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Hepatobiliary > Physiology/Pathophysiology > Flashcards

Physiology/Pathophysiology Flashcards

1
Q

What is the proposed definition for acute liver failure in the human literature (although not definitively established in the veterinary literature)?

A
  • The absence of pre-existing liver disease
  • The presence of HE occurring within 8 weeks of onset of hyperbilirubinemia
  • The presence of a coagulopathy (INR >/=5)
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2
Q

Compare direct and indirect mechanisms of hepatotoxicity.

A
  • Direct (destructive) mechanisms
    • Nonselective destruction of the structural basis of hepatocyte metabolism leading to total intracellular chaos and cell death
  • Indirect (disruptive) mechanisms
    • Selective disruption of cell function in a more discriminating fashion
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3
Q

List 5 environmental/food toxins implicated in ALF in dogs.

A

Sago (cycad) palms

Blue-green algae

Amanita mushrooms

Xylitol

Aflatoxins

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4
Q

What is the mechanism of toxicity associated with ALF secondary to blue-green algae?

A
  • Microcystin disruption of the hepatocyte cytoskeleton leading to hepatic necrosis
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5
Q

Describe the 4 phases of amanita mushroom toxicity leading to ALF.

What is the primary toxin responsible for the clinical course of toxicity?

A
  • Phase 1: latency period
  • Phase 2: 6-24 hours after ingestion, GI signs and severe abdominal pain
  • Phase 3: false recovery lasting anywhere from few hours to a few days
  • Phase 4: fulminant hepatic, renal and MOF within 36-84 hours of ingestion of the mushroom

**Amatoxin is the most potent; not destroyed by cooking, freezing or drying the mushrooms!!**

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6
Q

What is the dose of xylitol associated with ALF?

What is the proposed mechanism of hepatotoxicity associated with xylitol ingestion?

A
  • 0.5 to 16gm/kg
  • 2 syndromes associated:
    • Mild, self-limiting dose dependent increase in hepatic transaminase activities
    • Idiosyncratic ALF
  • MOA suggested include ATP depletion leading to hepatocellular necrosis and production of ROS
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7
Q

List 6 drugs implicated in development of canine ALF.

A

Carprofen (idiosyncratic reaction)

Acetaminophen (intrinsic reaction)

Phenazopyrindine (intrinsic reaction)

Sulfonamides (idiosyncratic reaction)

Lomustine (idiosyncratic reaction)

Zonisamide (idiosyncratic)

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8
Q

Patients with ALF can have defects in primary hemostasis…what are 3 causes of thrombocytopenia in these patients?

A
  • Decreased hepatic production of thrombopoetin which stimulates platelet production from megakaryocytes
  • Overstimulation of primary hemostasis by continuous, low-grade activation of endothelial cells and release of vWF
  • Increased platelet consumption secondary to hemorrhage
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9
Q

Why does thrombocytopathia occur in patients with ALF and what is the consequence?

A
  • Typically arises secondary to increased production of endothelial derived platelet inhibitors, nitric oxide, and prostacyclin
  • Leads to defective platelet adhesion
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10
Q

How does hypokalemia associated with ALF precipitate HE?

A
  • Hypokalemia can stimulate renal ammoniagenesis–stimulates increased production of ammonia in the proximal tubules of the nephron
  • Also increases the expression of HKATPase pumps in the collecting duct that facilitate reabsorption of K in exchange for H, resulting in a more acidic luminal environment which favors increased ammonia resorption
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11
Q

Why does hypophosphatemia develop in ALF and does it provide prognostic value?

A
  • Results from intracellular shift of phosphate due to hepatocyte regeneration; may be a positive prognostic indicator
  • (Hyperphosphatemia development in people with acetaminophen induced ALF is a poor prognostic indicator)
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12
Q

Prognostic models have not been validated for veterinary patients with ALF, however, list several biochemical markers associated with a worse prognosis in specific subsets of patients.

A
  • Granular cylindruria in dogs with aflatoxicosis
  • Higher ALT and bilirubin and lower albumin at presentation in dogs with sago palm (cycad seed) hepatotoxicity
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13
Q

What are the 3 classifications of hepatic encephalopathy?

A
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14
Q

Discuss ammonia metabolism in the intestines.

