Phenobarbital and the liver

What does phenobarbital do to the liver?

Phenobarbital induces hepatic microsomal enzymes in dogs, which leads to:

• The presence of increased serum liver enzyme activities without developing actual hepatocellular damage or biliary stasis.
  • Following the start of treatment, ALP concentrations can increase as early as two weeks later.
• Increased liver size/weight.
  • A moderate increase in liver size would be expected on abdominal radiography.
• An increase in the size and weight of the liver.
  • An abdominal radiograph would show a moderate increase in liver size.

• An increase in the metabolism of various drugs and endogenous substances (such as thyroid hormones).
• An accelerated metabolism of phenobarbital, which causes a reduction in its half-life and efficacy.
  • Some dogs will display this effect within a few weeks, months, or it is possible that it won’t happen at all.

Phenobarbital is generally well tolerated and effective for treating epilepsy, but hepatotoxicity is rare. If hepatotoxicity is seen then it can manifest in one of two ways:

1.  Acute hepatotoxicity is thought to be an idiosyncratic reaction (i.e. not dependent on dosage or duration of treatment).
2. When phenobarbital serum concentrations are high for a long time, chronic hepatopathy is more likely to occur. It is recommended to avoid serum phenobarbtial concentrations above 35 mg/L due to the increased risk of hepatotoxicity.

In stable epileptic patients, blood tests should be performed every 6 months to monitor hepatopathy and ensuring phenobarbital concentrations stay within the therapeutic range.

What do the liver enzyme results mean?

During phenobarbital therapy, many patients experience increases in liver enzyme activity (ALT, ALP, and GGT), which has limited diagnostic value in determining whether a patient has hepatocellular damage. In general, ALP concentrations consistently exceed the reference range and can be very high, whereas ALT and GGT3 do not increase as commonly. In other words, an increase in these enzymes is not enough to consider switching from phenobabrtial to another anti-epileptic drug, as the liver is likely to be functioning normally. ALP/ALT/GGT increases that are greater than 3-5x the upper reference range, while not pathognomonic for liver dysfunction, do warrant attention.

How do I know if liver enzyme elevations are due to liver problems rather than liver induction?

You should suspect a heaptopathy (i.e. poor liver function) when:

1. The patient has clinical signs of liver disease:

• Clinical signs of liver disease include sedation, weakness, anorexia, ataxia, vomiting/diarrhoea, PU/PD, weight loss, jaundice, ascites and coagulopathy.
• Potentially, a change in seizure frequency may occur; either:
  • Decreased (due to reduced liver clearance of phenobarbital) or,
  • Increased (due to hepatic encephalopathy).

2. Pre and post prandial bile acid concentrations are abnormal.
3. Other biochemical changes are present that are consistent with severely compromised liver function:

• Reduced albumin, glucose, cholesterol, and urea.
• Increased total bilirubin and ammonia.
• These findings are non-specific to liver disease but multiple aberrations on a biochemistry panel may increase suspicion.

4. Increased AST:

• While non-specific to liver tissue (AST is also found in muscle as well as hepatocytes), AST is not thought to be affected by microsomal enzyme induction, so increases in this enzyme could indicate hepatocellular damage.

5. Changes to liver architecture or echogenicity on ultrasound:

• If an ultrasound of the liver identifies any abnormalities then it is recommended to biopsy the liver to ascertain whether the liver damage is due to phenobarbital induced toxicity or if there is a concurrent, unrelated underlying liver pathology.

What to do if you now suspect a hepatopathy?

There are several options available if phenobarbital is suspected to be the cause of the hepatopathy:

1. Add in a alternative anti-epileptic drug that is not contraindicated in patients with pre-existing liver disease.
   • Either/or in combination:
     • Potassium bromide is a good option here. Some cases may require a loading dose to quickly achieve therapeutic serum concentrations. Be aware that loading is associated with severe side effects and should be reserved for dogs with severe epileptic seizure frequency.
     • Levetiracetam can be considered as an off-license medication in the management of epilepsy and will reach steady state concentrations much faster in those dogs with a more urgent problem.
2. Carefully wean the dog from the phenobarbital therapy. If this needs to be done rapidly (i.e. within 7 days) then hospitalisation is advised.
   • If this is not possible then reduce to the lowest effective dose and monitor liver function carefully.
3. Consider the addition of further liver support:
   • S-Adenosylmethionine (SAMe): at least 100mg for every 10kg PO SID.
   • Ursodeoxycholic acid if biliary stasis is present: 10-15mg/kg PO SID.
   • Vitamin E supplementation.
4. Monitor bloods to assess liver function (haematology, biochemistry, fasting and post-prandial bile acids) weekly.