Liver/Biliary Flashcards
T/F: Young GSD with EPI are prone to mesenteric volvulus
True
Most common causes of hemoabdomen in cats
Non-neoplastic causes (54%)
Difference between BG and peritoneal fluid glucose suggestive of septic abdomen
> 20 mg/dL - in dogs 100% sens/specific, in cats 86% sensitive/100% specific
Difference between blood lactate and peritoneal fluid lactate suggestive of septic abdomen
> 2 mmol/L
Fluid to serum potassium ratio for diagnosis of uroabdomen in dogs vs. cats
Dogs: 1.4:1
Cats: 1.9:1
Fluid to serum creatinine ratio for diagnosis of uroabdomen in dogs and cats
2:1
Fund to blood bilirubin ratio for diagnosis of bile peritonitis
> 2:1
Two subcategories of acute pancreatitis
Interstitial edematous pancreatitis
Necrotizing pancreatitis
Risk factors for development of pancreatitis in dogs
Hypertriglyceridemia
Endocrine disease
Drug reactions (Azthioprine)
Surgery
Hypercalcemia
Biliary duct obstruction
Biliary reflux
Pancreatic trauma
Dietary factors
What anatomical feature may predispose cats to development of pancreatitis?
80% of cats only have one pancreatic duct that joins the bile duct prior to entering the duodenum (vs. in dogs they remain separate) –> may predispose to biliary reflux
Which pancreatic enzyme activates the other pancreatic enzymes?
Trypsin
If more than ___% of trypsin is activated, trypsin inhibitor can no longer inactivate trypsin
10%
T/F: Trypsin and chymotrypsin can initiate neutrophil migration into the pancreas
True
Neutrophil migration into the pancreas results in:
ROS production
Nitric oxide production
What enzyme can result in increased vascular permeability, specifically in the lungs, kidneys, and liver
Elastase
What enzyme associated with acute pancreatitis results in degradation of surfactant
Phospholipase A2
Trypsin can also activate ______ which may result in hypotension, vasodilation, AKI
Kallikrein-kinin system
Hypocalcemia associated with acute pancreatitis is uncommon but is more common in dogs/cats
Cats
In dogs and cats with acute pancreatitis, cytology of the pancreas consists of _____ and large numbers of _____
Degenerate acinar cells and neutrophils
Four proposed independent risk factors for short-term death in dogs with acute pancreatitis
SIRS
Coagulation disorders
Increased creatinine
Ionized hypocalcemia
How does PANOQUELL®-CA1 (FUZAPLADIB SODIUM FOR INJECTION) supposedly work
Fuzapladib sodium is a leukocyte function-associated antigen-1 (LFA-1) activation inhibitor which is reasonably expected to block the specific pathway of inflammation associated with acute canine pancreatitis.
Two main histologic subtypes of cholecystitis in dogs and cats
Neutrophilic cholecystitis
Lymphoplasmacytic, follicular cholecystitis
Most common bacterial species implicated in infectious cholecystitis in dogs and cats
Enteric pathogens: E. coli (gas-producing), Enterococcus, Clostridium spp. (also gas-producing)
Sources of bactobilia
Reflux of duodenal contents into the biliary tree, hematogenous spread
Breed of dog that seems to be predisposed to bacterial cholecystitis
Dachshunds
Three classifications of necrotizing cholecystitis
Type I: Areas of necrosis without gallbladder rupture
Type II: Acute inflammation with rupture
Type III: Chronic inflammation with adhesions and/or fistulae to adjacent organs
Most frequently seen feline parasites which can cause cholecystitis/cholangitis
Platynosomum concinnum
Amphinerus pseudofelineus
Dilation of the common bile duct in the case of EHBDO occurs within ____ hours; dilation of the intrahepatic biliary tree occurs within ___-___ days
24 hours
5-7 days
Most common constituents of choleliths
Calcium carbonate and bilirubin pigments (bilirubin or calcium bilirubinate)
Gallbladder mucocele in dogs has been associated with
Glucocorticoid administration/excess
Dyslipidemias
Cushing’s
Histopathology of the gallbladder from dogs with mucoceles often reveals
Cystic mutinous hyperplasia in addition to other changes consistent with necrotizing cholecystitis
T/F: Bacterial infection is uncommonly seen in conjunction with GB mucocele
True- only seen in about 20%
Elective cholecystectomy has a much better prognosis (__% mortality) as compared to non-elective cholecystectomy (__% mortality)
2% vs. 20%
Proposed benefits of ursodiol
Increase bile flow (choleresis)
Immunomodulatory properties
May decrease mucin production
May improve GB motility
Two factors associated with negative prognosis for surgery on GB mucocele dogs
Hyperlactatemia and hypotension in the period period
Gallbladder infarction is associated with GB rupture in ____% of cases
50%
Cholangitis in cats is typically _____ or _____ cholangitis; in dogs, neutrophilic cholangitis is most common
Neutrophilc or lymphocytic
T/F: Neutrophilic cholangitis in dogs is more commonly associated with bacterial involvement.