A
  • Source of net ammonia gain
  • Urease producing bacteria produce ammonia by breaking down nitrogenous products such as urea
  • Enterocytes themselves also have a high glutaminase activity which metabolizes glutamine to ammonia (and glutamate)–>metabolic activity of the mucosa itself can lead to ammonia production
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15
Q

Discuss ammonia handling in the liver.

A
  • Main site of ammonia detoxification occurring via two metabolic pathways.
  • Urea-cycle
    • Ammonia converted to urea by periportal hepatocytes
    • Low affinity for ammonia but high capacity
  • Glutamine synthesis
    • Perivenous hepatocytes
    • High affinity for ammonia but low capacity
  • In liver failure, the ability of the liver to convert ammonia to glutamine or urea is reduced, contributing to hyperammonemia
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16
Q

Discuss ammonia handling in the kidney.

A
  • Kidneys contain both glutaminase and glutamine synthetase, therefore are capable of either the synthesis or metabolism of glutamine (either using or producing NH3)
  • Kidneys can be a source of production of NH3 or a site of excretion
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17
Q

Discuss skeletal muscle ammonia handling.

A
  • Skeletal muscle can act as an ammonia “sink” in patients with acute and chronic liver disease
    • Has a large quantity of glutamine synthetase
  • Loss of skeletal muscle mass in patients with chronic liver disease is recognized as a predisposing factor for HE
18
Q

Discuss ammonia handling by the cerebrum.

A
  • The astrocytes have a high glutamine synthetase activity
  • Neurons have a high glutaminase activity
  • In liver failure, the cerebrum acts as an organ of net ammonia removal.
  • Accomplished by formation of glutamine by astrocytes and subsequent release into systemic circulation
19
Q

How does ammonia contribute to the development of HE?

A
  • Once the capacity of the liver for managing ammonia is overwhelmed, the astrocytes become more involved in ammonia metabolism
  • Astrocytes detoxify ammonia by converting glutamate to glutamine
  • Glutamine can enter the astrocytes mitochondria where it is metabolized back to ammonia, leading to mitochondrial damage, the production of ROS and osmotic swelling
  • **Astrocyte swelling is the hallmark histo change with HE!!**
  • Ammonia may also lead to upregulation of aquaporin-4 channels in astrocytes and loss of cell volume regulation
  • Can increase BBB permeability
20
Q

What role does inflammation/infection play in the development of HE?

A
  • Inflammatory mediators may trigger HE by exacerbating the effects of ammonia upon the cerebrum
  • Enhanced neutrophil migration in SIRS/sepsis across the BBB may occur, which can lead to production of chemokines, cytokines, etc, further increasing BBB permeability and allowing for increased ammonia diffusion into astrocytes
21
Q

How do neurosteroids contribute to the development of HE?

A
  • Neurosteroids are synthesized in the central/peripheral nervous system
  • Production is regulated by the peripheral type benzodiazepine receptor (PTBR)
  • Ammonia and manganese accumulation activate the PTBRs leading to increased NS synthesis and brain accumulation
  • GABA
    • NS may contribute to the enhanced GABA-ergic tone seen in people with HE
    • May also be due to action of endogenous BZDs as well
22
Q

What role does oxidative stress play in the development of HE?

A
  • Ammonia metabolism leads to development of oxidative stress in astrocytes secondary to accumulation of ROS, RNS
  • INflammatory cytokines can also lead to oxidative stress
23
Q

What role does manganese play in the development of HE?

A
  • Serum manganese concentrations are increased in people with cirrhosis, HE due to decreased biliary excretion
  • Believed to synergize with effects of ammonia causing HE
24
Q

What role do false neurotransmitters play in the development of HE?

A
  • An imbalance of branched chain and aromatic amino acids develops in people with liver disease, leading to an increased concentration of AAA in the brain
  • Increased AAA can lead to production of false NTs such as octopamine, resulting in neural excitation
  • **theory has fallen out of favor however, metanalyses in people failed to show improvement in signs of HE in people supplemented with BCAA**
25
Q

List possible precipitating factors for the development of HE and their proposed MOA.

A
26
Q

How do non-absorbable disaccharides (i.e. lactulose) work? List 5 potential benefits of these medications in management of HE.

