Flashcards in Patterns of Disease: Liver Deck (45):
Made up of hepatocytes, which are arranged in lobules- hexagonal units of hepatocyte cords arranged around a central vein, with sinusoids between the cords.
A portal triad is present at each corner of the hexagon, comprised of a bile duct, hepatic venule and hepatic artery.
BLOOD flows from PERIPHERAL to CENTRAL
BILE flows from CENTRAL to PERIPHERAL.
Blood supplies mix in the sinusoids.
The portal venule provides 60-70% of blood supply, and the hepatic artery provides 30-40%.
The liver is the largest internal organ, making up a significant proportion of the whole bodyweight.
Hepatic lobules can be split in to three zones:
Zone 1- Periportal- most peripheral, nearest to the portal triads. This zone is the most oxygenated.
Zone 2- Midzonal- in the middle.
Zone 3- Centrilobular- closest to the central vein. This zone is the most prone to ischaemic damage, as it is the least oxygenated.
FUNCTIONS OF THE LIVER
1. Carbohydrate metabolism- the liver is a storage site for glycogen.
2. Fat metabolism- processing of dietary fats to lipoproteins (VLDL- simple/fast energy source)
3. Protein metabolism- liver is a major site of protein synthesis (albumin)
4. Bile synthesis, excretion and recirculation- abnormal bile metabolism can lead to jaundice.
5. Storage- glycogen, iron, copper, fat soluble vitamins.
6. Detoxification- particularly nitrogenous compounds, hormones and drugs.
Physical- skin, ribs, omentum.
Cellular- Kupffer cells- fixed macrophages in sinusoid lumen on endothelial cell surface.
Particularly important in endotoxin removal from portal blood.
Some infections may preferentially infect Kupffer cells eg. Canine Adenovirus 1.
PORTALS OF ENTRY TO THE LIVER
1. Direct extension
3. Retrograde biliary transport.
ENTRY- DIRECT EXTENSION
Penetrating trauma, infectious agents- can be external or from the GI tract.
eg. fissured/torn/haemorrhagic liver as a result of RTA and subsequent broken ribs.
eg. Hardware disease- bovine traumatic reticuloperitonitis with abscessation. Direct extension from GI tract.
eg. LIVER ABSCESSES IN CATTLE- seen in young, fast growing, grain fed animals.
Grain overload causes rumenal overload -> carbohydrate engorgement -> lactic acidosis -> rumenitis -> overgrowth of A. pyogenes, F. necrophorum -> haematogenous spread to portal vein ->
eg. Ascaris suum infection in pigs- migration to liver in the portal vein causes tracts of hepatocellular necrosis, inflammation, then fibrous tissue scarring- milk spot liver.
ENTRY- RETROGRADE BILIARY TRANSPORT
Ascending parasitic/bacterial infections can gain entry this way.
TOXIC LIVER DISEASE
The liver is a common site of toxic injury.
This is due to 2 main factors:
-THE PORTAL VEIN DRAINS TOXINS FROM THE INTESTINE
-HEPATOCYTES REMOVE TOXINS.
Hepatic enzymes make endogenous and exogenous substrates suitable for elimination:
Lipid soluble compounds are made water soluble, allowing renal excretion.
BIOTRANSFORMATION CAN CREATE TOXIC METABOLITES.
Hepatocytes vary in their enzyme components- centrilobular hepatocytes contain the cytochrome p450 pathway- mixed function oxidases- consider toxic metabolites, as these hepatocytes has the poorest blood supply, so are most prone to damage.
COMMON HEPATIC POISONS
-Ragwort- pyrrolizidine alkaloid, affects cows and horses.
-Blue-green algae- toxic polypeptides, affects dogs, cattle and sheep.
-Mycotoxins- fungal metabolites, affects all species.
-Copper- affects sheep
Often a management issue- don't use pig slurry on sheep pasture.
Copper is sequestered in the liver.
Delayed biliary excretion leads to SUDDEN release, causing HAEMOLYSIS, SEVERE ANAEMIA, CENTRILOBULAR NECROSIS.
The internal organs appear golden-yellow on post mortem.
Ingested alkaloids are converted to pyrrolic esters (TOXIC) by cytochrome p450 enzymes.
Pigs most susceptible > cattle/horses > sheep.
Chronic ingestion leads to hepatic fibrosis.
Characteristic histology- MEGALOCYTES (often massive hepatocytes), due to increased DNA but suppressed cell division.
Biliary hyperplasia can be seen.