True
Dog breeds predisposed to chronic hepatitis
American Cocker Spaniel
Bedlington Terrier
Dalmation
Doberman Pinscher
English Cocker Spaniel
English Springer Spaniel
Labrador Retriever
Skye Terrier
Standard Poodle
West Highland White Terrier
Proven or suspected copper hepatopathy breeds
Bedlington Terrier
Dalmation
Doberman Pinscher
Labrador Retriever
Skye Terrier
West Highland White Terrier
Over ___ of dogs with chronic hepatitis have excess hepatic copper levels
Over 1/3
Excess liver copper causes what
Oxidative stress
Cellular degeneration
Cell death associated with inflammation
Infectious canine hepatitis virus
Canine adenovirus I
*Uncommon because of cross-reaction with CAV-2 vaccine
Infectious canine hepatitis disease course is dependent upon the patient’s level of antibody response; animals with ____ antibody response can die acutely
Decreased antibody response
Liver involvement can happen in __-__% of canine Leptospirosis cases
20-90%
Two serovars of Lepto that are more often associated with liver involvement
L. icterohemorrhagicae
L. pomona
The liver can regenerate ___% of its functional capacity in only a few weeks.
75%
Hepatic encephalopathy (HE) secondary to liver failure in dogs and cats typically arises when more than ___% of liver function is lost
More than 70%
Toxins implicated in development of hepatic encephalopathy
Ammonia
Aromatic amino compounds
Bile acids
Decreased alpha-ketoglutaramate
Endogenous benzodiazepines
False neurotransmitters
GABA
Glutamine
Manganese
Phenol
Short chain fatty acids
Tryptophan
In general, how are these toxins suspected to lead to HE?
May impede neuronal and astrocyte function, causing cell swelling, inhibition of membrane pumps or ion channels leading to increased intracellular calcium concentrations, depression of electrical activity, and interference with oxidative mechanisms.
Three types of hepatic encephalopathy
Type A: acute, associated with ALF
Type B: bypass, associated with shunts
Type C: chronic, found with cirrhosis and portal hypertension
Ammonia is normally converted to ___ and ___ in the normal liver
Urea
Glutamine
(via the Urea cycle)
Ammonia is ____ and associated with release of glutamate, the major excitatory hormone in the brain.
Excitotoxic
What is one of the mechanisms for HE-associated seizures?
Over-activation of glutamate receptors, mainly N-methyl-D-aspartate receptors
With chronicity, inhibitory factors such as ___ and ___ surpass the excitatory stimulus, causing CNS depression
GABA and endogenous benzodiazepines
Proposed mechanisms suggested for hyperammonemia
Increased brain tryptophan and glutamine
Decreased ATP availability
Increased excitability
Increased glycolysis
Brain edema
Decreased microsomal N/K/ATPase in the brain
Proposed mechanisms suggested for aromatic amino acids
Decreased DOPA neurotransmitter synthesis
Altered neuroreceptors
Increased production of false neurotransmitters
Proposed mechanisms suggested for bile acids and HE
Membranocytolytic effects alter cell/membrane permeability
BBB more permeable to other HE toxins
Impaired cellular metabolism
Proposed mechanisms suggested for decreased alpha-ketoglutaramate
Diversion from Krebs cycle for ammonia detoxification
Decreased ATP availability
Proposed mechanisms suggested for endogenous benzos
Neural inhibition
Hyperpolarized neural membrane
Proposed mechanisms suggested for false neurotransmitters
Decreased norepinephrine action
Synergistic with ammonia and SCFA
Proposed mechanisms suggested for GABA
Neural inhibition
Hyperpolarized neural membrane
Proposed mechanisms suggested for glutamine
Alters BBB amino acid transport
Proposed mechanisms suggested for manganese
Seen in hepatic failure and HE and results in neurotoxicity
Proposed mechanisms suggested for short-chained fatty acids (SCFA)
Decreased microsomal N/K/ATPase in brain
Uncoupled oxidative phosphorylation
Impaired oxygen use
Proposed mechanisms of coagulopathy in liver disease
Decreased coagulation factor synthesis
Increased consumption of coagulation factors
Decreased coagulation factor turnover
Increased fibrinolysis and tissue thromboplastin release
Synthesis of abnormal clotting factors (dysfibrinogenemia)
Decrease PLT function and numbers
Vitamin K deficiency (esp. in patients with bile duct obstruction)
Increased production of anticoagulants
Euglycemia can be maintained up until ___% or more of the liver is nonfunctional.
