Hepatobiliary Flashcards
What are most common organisms in cholecystitis
E. coli, Enterococcus, Bacteroides, Clostridium
Which gas producing bacteria cause emphysematous cholecystitis
E. coli, Clostridium
What are the 3 types of necrotizing cholecystitis?
Type 1- necrosis without rupture
Type 2- acute inflammation with rupture
Type 3- chronic inflammation with adhesions and/or fistulae
What bilirubin concentration in effusion is consistent with bile peritonitis?
bilirubin 2x that of serum
What are the two types of parasites in the gallbladder and what is the treatment of choice?
Life cycle?
Platynosomum conciccum
Amphimerus pseudofelineus
Praziquantel
Eggs in snail, ingested by arthropod intermediate host, which is ingested by cat.
How long after obstruction does it take for gall bladder and cystic duct to become dilated? Intrahepatic bile ducts?
GB, CD: 24 hours
Intrahepatic BD- 5-7 days
What is the difference in composition of choleliths in dogs and cats vs humans?
Calcium carbonate and bilirubin vs. cholesterol in people
What mutation has been identified in shelties associated with gallbladder mucocele formation?
Insertion mutation on ABCB4 gene, which encodes for a protein that translocates phosphatidylcholine from the hepatocyte to the biliary canalicular lumen
What conditions are associated with an increased risk of developing GB mucocoele?
HAC.
Also associated with dyslipidemias.
MOA of ursodeoxycholic acid (ursodiol)
Causes choleresis
Immunomodulatory properties
May decrease mucin secretion
May improve gallbladder motility
List at least 10 hepatotoxins
acetaminophen aflatoxin amiodarone nsaids- aspirin and carprofen azathioprine azole antifungals cycads diazepam (oral, cats) halothane lomustine methimazole anticonvulsants- phenobarbital, phenytoin, zonisamide t/c TMS xylitol blue green algae mushrooms (aminita) canine adenovirus type 1 hepatic lipidosis (cats) stazolol - cats
% of cats with neutrophilic cholangitis who have fever?
19%-37.5%
~20-40%
% cats with neutrophilic cholangitis with positive bacterial culture and what bugs?
20-60% or more
E coli, enterococcus, clostridium, staph.
Classifications of hepatic encephalopathy?
Type A- [A]cute liver failure
Type B- [B]ypass - PSS
Type C- [C]irrhosis, portal hypertension, or acquired shunting
Type C is sub classified into episodic, persistent, or minimal/covert (i.e., normal mental/neuro status but abnormal test results on psychometric tests)
Two main causes of HE in cats
congenital PSS
Arginine deficiency secondary to hepatic lipidosis
Major c/s of cat with HE?
ptyalism
2 sources of ammonia in the GIT
Ureas producing bacteria- esp colonic, but also helicobacter pylori in stomach.
Enterocyte production of ammonia from glutaminase catalyzed reaction glutamine -> glutamate + NH3
2 pathways of ammonia detoxification in liver and differences in terms of affinity and capacity
Urea cycle- low affinity, high capacity
High glutamine synthetase activity- high affinity, low capacity
What cells in the brain have the highest glutamine synthetase activity and what have the highest glutaminase activity?
Astrocytes- glutamine synthetase
Neurons- glutaminase
Precipitating factors for HE?
sepsis, GI hemorrhage, constipation, excess dietary protein, dehydration, drugs, hypokalemia, hyponatremia, alkalosis, uremia, hepatic injury, blood transfusion, arginine deficiency in cats.
How does sepsis precipitate HE?
inflammatory mediators have synergistic effect with ammonia
inreased BBB permeability
How does constipation precipitate HE?
Dehydration
Electrolyte abnormalities
Bacterial overgrowth and bacterial translocation
How does dehydration precipitate HE?
Electrolyte changes
Increased renal ammoniagenesis
How does hypokalemia precipitate HE?
Movement of intracellular potassium into the extracellular space leads to intracellular acidosis and trapping of ammonium ions within cells
How does hyponatremia precipitate HE?
enhanced astrocyte swelling
How does alkalosis precipitate HE?
Increased access of ammonia to neurons (due to shift in equilibrium from ammonium ions to ammonia, which can pass through cell membrane)
How does uremia precipitate HE?
increased renal ammoniagenesis
Benefits of lactulose
- trapping of ammonium
- inhibition of ammonia production by colonic bacteria
- incorporation of ammonia within bacterial proteins
- reduced intestinal transit times
- increased fecal excretion of nitrogenous compounds
Antibiotic used in humans for HE
rifaximin
Efficacy of L-ornithine-L-aspartate (LOLA) for treatment of HE and MOA?
L-ornithing- substrate of urea cycle and L-aspartate substrate of reaction converting ammonia-> glutamine. LOLA is thought to increase rate of ammonia detoxification through both pathways.
Metaanalysis in humans should good efficacy for mild-mod overt HE.
What is role of manganese in HE ?