Nodular regeneration may or may not occur- alkaloids prevent hepatocyte proliferation, but ragwort ingestion is periodic, which may allow regeneration between times.
Ammonia build up may cause neurological signs- hepatic encephalopathy in the horse (aka. hepatic coma, portosystemic encephalopathy)
SARCOMAS mainly metastasise via HAEMATOGENOUS route.
CARCINOMAS mainly metastasise via LYMPHATIC route (thoracic duct).
This can involve spread to the liver.
NAVEL ILL (OMPHALOPHLEBITIS)
Haematogenous spread of infection from the urachus to the umbilical vein to the liver.
Possible sequelae- Septicaemia, hepatic abscesses, polyathritis.
Affects young animals.
MECHANISMS OF LIVER INJURY
1. Metabolic bioactivation of chemicals eg. cytochrome p450 to reactive species. Centrilobular enzymes.
2. Stimulation of autoimmunity.
3. Stimulation of apoptosis.
4. Disruption of Ca homeostasis -> cell surface blebbing and lysis.
5. (Bile) canalicular injury
6. Mitochondrial injury.
POSSIBLE LIVER REACTIONS TO INJURY
1. Degenerative changes (sublethal/reversible)
5. Inflammation- often begins round portal areas
6. Cholestasis (bile stasis)
MAIN TARGETS OF LIVER INJURY
EPITHELIAL CELLS- hepatocytes, biliary epithelium.
-> Sublethal/reversible injury- eg. cell swelling- hydropic degeneration or fatty change.
eg. atrophy- may be seen in a chronically congested liver, as the congestion fills up space, meaning hepatocytes have less space so become atrophied.
-> Lethal/irreversible injury- necrosis, apoptosis- can be caused by the same agent and can occur in the same liver.
GLYCOGEN ACCUMULATION IN THE LIVER
eg. steroid hepatopathy.
Gross- swollen, uneven liver
Histology- Accumulations in hepatocytes (can't tell if this is water or steroid- they appear the same), sinusoids not visible due to swelling.
Glycogen accumulation often starts in the midzonal areas of the liver, then spreads.
Hypoxic damage or toxic/metabolic injury causes lipid vacuolation in cells.
Especially seen in cells involved with fat metabolism- hepatocytes, myocardial cells, renal tubule cells.
Gross- enlarged, pale, greasy.
Histology- Circular, clear cytoplasmic vacuoles (appear red on fresh frozen sample stained with oil red 0)
Possible causes of glycogen accumulation in liver:
1. Increased uptake from gut or stored fats.
2. Decreased catabolism of fatty acids due to toxins/hypoxia (mitochondrial damage)- relies on oxidation.
3. Impaired apoprotein synthesis due to carbon tetrachloride, toxicosis, aflatoxicosis.
'Normal' fatty changes can be seen in localised areas eg. at ligamentous attachments where the liver is held in place.
POSSIBLE SEQUELAE TO FATTY LIVER
RUPTURE- with subsequent haemoabdomen and death.
Pink, amorphous material is deposited in the space of Disse (perisinusoidal space).
Severe cases result in hepatic dysfunction or failure, as hepatocytes atrophy due to decreased space.
Associated with CHRONIC antigen stimulation/inflammation/infectious processes.
Serum protein (an acute phase protein- B-pleated sheet) formed by liver.
Gross- firm, waxy liver. Less friable and greasy than fatty liver.
Histology- Disorded lobules/cords of hepatocytes, amyloid accumulation in space of Disse (thin line either side of sinusoids)
PATTERNS OF HEPATOCELLULAR DEGENERATION AND NECROSIS
1. RANDOM- multifocal necrosis, caused by viral, bacterial and protozoal infection.
2. ZONAL- produces an enlarged, rounded liver. Specific zones degenerate- centrilobular zone often first affected.
3. MASSIVE- entire lobule or contiguous lobules. eg leptospirosis.
RANDOM HEPATOCELLULAR NECROSIS
eg. Equine herpesvirus infection in the foal- herpesvirus infection is important when animals cannot thermoregulate eg. neonates- causes severe disease.
Characterisic eosinophilic intranuclear inclusions with a clear zone around the dispersed chromatin.
Gross lesions are visible on the liver, kidneys, lung, spleen- multifocal necrosis.