A
  • They are fermented by the GI microbiota, resulting in the production of volatile fatty acids, a decreased colonic pH and movement of water into the colon by osmosis
  1. Trapping of ammonia ions within the colon (leading to decreased absorption of ammonia into the portal circulation)
  2. Inhibition of ammonia production by colonic bacteria
  3. Stimulation of incorporation of ammonia within bacterial proteins
  4. Reduced intestinal transit times leading to decreased bacterial ammonia release
  5. Increased fecal excretion of nitrogenous compounds
27
Q

What role do antimicrobials play in management of HE?

A
  • lteration in the intestinal microbiome, reducing ammoniagenesis
  • Neomycin was previously used, however, no longer recommended in people as there is inadequate evidence to support efficacy and is associated with risk of serious renal injury and ototoxicity
  • Metronidazole, vancomycin, rifaximin in people
28
Q

What is the purpose of flumazenil in the treatment of HE?

A
  • IV BZD receptor antagonist that is used for short-term treatment of overt HE–role of endogenous BZDs in pathogenesis of HE is controversial
  • Consensus among investigators is that it is useful in patients with HE who have taken BZDs
29
Q

List 3 additional (beyond lactulose, abx, flumazenil) that may be useful in management of HE>

A
  1. LOLA (l-ornithine-L-aspartate)
  2. L-carnitine
  3. Prebiotics, probiotics, synbiotics
30
Q

How does portosystemic shunting lead to the development of HE in dogs and cats?

A

Permits ammonia rich blood from the portal circulation to bypass the liver and flow directly into the systemic circulation

Important cause of HE in dogs and cats

Can be due to congeintal anomalies or the development of acquired portosystemic collateral vessels as a result or pre-hepatic/hepatic portal hypertension

31
Q

LIst the grading scheme for canine HE (grades 0-4, associated signs)

A
32
Q

What are the most common bacterial species isolated from dogs and cats with cholecystitis?

A

Enteric origin bacteria; e.coli, enterococcus, bacteroides, clostridium

33
Q

How does infectious cholecystitis arise?

A

Bacterial colonization of bile may occur via reflux of duodenal bacteria or by hematogenous spread through the portal vasculature.

The presence of bacteria within bile, combined with increased biliary pressure as the result of an obstructive process, leads to infection of the bile and cholecystitis.

34
Q

Describe the three types of nectrotizing cholecystitis.

A
  1. Type I: areas of necrosis without GB rupture
  2. Type II: acute inflammation with GB rupture
  3. Type III: chronic inflammation with adhesions and/or fistula to adjacent organs

HAs been associated with infection with e.coli and clostridium

35
Q

List some causes of EHBO.

A
36
Q

What is the proposed mechanism of development of GB mucoceles?

A
  • Increased mucin production and decreased GB motility
  • Genetic susceptibility; ABCB4 gene mutation in Shelties has been seen
  • Associated with dyslipidemias, hhyperadrenocorticism
37
Q

What potential benefits does ursodiol (UCDA) have in management of mucoceles?

A

Causes choleresis, has immunomodulatory properties, may decrease mucin secretion and may improve GB motility

38
Q

Infection with which serovars of Leptospirosis are more likely to result in liver involvement?

A

L. icterohaemorrhagiae

L. pomona

39
Q

What are the most common clinical signs seen in a patient with portal hypertension?

A

Abdominal pain, abdominal disention, melena, diarrhea, hypovolemia

**Increase in portal venous pressure leads to venous congestion of the abdominal organs normally drained by the portal system; vascular fluid loss in the form of ascites, organ edema and intestinal fluid losses (including hemorrhage) can occur**

40
Q

Pressures > ___ mmHg are considered portal hypertension in dogs and cats.

A

>11 mmHg Dog, >12mmHg Cat

41
Q

List factors that may lead to cerebral edema and increased ICP in patients with ALF.

A

Hyperammonemia

Astrocyte swelling and loss of cell volume regulation

Increased cerebral blood flow

Increased production of inflammatory mediators

42
Q

Describe how alterations in cerebral blood flow in patients with ALF can lead to increased ICP.

A
  • Cerebral blood flow autoregulation may be interrupted due to cerebral vasodilation
  • Cerebral vasodilation results in an increase in cerebral blood flow, increased hydrostatic pressure in brain capillaires and increased delivery of ammonia to the brain, which lead to an increased ICP

Hepatobiliary (2 decks)

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