Neurotoxin believed to synergize with ammonia in causing HE. Dogs. w/ PSS have increased levels compared to healthy dogs, and evidence of manganese deposition in brain on MRI.
What aromatic amino acid is increased in HE in dogs?
phenylalanine.
Lester Retrospective evaluation of acute liver failure in dogs (1995-2012): 49 cases.
Definition of ALF? Incidence of neuro signs? Top causes? Survival? What factors associated with survival?
ALF: acute onset of clinical signs, hyperbilirubinemia, coagulopathy (PT>1.5 times ref), +/- HE
Neuro signs in 57%
Neoplasia- 27%, Lepto- 8%, Ischemia 2%, remainder idiopathic with ~50% of those having exposure to possible hepatotoxins
14% survival
Survivors had higher ALT, more likely to maintain normal albumin concentrations and not develop clinical bleeding or ascites.
What is the current definition of acute liver failure in human medicine (ALF in dogs and cats, JVECC 2015)
1- Absence of pre-existing liver disease
2-HE occuring within 8 weeks after onset of hyperbilirubinemia (>2.9mg/dL)
3- Presence of coagulopathy, (INR> 1.5)
Prognostic indicators for cycad ingestion (JVIM 2011)
Higher bilirubin and lower albumin at presentation negative indicator. Higher proportion of nonsurvivors had prolonged PT/PTT. Administration of charcoal as part of initial treatment plan had protective effect.
MOA of blue green algae toxicosis
Microcystins disrupt hepatocyte cytoskeleton leading to hepatic necrosis.
Stages of toxicity with amanita mushrooms
1- Latency period
2- 6-12 hours: GI signs
3 - False recovery - few hours to few days
4- fulminant hepatic, renal, MOF 36-84 hours after ingestion
What is recommended treatment for amanita mushrooms? What is prognosis?
Penicillin G
Silymarin
40-100% reported in people
What biomarkers were found to be helpful in determining aflatoxin exposure?
Hypocholesterolemia
Decreased plasma protein C
Decreased antithrombin
What are 2 forms of aflatoxicosis and what is MOA of toxin?
Acute aflatoxicosis- rapidly fatal
Chronic aflatoxicosis- immunodeficiency and hepatic neoplasia
Effects are dose dependent and due to toxic metabolites produced by cytochrome p450 enzymes in liver causing direct damage and secondary oxidative damage due to depletion of intracellular glutathione
Diagnosis of aflatoxicosis?
Aflatoxin B1 in urine- only w/in 48 hours of ingestion
What is a negative prognostic indicator for aflatoxicosis?
granular cylindruria
When is onset of hypoglycemia and when is onset of hepatotoxicity with xylitol
30-60 minutes, lasting up to 12 hours.
1-3 days later- hepatotoxicity.
What is dose of xylitol associated with hepatic failure? Is the dose significant re: survival?
0.5-16 g/kg
Dose does not correlate with survival
What are 2 syndromes associated with xylitol hepatotoxicity and what is poor prognostic indicator?
mild, self-limiting elevations in ALT, and idiosyncratic ALF.
Hyperphosphatemia poor prognostic indicator
Suggested mechanisms of xylitol tox?
ATP depletion leading to hepatocellular necrosis
and
production of ROS.
What dose of acetaminophen is associated with hepatotoxicity?
> 100 mg/kg
What is phenazopyridine and what is toxic metabolite responsible for toxicity?
Genitourinary analgesic used in people- acetominophen is toxic metabolite.
Which of these drug’s liver toxicity is idiosyncratic?
TMS
Zonisamide
both
Hepatotoxicity of lomustine (CCNU)?
Idiosyncratic increases in LE in up to 86% of dogs receiving therapy.
Denamarin shown to improve ALT, AST, ALP and bilirubin in patients receiving CCNU .
Which 2 lepto strains are thought to produce hepatic disease more commonly than other serovars?
icterohemorrhagiae, pomona
What is incubation of lepto?
7 days but can be shorter or longer depending on inoculum.
When should blood and when should urine PCR be performed for lepto?
within first 10 days of infection, highest in blood.
after 10 days, highest in urine.
LE pattern in hepatic lipidosis and what are prognostic indicators?
ALP, ALT, AST, bilirubin»_space;» GGT (normal)
Negative prognostic indicators- anemia, hypokalemia, older patient
Cats with ______ are more likely to develop delayed ALF when given stanozolol.
gingivitis and stomatitis
mechanism of hyperbilirubinemia in ALF
Intrahepatic cholestasis secondary to -
-leakage of tight junctions that separate bile canaliculi from blood (esp w/ toxic or infectious disease)
- swelling of hepatocytes to extent that canalicular flow is obstructed
- necrosis of hepatocytes
Causes of thrombocytopenia in ALF
- decreased hepatic production of thrombopoeitin
- overstimulation of primary hemostasis by continuous, low-grade activation of endothelial cells, releasing VWF
- consumption secondary to hemorrhage
Causes of thrombocytopathia with ALF
Defective platelet adhesion due to increased production of endothelial-derived platelet inhibitors, NO, and prostacyclin
What is a cause of hyperfibrinolysis in ALF?