Initially oronasal multiplication, then enters bloodstream via infected macrophages.
eg. Salmonellosis in the pig- faecooral infection, then colonisation of the oral and gut lymphoid tissues- can survive and multiply within macrophages -> travel in portal circulation to liver, causing random hepatocellular necrosis and inflammation.
eg. Canine infectious hepatitis (Canine Adenovirus 1)
CANINE INFECTIOUS HEPATITIS
Caused by CAV 1.
Pathogenesis- Oral/urinary infection
-Viral replication in tonsils
-Spread to local lymph nodes, then systemic circulation via thoracic duct
-Predilection for hepatocytes/vascular endothelium/renal epithelium.
-> fulminant (sudden) diseasee- HEPATIC NECROSIS, WIDESPREAD HAEMORRHAGE.
Often see CENTRILOBULAR pattern of necrosis (vascular stasis and hypoxia affects those cells in the centrilobular zone first)
Virus induced endothelial damage may also lead to DIC.
Some recovering dogs can go on to develop an immune complex uveitis (type II hypersensitivity) causing degeneration and necrosis of the corneal endothelium with resulting corneal oedema (Blue Eye)
Gross- Gall bladder oedema.
-Enlarged, friable liver, often with fibrin on capsule
CENTRILOBULAR DEGENERATION AND NECROSIS
Zonal degeneration- zone 3.
Common- this area receives the least oxygenated blood, so is susceptible to hypoxia.
It also has the greatest enzymatic activity (mixed function oxidases)- activation of compounds to toxic forms.
Possible causes of centrilobular necrosis: Severe anaemia, right sided heart failure, passive congestion of liver- hypoxia seen due to blood stasis and atrophy of centrilobular hepatocytes.
HEPATIC CIRCULATORY DISTURBANCES
-Passive venous congestion- increased pressure in hepatic veins/venules relative to portal venules- blood cannot leave as easily.
Possible causes- congestive heart failure (underlying cardiac/pericardial disease), partial obstruction of larger hepatic veins or caudal vena cava (by abscess, neoplasm, thrombus, dirofilariasis)
-Acute passive congestion- sudden engorgement with blood eg. due to anaphylaxis (massive type I hypersensitivity), shock, euthanasia.
-Chronic passive congestion- NUTMEG LIVER- dark red centrilobular zones of congestion with necrosis of hepatocytes and dilated central veins, and pale, swollen periportal hepatocytes with fatty degeneration. Especially seen in ruminants and horses.
MIDZONAL DEGENERATION AND NECROSIS
Zonal degeneration- zone 2.
Unusual in domestic species.
Occasionally seen in aflatoxicosis in pigs and horses (ingestion of toxic fungal metabolites- aspergillus)
PERIPORTAL DEGENERATION AND NECROSIS
Zonal degeneration- zone 1.
Seen with toxin exposure- to toxins that don't require mixed function oxidase enzyme action (present in zone 3) eg. phosphorous toxicity in the horse.
Entire lobule or contiguous lobules are affected.
-Disassociation of hepatocytes eg. leptospirosis- enters through mucous membranes or damaged skin, infects red blood cells, kidney and liver, causing marked necrosis.
Several serovars can cause intravascular haemolytic anaemia, then ischaemic damage to the liver -> massive necrosis, icterus.
Liver is swollen and yellow.
Hepatocytes are very brightly eosinophilic with pyknotic nuclei, and are becoming individualised. Sinusoids are closed by swollen hepatocytes.
-Massive necrosis- cause unknown eg. collapse of the liver, often seen in young, fit working dogs and in pigs. Causes sudden death.
DISTURBANCES TO BILE FLOW
Hepatic injury often manifests as hyperbilirubinaemia- .2g/dL.
Seen as jaundice/icterus, tissues rich in elastin are bright yellow.
Accumulation in tissues takes 2 days- in acute hepatic injury cases, the animal may be only slightly jaundiced.
Bilirubin is a yellow-brown breakdown pigment of haem.
Accumulates in the liver due to excessive production or failure of removal (damaged hepatocytes)
Accumulates in tissues due to derangement in liver secretion and/or biliary tract obstruction.
Jaundice is COMMON in CATS/DOGS, UNCOMMON in CATTLE.
ENTEROHEPATIC CIRCULATION OF BILIRUBIN
Bilirubin must undergo enterohepatic circulation, as bile cannot be produced fast enough:
1. Breakdown of old red blood cells
2. Extrahepatic bilirubin bound to serum (by haemoxygenase, bilirubindeoxygenase)
3. Hepatocellular uptake
4. Bilirubin glucuronidation in the ER- products are water soluble and readily excreted in bile -> duodenum.
5. Gut bacteria deconjugate bilirubin and degrade to colourless urobilinogens- excreted in faeces.
Some bilirubin in reabsorbed (enterohepatic recycling) and some is excreted in urine.