75% or more
Mechanisms for sepsis in liver failure
If severe liver dysfunction present, impaired ability to clear bacterial pathogens passing through from portal system
Inhibition of metabolic activity of granulocytic cells, cell adhesion, and chemotaxis, has been described.
Liver macrophage cells
Kuppfer cells
Most common organisms seen with liver failure and sepsis
Gram negative enteric organisms
Staph
Fungal organisms
What happens during portal hypertension
Massive sinusoidal collapse can block intrahepatic blood flow, causing portal pressure elevations
T/F: Dogs and cats with liver failure secondary to congenital PSS should not be hyperbilirubinemic
True
T/F: GGT is useful in the diagnosis of cholestatic disease and is more specific but less sensitive than ALP (esp. in cats)
True
Bilirubin is a breakdown product of
Hemoglobin
Myoglobin
Cytochromes
Albumin represents ___% of all of the liver proteins synthesized
25%
Altered albumin production is not seen until more than ___ to ___% of the liver function is lost.
66-80%
How long is albumin’s half life and why is that important for determining degree of liver dysfunction
Half life is long (8 days in dogs and cats) and so hypoalbuminemia is a hallmark of chronic liver dysfunction
Cholesterol synthesis occurs in many different tissues; ___% occurs in the liver
50%
The cat renal threshold for bilirubin is ____ times higher than dogs
9 times higher
Three drugs proposed to theoretically decrease fibrous tissue formation in the liver
Prednisone
D-penicillamine
Colchicine
Milk, soy, and vegetable proteins are lower in _____ and higher in _____ than animal proteins and are considered less likely to potentiate HE
Lower in aromatic amino acids
Higher in branched chain amino acids (valine, leucine, isoleucine)
Poor prognostic indicators for liver ~
PT > 100 seconds
Very young or very old animals
Viral or idiosyncratic drug reaction
Markedly increased bilirubin level
Portal venous pressure (PVP) =
PVP = portal blood flow (PBF) x intrahepatic venous resistance (IHVR)
Portal hypertension is caused by
Increased resistance in the portal pre hepatic, hepatic, or post hepatic circulation followed by an increase in portal blood flow
Portal hypertension- three classifications
Prehepatic: increased resistance in the extrahepatic portal vein associated with intraluminal obstruction or extraluminal compression
Intrahepatic: increased resistance in the hepatic microcirculation which can be pre sinusoidal, sinusoidal, or post sinusoidal
Posthepatic: obstruction of the larger hepatic veins, the posthepatic caudal vena cava, or right atrium
Increased intrahepatic resistance is caused by damage and remodeling of the ____ and ___
Hepatocytes and non-parenchymal cells
Two cell types which are phenotypically altered during liver injury
Sinusoidal epithelial cells (SECs)
Hepatic stellate cells (HSCs)
Presinusoidal PH
Occurs because of increased resistance in the terminal intrahepatic portal vein tributaries
Sinusoidal PH
Most often is the result of fibrotic hepatopathies
Postsinusoidal PH
Associated with veno-occlusive disease which is caused by damage to the sinusoidal endothelium and hepatocytes in the centriobular region
Budd-Chiari like syndrome
Obstruction of hepatic venous outflow in the caudal vena cava or larger extra hepatic vessels
Prehepatic and pre sinusoidal PH typically results in a ____ protein effusion
LOW ≤2.5 g/dL
Posthepatic, post sinusoidal, sinusoidal intrhepatic PH typically increases ____ formation resulting in loss of _____ fluid from the leaky sinusoidal endothelium
Increases hepatic lymph formation resulting in effusion with a higher protein ≥2.5 g/dL
Ultrasonographic features associated with portal hypertension
+/- multiple small shunts (acquired) in the left perirenal area
Enlarged portal vein
Decreased portal blood flow velocity (<10 cm/s)
Portal vein to aorta ratio <0.65
Acquired portosystemic collaterals (APSCs) occur as a result of
Neoangiogenesis through growth factor signaling as well as the dilation of embryonic remnant vessels
Form over a period of 5-14 weeks
Why is hyponatremia seen in PH
Dilutional (hypervolemic) hyponatremia is seen due to nonosmotic release of ADH in response to decreased effective blood volume secondary to peripheral vasodilation
What percentage of ascites volume should be removed (i.e. removal of more of this can lead to circulatory collapse)
20-50%
Risk for development of neurological complications post surgical shunt attenuation goes up with
Patients who already have HE
Older dogs
What is the typical mechanism of hypoalbuminemia seen in PSS patients
Chronic disease
Use of ____ may decrease disk of post-attenuation seizures
Keppra
The “safe” degree of PSS attenuation
Increase in portal pressure with temporary or complete PSS attentuation of no greater than 10 cm H2O
Surgical attentuation of a PSS can lead to portal hypertension because of
Increase in portal vein blood flow - pre hepatic PH
Post-operative seizures have been reported to occur as many as __ hours following surgery in dogs, and __ days in cats.
