholestasis - Abnormal accumulation of bile within the liver (intrahepatic), extrahepatic bile ducts or the gallbladder.Icterus Yellow discoloration of tissues andIcterus – Yellow discoloration of tissues and body fluids due to hyperbilirubinemia
Yellow discoloration of the oral mucosa (Icterus)
Elevations in bilirubinHyperbilirubinemia (> 2 mg/dl) leads to icterus best yp ( g )
seen in tissues rich in elastin (sclera, aorta, etc)
CausesOverproduction of bilirubin (prehepatic jaundice)
H l i i t t l• Hemolysis - intra- or extra-vascularDecreased uptake, conjugation or secretion of bilirubin (hepatic jaundice)
• Severe hepatocellular injurySevere hepatocellular injury• Impairment of flow within canaliculi
(intrahepatic cholestasis)Reduced outflow of bile in extrahepatic bile d t d llbl dd ( t h ti j di )ducts and gallbladder (post hepatic jaundice)
• Mechanical obstruction of bile ducts (extrahepatic cholestasis) or gallbladder (cholelithiasis)( )
Conjugated vs unconjugated bilirubinbilirubin
U j t d bili bi
Why is this important?
Unconjugated bilirubin• Toxic to tissues• Not soluble in aqueous solutions• Not soluble in aqueous solutions• Tightly complexed to albumin• Cannot be excreted in the urine even when blood
levels are highConjugated bilirubin• Water soluble• Water-soluble• Non-toxic• Loosely bound to albuminy• Excreted in urine (bilirubinuria)
Diagnosis of icterus and cholestasischolestasis
Gross• Generalized yellowish
discoloration• Yellowish/greenish brown
liverHisto• Bile pigment in canaliculi & p g
hepatocytesClinical chemistryElevated blood levels of
Abundant pigment inclusions in hepatocytes. Human with Dubin-
Johnson syndromeCanalicular (intrahepatic) cholestasis
Illustration of the morphologic features of cholestasis and comparison with normal liver.
Metabolic Disturbances of H ti F ilHepatic Failure
Hemorrhagic diathesis or bleeding tendenciesg g• Impaired synthesis of clotting factors• Reduced clearance of products of clotting and FDPs• Impaired platelet functionImpaired platelet function• Impaired absorption of vitamin K • Disseminated intravascular coagulation (DIC)Intravascular hemolysisIntravascular hemolysis • Mainly in horsesHypoalbuminemia• Decreased production• Loss in ascites or GIT
Vascular and hemodynamic lt tialterations
Portal hypertensionAcquired portosystemic shuntsAscites (Most common
PhotosensitizationActivation of photodynamic pigments by UV light of 290 to 400 nm
Primar
Activation of photodynamic pigments by UV light of 290 to 400 nm
Primary• St John’s wort (Hypericum
perforatum)• Chlorpromazinep• Phenothiazine
Secondary (hepatogenous)• Herbivores with impaired
excretion of phylloerythrin• Most common formCongenitalCongenital• Abnormal metabolism of
heme Retention of porphyrins p p y
Hepatocutaneous syndrome
• Rare disease in dogs• Crusting erosions & scaling C ust g e os o s & sca g
especially at mucocutaneous junctions and footpads
Footpad. Note the fissure (arrow) and crusts The crusting is due largely to the
Superficial necrolytic dermatitis, skin, dog. The epidermis has a trilaminar pattern: (1) parakeratotic layer (P), (2) edema/necrolytic layer (N), and (3) deep
epidermal hyperplasia layer (H).
crusts. The crusting is due largely to the parakeratosis
• Occlusion of central vein due to fibrosis• Pyrrolizidine alkaloidsy• Vitamin A toxicity in captive cats
Veno-occlusive disease. A reticulin stain reveals the parenchyma framework of the lobule and the
marked deposition of collagen within the lumen of the central vein.
Passive congestionPassive congestion
Acute congestiong• Slight enlargement of liver• Prominent reticular pattern
Ch i tiChronic congestionNutmeg appearance
• Centrilobular congestion• Midzonal fatty change• Periportal areas almost
spared• Later, centrilobular fibrosis
& hemosiderosis
Examples of Examples of chronic passive congestionchronic passive congestionIn dogs (top and bottom left) and a cat In dogs (top and bottom left) and a cat (bottom). Note the rounded edges (liver (bottom). Note the rounded edges (liver
expansion) and extensive areas of expansion) and extensive areas of subcapsularsubcapsular fibrosis due to chronic exudation fibrosis due to chronic exudation
of lymph.of lymph.
Microscopic lesions in chronic passive congestion, liver