Decreased clearance of plasminogen activators by failing liver
What is a distinguishing feature in ALF vs. DIC?
Increased factor 8 in liver failure and decreased in DIC
When is peak ALT activity after acute liver injury
approx 5 days following hepatocellular injury.
What toxin inhibits transaminase gene transcription and thus may not see rise in ALT?
aflatoxin/ microcystins
What anchors inducible enzymes to hepatocyte membranes?
glucosyl phosphatidylinositol linkages that must be cleaved by endogenous phospholipase before soluble form of enzymes can be distributed to circulation.
Mech of hypophosphatemia in ALF?
Intracellular shift of phosphate due to hepatocyte regeneration. May be positive prognostic indicator.
In patients with hepatic dysfunction is arterial or venous ammonia concentration higher
arterial
When is vitamin E contraindicated in liver disease?
coagulopathy- competes with vitamin K
SAME
synthesized by ATP in cells and crucial component of transmethylation, transsulfuration, and aminopropylation. - helping to maintain cell membrane integrity, generate glutathione and anti-inflammatory effects (respectively).
NAC MOA
thiol donor Stimulates GSH synthesis Detoxifies hepatotoxins- acetominophen Free radical scavenger May improve microcirculatory blood flow
Why is prolonged doses of NAC not recommended
can precipitate hyperammonemia. also can have SE in ppl of increased ICP
How to diagnose bartonella induced hepatic disease?
PCR on hepatic tissue.
What RBC changes can be seen with liver dysfunction?
target cells, acanthocytes, anisocytosis
According to silverstein at what bilirubin level does the patient appear icteric?
2.3-3.3 mg/dL
What type of protein is recommended for HE?
Milk and vegetable proteins are lower in aromatic amino acids and higher in BCAA (valine, leucine, isoleucine) than animal proteins and are less likely to potentiate HE.
What other substances other than ammonia are implicated in HE?
glutamate, gaba, endogenous benzodiazepines, increased aromatic amino acids, mercaptans, opioids, manganese, tryptophan/serotonin
What amino acid is important in the urea cycle?
arginine
What can cause an elevated ammonia with normal liver function
Selective cobalamin deficiency
What syndrome is involved with selective cobalamin deficiency and what breed has it been described in?
anemia, neutropenia, proteinuria, hyperammonemia.
Border collie
What are ROS?
peroxides, superoxide, hydroxyl radical, singlet oxygen
How does ammonia induce cerebral edema?
Crosses BBB, induces astrocyte swelling by:
1- inserting Aquaporin-4 into astrocyte membranes
2- Inhibiting glutamine transport out of astrocytes, accumulates within astrocytes and causes cell swelling due to osmotic effects.
What are aromatic amino acids and what are they precursors to?
phenylalanine, tyrosine, tryptophan -
precursors to dopamine, NE, serotonin.
What are BCAA?
Leucine, valine, isoleucine
Function of manganese in HE?
Increased in chronic liver disease
May contribute to alzheimer type 2 astrocytosis
Potential role in aquaporin 4 upregulation
Findings w/ protein C in liver disease?
Low with PSS, Normal with MVD
MOA ammonia in HE
increased brain tryptophan and glutamine Decreased ATP availability Increased excitability Increased glycolysis Brain edema Decreased microsome Na/K ATPase
MOA aromatic AA in HE?
Decreased DOPA neurotransmitter synthesis
Altered neuroreceptors
Increased production of false NT
Bile acids MOA in HE ?
Membranocytolytic effects alter cell/membrane permeability
BBB more permeable to other HE toxins
Impaired cellular metabolism
MOA decreased alpha-ketoglutamate in HE?
Diversion from Krebs cycle for ammonia detoxification; decreased ATP availability
What are false NT and what are their MOA in HE?
Tyrosine-> Octapamine Phenylalanine-> PHenylethylamine Methionine -> Mercaptans Impairs NE action; synergistic w/ ammonia and SCFA; decreases ammonia detoxification in brain urea cycle Decreased microsomal Na/K/ATPase
MOA GABA in HE?
Neural inhibition; hyperpolarize neuronal membrane, increase BBB permeability to GABA
MOA Glutamine in HE?
Alters bbb aa transport
MOA manganese in HE?
Neurotoxin associated with disruption of gluatmine/GABA cycle between astrocytes and neurons, leading to changes in glutaminergic or GABAergic transmission and glutamine metabolism
MOA phenol in HE?
Derived from phenylalanine and tyrosine. Synergistic with other toxins
Decreases cellular enzymes, neurotoxic and hepatotoxic
MOA SCFA in HE?
Decreased microsomal Na/K/ATPase in brain
Uncouples oxidative phosphorylation
Impairs oxygen use, displaces tryptophan from albumin, increasing free tryptophan
MOA tryptophan in HE?
Directly neurotoxic, increases serotonin- neuroinhibition
