Therapeutics for Hepatic Disease Flashcards
Describe the proposed mechanism of action of SAMe
- SAMe is formed endogenously from methionine and ATP, a reaction catalysed by SAMe synthetase
- SAMe synthetase is the rate limiting step with hepatic compromis
- SAMe is essential for three major biochemical pathways
- Transmethylation
- methyl donor in the transmethylation of phospholipids
- Transsulfuration
- Transsulfuration is important for detoxifying and as a precursor for glutathione
- Aminopropylation
- Transmethylation
- These three pathways are especially important in the liver for activation/elimination of drugs and substances
- Conversion to glutathione requires folate, cobalamin and pyridoxine (Vit B6)Glutathione is important for many detoxification and metabolic processes
- SAMe supplementation helps to limit reduction or increase of glutathione with liver disease
- SAMe also affects serotonin turnover and increases dopamine and norepinephrine levels in the human brain - exerts an anti-depressive effect.
What evidence exists for the beneficial effects of SAMe and when might its use be indicated?
Evidence:
Evidence is either based on small, non-randomized clinical studies, though a few small placebo controlled studies exist. Evidence in humans suggests hepatoprotective effects and enhancement of hepatic function (decreases in bilirubin and AST, but not ALT). Studies have shown it to be safe and to increase glutathione levels (or prevent their decrease).
Evidnece is largely based on physiological principles of benefit, rather than definitive evidence. Human studies have shown the use of UDCA may be more beneficial in some chronic hepatopathies
What is the mechanism of action of NAC in liver disease?
When is the use of NAC indicated?
What evidence exists for the use of NAC in dogs and cats?
- Provides an alternative substrate for conjugation reactions with reactive metabolites of acetaminophen or phenol.
- Thus, glutathione levels are preserved or restored
- These conjugations reactions are catalysed by glucuronyl transferase
Indications:
- NAC use is primarily indicated in cats or dogs after paracetamol ingestion
- Can also be administered via nebulisation to help breakdown mucus and increase bronchial clearance
Evidence:
- Survival benefit and indicated for treatment after paracetamol ingestion / overdose in both species
- Use in critically ill dogs and cats does stabilise RBC glutathione levels, though the clinical significance of this has not been identified in short term (~48 hours) or long term (30 days) studies - variable diseases
- NAC may provide anti-oxidant support and reduce oxidative stress in canine parvovirus.
What is the mechanism of action of silymarin?
What evidence exists for its use in dogs and cats?
- Inhibits lipid peroxidase and beta-glucoronidase
- B-glucoronidase:
- breaks the bond between toxins and glucuronic acid
- Breaks down mucopolysaccarides
- Converts conjugated bilirubin to uncongugated bilirubin for reabsorption
- B-glucoronidase:
- Acts an a free-radical scavenger and anti-oxidant
- Inhibits the actions of TNF
- May stabilise hepatocyte membranes helping to prevent toxin penetration - mechanism for amanita mushroom toxicosis
- Reduced binding of phalloidin toxin to hepatocytes and inhibits enterohepatic cycling
- Reduce hepatic collagen production and increase hepatic glutathione content
Evidence:
Minimial. Most evidence is not controlled or from translational or experimental in vitro studies. No standard dosage recommendation for either form or concentration
Evidence of hepatoprotective effect with acute hepatic necrosis secondary to amanita mushroom toxicosis - study in beagles.
May help prevent the negative affect of certain chemotherapeutics
What are the proposed mechanisms of action of UDCA?
- UDCA is a secondary bile acid produced by intestinal bacteria and the liver of some species
- UDCA supresses hepatic synthesis and secretion and intestinal absorption of cholesterol
- It slowly alters the components of the bile to contain less cholesterol and more hydrophilic bile acids which are less hepatotoxic.
- Experimentally, UDCA has been shown to have immunomodulatory and anti-inflammatory effects in the GIT
- The drug maintains cholerhetic properties and helps limit the oxidative damage caused by cholestasis and hepatocyte exposure to the detergent like effects of some bile salts.
What evidence supports the use of UDCA in canine and feline liver disease?
- The drug is well tolerated with minimal or rare known adverse effects
- The drug is well absorbed from the intestine with the majority undergoing enterohepatic cycling, therefore minimal amounts enter the systemic circulation
There is minimal evidence to prove benefical effects
- The evidence is largely extrapolated from in vitro studies or experimental studies in lab animals. UDCA has been shown to prevent glutathione deficiency by upregulating GCS, the rate limiting enzyme in the production of cysteine
What are the indications and contraindications for the use of UDCA?