As far as 72 hours post op in dogs, as many as 5 days later in cats
Post-operative neurologic signs have been reported in __-__% of cases of dogs undergoing PSS attenuation
5-18%
Cats tend to have a higher incidence of post-operative neurologic dysfunction than dogs, and ___% of cats developed neuro complications and __% developed seizures
37%
23%
Most prominent feature of acute HE
Cytotoxic brain edema
How does cytotoxic edema develop
Ammonia inhibits glutamine release from astrocytes
Glutamine is osmotically active
Promotes cellular swelling
Anticoagulant protein C
Synthesized by the liver
Has been used to evaluate response to shunt attenuation post operatively
Lactulose changes the GI pH-
Decreases pH which converts NH3 to NH4 and traps it in the gut
Idiopathic chronic hepatitis WSAVA definition
Hepatocellular apoptosis or necrosis
Mononuclear or mixed inflammatory cell infiltrate
Regeneration and fibrosis
Normal function of stellate cells
Reside in the space of Disse
Normal function - storage site of vitamin A, synthesize extracellular matrix components, MMPs, cytokines and growth factors
What are the proposed etiologies of idiopathic chronic hepatitis
Metabolic
Copper
Autoimmune
Toxic
Infectious
With chronic injury, how do stellate cells change
They transform into collagen-secreting, activated stellate cells, which express smooth muscle-specific-actin and secrete high-density matrix and collagen
–> fibrosis
Liver biopsy recommendations
At minimum 5 biopsies from at least 2 liver lobes
Copper metabolism- copper is absorbed in the _____ with the copper transporter _____
Absorbed in small intestine; copper transporter is CTR1
Mutation of Bedlington Terriers leading to copper storage
Autosomal recessive
Mutation in COMMD1
Are male or female dogs more predisposed to copper storage in Labradors and Dobies
Females
Urinalysis findings in dogs with copper storage disease
Evidence of proximal tubular dysfunction- dilute urine, proteinuria, glucosuria
Copper accumulation is most frequently seen in what area of the liver on biopsy
Hepatic copper accumulation most often located in centrilobular areas (Zone 3)
Dogs with Cushing’s disease are ____ times more likely to have mucoceles
29 times more likely
Hypothyroid dogs are ___ times more likely to have a GB mucocele
3 x more likely
How does thyroxine affect bile composition/bile movement
Thyroxine may affect bile acids composition, and does affect relaxation of sphincter of Oddi
Shelties may have a gene mutation of ____ leading to abnormalities in phospholipid metabolism on the canalicular membrane
ABCB4 gene
Where is the space of Disse located
Between the hepatocytes and sinusoids
Kuppfer cells make up __-__% of the tissue macrophages in the body
80-90%
Zones of the liver acinus
Zone 1: periportal/central; most vascular supply
Zone 2: midzonal/intermediate
Zone 3: centrilobular/peripheral *MOST sensitive to anoxic injury
What transporter uptakes bilirubin in the liver
OATP (organic ion transporting polypeptide)
** can be suppressed by cytokines
What can explain some of the protracted duration of icterus in some patients after cholestasis is resolved
Bilirubin can become irreversibly bound to albumin as biliprotein/delta-bilirubin, and the half life matches that of albumin (6-8 days)
T/F: Ammonia is freely permeable across the BBB
True
Microcytosis in liver disease is due to
Abnormalities in iron metabolism
S-adenosylmethionine (SAMe)
Hepatoprotective, antioxidant, anti-inflammatory
Precursor of glutathione production which is important for hepatocyte detoxification
Vitamin E
May help decrease lipid peroxidation within hepatocytes
Silymarin (milk thistle)
Antioxidant
Inhibits lipid peroxidation of hepatocyte and microsomal membranes
Increases hepatic glutathione content, slows hepatic collagen formation
Ursodeoxycholic acid
Anti inflammatory
Immunomodulatory
Decreases toxic effects of hydrophobic bile acids on hepatocytes
Promotes choleresis