BILIARY SYSTEM- DEFENCES
-Mucosal secretion- IgA from GI plasma cells.
-Terminal sphincter of common bile duct- physical barrier to ascent of gut bacteria and continuous bile flow. Halting of bile flow may be seen normally during fasting/starvation.
PORTALS OF ENTRY TO BILIARY SYSTEM
-Direct extension- internal (GI tract) or external
-Haematogenous- localisation within capillary beds of wall of gallbladder or small arterioles of biliary tree.
-Retrograde biliary transport- ascending bacterial/parasitic infections gain access this way. eg. Liver fluke (fasciola hepatica) in cattle/sheep, coccidiosis (Eimeria steidiae) in rabbits. (see ppt page 11, 12)
RESPONSE OF THE LIVER TO INJURY
3. Biliary hyperplasia
It is normal to see low levels of liver cell proliferation.
The liver has massive potential for regeneration- ORDERLY REPAIR OF FOCAL NECROSIS.
Repeated damage leads to distorted repair.
Nodular hyperplasia is a normal finding in older dogs.
If reticular network supports hepatocytes. If it is intact, there is no scarring.
66% of damage can be regenerated. Hepatocytes, biliary epithelium, endothelium and sinusoidal lining cells replicate.
Existing lobules increase in size.
Occasional new lobule formation can occur, via subdivision of existing lobules.
Individual/small foci of necrosis can be seen due to proliferation of adjacent hepatocytes.
Large areas of necrosis eg. toxin induced can be seen +/- proliferation of hepatocyte stem cells (oval cells) in connective tissuse in portal areas. These can differentiate in to various liver cells.
Growth factors- hepatocyte growth factor, TGF-a.
If an individual hepatocyte is damaged, it's neighbour can phagocytose it.
Seen in response to chronic injury.
Pattern of fibrosis may suggest underlying cause- Centrilobular- chronic toxic change, cardiovascular dysfunction.
Periportal- chronic inflammatory changes.
Hepatic fibrosis can be fatal.
Early fibrosis extends out from the central vein.
Progressive fibrosis shows central-portal bridging and/or central-central bridging fibrosis.
Hepatocyte function is decreased.
Nodular regeneration occurs with fibrosis of either type.
Proliferation of bile ducts- portal, periportal parenchyma.
Usually seen in longstanding liver injury.
Often seen after disease that obstruct bile drainage (cholestasis).
END-STAGE LIVER- DIFFUSE FIBROSIS WITH HYPERPLASTIC NODULE FORMATION.
-Total absence of any normal lobular architecture- disorganised.
-Caused by: chronic toxicity, chronic cholangitis/obstruction, right sided heart failure, chronic hepatitis, inherited metal metabolic disorders (copper- bedlington terriers), idiopathic.
-Liver is small, gall bladder is distended.
Causes vary between species.
HORSE- Ragwort, parasitic hepatitis, unknown.
COW/SHEEP- Parasitic hepatitis, ragwort, uknown.
CAT- Cholangiohepatitis (inflammation begins in bile duct), lymphocytic cholangiohepatitis.
DOG- unknown, steatosis (fatty liver), chronic hepatitis, post-viral, copper overload (Bedlington and WHW terriers)
SEQUELAE TO CIRRHOSIS
Dysfunctional end stage liver -> decreased albumin production -> hypoproteinaemia -> decreased colloid osmotic pressure -> ascites and oedema.
PORTOSYSTEMIC SHUNTS AND THE LIVER
Shunts are seen normally in the foetus as vascular channels that allow blood to bypass the liver (maternal circulation does all the work).
If they remain open after birth, they are considered a disorder.
Congenital or acquired.
Results in failure to detoxify ammonia.
CONGENITAL PORTOSYSTEMIC SHUNTS
aka. portocaval shunts.
Most common in dogs and cats.
-INTRAHEPATIC- persistence of ductus venosus (joins vena cava and portal vein), seen in large dogs.
-EXTRAHEPATIC- portal vein to caudal vena cava
-portal vein to azygos.
Seen in small breed dogs and cats.
Produces a small liver and underperfusion of blood vessels within portal triads.
ACQUIRED PORTOSYSTEMIC SHUNTS
Seen due to liver damage.
Small vessels dilate to allow blood to continue to move away from the liver.