- Treatment in patients with biliary obstruction has been considered the major contraindication as the drug is cholerhetic, however, studies in rats has shown UDCA to be hepatoprotective in bile duct ligation models, improving markers of oxidative damage and apoptosis
- Indicated for immature mucocoele or following gallbladder removal
- Theoretical benefits in chronic hepatitis due to anti-apoptotic, anti-oxidant and immunomodulatory properties. Efficacy in this disease has not been proven
What is the mechanism of action of vitamin E in the setting of canine or feline liver disease?
What evidence supports the use of vitamin E?
- Vitamin E is a free radical scavenger and anti-oxidant that protects phospholipids (cell membranes) from oxidative damage.
- Based on experimental studies or extrapolated from studies in other species, Vitmain E has been indicated for use in liver disease that can lead to oxidative damage
- Acute hepatopathy due to drugs or toxins
- Feline hepatic lipidosis
- Chronic hepatitis
- Copper associated CH
Evidence:
- Current clinical evidence of proven benefit in liver disease is lacking
Corticosteroids have been used to manage both canine and feline inflammatory liver disease.
When is the drug indicated and what precautions must be taken prior to use.
How can you monitor the treatment response to corticosteroids?
- Corticosteroids are likely to be indicated and beneficial in chronic hepatitis that is caused by immune mediated mechanisms. Given the difficulty in identifying an underlying cause (majority of cases are considered idiopathic), definitive recommendation is difficult.
- A few retrospective studies have identified a survival benefit for CH with prednisolone treatment, with a 1988 study quoted!
- Corticosteroids have been shown to reduce hepatic inflammation on repeat biopsy, improve coagulation parameters and in some cases reduce hepatic fibrosis
- Indicated for the treatment of feline lymphocytic cholangitis and chronic neutrophilic cholangitis that has not responded to antibiotics or is culture negative.
Precautions:
- Generally only indicated after histopathology confirms moderate to severe inflammation, culture excludes bacterial infection (especially in cats) and there is no evidence of significant chronic copper accumulation
Monitoring:
- Difficult in dogs due to steroid induced hepatopathy - enzymes may not improve despite improvement in inflammation.
- Monitoring of liver enzymes may be more useful in cats
- Repeat biopsy is considered gold standard but rarely performed.
List the treatment options for management of hepatic copper accumulation
- D-penicillamine
- Trientine
- Zinc
Describe the mechanism of action of D-penacillamine, trientine and zinc in the management of hepatic copper storage.
- D-Penacillamine
- Chelating agent that combines with copper and other heavy metals
- Allows mobilisation of copper from the liver and urinary excretion
- Anti-fibrotic effect by blocking collagen crosslinkages
- Trientine
- Chelating agent generally used if D-penacillamine is not tolerated
- May remove more copper from the circulating pool - good choice for haemolytic anaemia caused by high serum copper levels
- Zinc
- Induces epithelial cell synthesis of metallothionein which binds both zinc and copper
- The copper is bound within the cytosol and lost into the intestine when the epithelial cells slough
- May not reduce copper in Labradors more than dietary management alone
- Most often used in combination with dietary management after chelation therapy has reduced hepatic copper stores
List the various clinical sequelae to acute liver injury that require specific management
- Dehydration
- Nausea/vomiting
- Cerebral oedema
- Gastrointestinal ulceration
- Coagulopathy
- Including vitamin K deficiency
- Haematological abnormalities - thrombocytopenia
- Sepsis
Describe the treatment considerations for dogs with acute hepatic injury
- Support circulation with IV fluids
- Provision of pain relief - opiates most effective
- Anti-nausea management for vomiting - ondansetron, metoclopramide of maropitant (metabolised by CyP450)
- Gastroprotection
- omeprazole / pantoprazole and sucralfate
- Anti-oxidative damage medications
- SAMe, silymarin, vitamin E
- NAC if oral medications not tolerated
- Specific anti-dotes
- Silymarin for amanita mushroom toxicity
- Management of potential cerebral oedema
- mannitol infusion / hypertonic saline?
- head elevation
- Vitamin K for severe cholestatic liver disease
- Antibiotics if there is suggestion of sepsis or bacterial infection
- Blood products including plasma or packed RBCs if indicated. As spontaneous bleeding is rare despite coagulopathy, transfusion reserved for those patients actively bleeding
What are the causes of chronic hepatitis in dogs?
- Copper accumulation
- may be a primary cause of hepatitis or secondary to hepatitis and cholestasis (reduced biliary excretion)
- Breed associated
- Infection
- Bartonella, schistosomiasis, mycobacterium, fungal infection
- Chronic drug exposure
- Phenobarbital
- Idiopathic / immune mediated
Name the various inflammatory liver diseases in cats
Cholangitis and cholanhiohepatitis are much more common in cats that primary hepatitis.
- Acute neutrophilic cholangiohepatitis
- Lymphocytic cholangitis / cholangiohepatitis
- Chronic neutrophilic cholangiohepatitis
