Drugs Causing Hepatic Disease
Adverse drug reactions may cause mild to fatal hepatic disease. They can be due to almost any drug (e.g., cimetidine, amoxicillin, clindamycin, etc.); however, some drugs are clearly more likely to cause hepatic disease than others. Whenever there is any doubt as to whether a particular drug might be responsible for hepatic disease in a patient, stop administering it and observe the results. The healthier the patient is, the more inclined we are to wait and see what happens after stopping the drugs. The sicker the patient is, the quicker we are to biopsy, just in case there is something more significant that we need to eliminate now. Any drug can cause hepatic damage, but some are famous for affecting the liver:
Doxycycline occasionally causes increased ALT and even icterus. Although this is not a commonly recognized problem, we use so much doxycycline for suspected rickettsial diseases that it is very important to recognize the possibility. I have seen a few dogs that appeared to have substantial hepatic side effects (including icterus) from doxycycline administration.
Sulfa drugs are famous for causing severe hepatic disease (as well as bone marrow, cutaneous, joint, ocular and renal problems). Furthermore, the hepatic disease caused by sulfa drugs may not occur for 1–2 weeks after starting the drug, even if the patient has not received the drug for over a week. The hepatic lesions caused by sulfa drugs can look a lot like idiopathic chronic hepatitis. Doberman pincers and Rottweilers appear to be especially sensitive to sulfa drugs.
Carprofen (i.e., Rimadyl) causes hepatotoxicity in dogs, especially Labrador retrievers. The histologic changes seen in carprofen hepatotoxicity can resemble chronic hepatitis, so be sure that you have an adequate history. Also, be aware that hepatotoxicity may not be seen until 1–2 weeks after starting a drug; in fact, the patient may have stopped taking the medication several days before clinical signs of toxicity occur.
Anticonvulsants (i.e., phenobarbital and primidone) are famous for causing severe hepatic disease, eventually resulting in cirrhosis. This is why it is so important to perform therapeutic blood monitoring and measure the serum phenobarbital levels in patients receiving these drugs.
Chronic Hepatitis in Dogs
Chronic hepatitis is probably one of the main reasons it is a good idea to biopsy dogs' livers. It is a reasonably common disease, and a lot can often be done for the dog if you diagnose it before the hepatitis causes cirrhosis. Chronic hepatitis can be found in almost any breed of dog. There are several clinical presentations of this disease. First, one may see a chronically ill dog with high ALT and SAP. Second, one may be presented with a dog that was normal until it was stressed (e.g., underwent surgery or anesthesia). Third, one may see a dog that was normal until a few days ago but that now suddenly presents with signs of hepatic failure and is found to have an absolutely end stage cirrhotic liver (see discussion under cirrhosis) even though the clinical signs have only been present for 1–3 days. Finally, one may see a clinically normal dog that has an increased ALT that was fortuitously found during routine health screening or during a preanesthetic work up for a dental. Chronic hepatitis is more common than many people realize and is one reason why it is better to biopsy clinically normal dogs with persistent increases in ALT rather than wait until clinical signs occur.
Treatment of chronic hepatitis usually centers around a) removing the cause, if possible, b) administration of supportive therapy (i.e., ursodeoxycholic acid and antioxidants), and sometimes c) administration of anti-inflammatory therapy (i.e., steroids, azathioprine).
Two causes of chronic hepatitis that you might be able to remove are drugs and copper. Dalmatians, Labrador retrievers and Skye terriers have recently been reported to have a copper-associated hepatic disease in which accumulation of copper by the liver may be the cause of the clinical disease. Recently, there is increased concern that many dog foods have increased amounts copper that is more bioavailable than before, making it easier for some breeds (e.g., Labrador hepatitis. Biopsy with special stains or preferably quantitated copper analysis performed on frozen hepatic tissue is required for diagnosis. Copper is a bit confusing in that it can be the cause of chronic hepatitis, it can be secondary to chronic hepatitis but not causing a clinical problem, and we think that it can sometimes be secondary to chronic hepatitis and yet be severe enough to cause disease in and of itself. There has been one report that seemed to show that removing copper from the liver of dogs with chronic hepatitis in which the copper accumulation clearly appeared to be secondary to the hepatic disease was clinically beneficial to the dogs. You can measure copper levels in biopsies, or you can do special stains on hepatic biopsies. If the decision is made to remove copper, then one may elect oral zinc therapy before meals or copper chelation with d-Penicillamine. Feeding a copper-restricted diet is reasonable; but, feeding a copper restricted diet by itself often will not lower hepatic copper concentrations sufficiently. One exception to this may be the Labrador retriever. Chelator therapy or zinc therapy must also be used. D-penicillamine (10–15 mg/kg BID) is the drug typically used to lower hepatic copper concentrations. This drug occasionally causes vomiting, and administering it with food seems to lessen that problem. If the dog is clearly being intoxicated by very large concentrations of hepatic copper, chelators should be used. Zinc can be used to prevent copper accumulation, but it can also act as an antifibrotic agent. Various forms can be given, but the idea is to administer approximately 100 mg of elemental zinc daily for 3–6 months and then decrease it to about 50 mg daily. Zinc should be administered on an empty stomach, and generally should not be given with copper chelators. Be aware that zinc administration can rarely cause hemolytic anemia, and periodic blood zinc measurements are not a bad idea in patients receiving zinc therapy.
Dogs with chronic hepatitis not due to copper accumulation or drugs often need anti-inflammatories, and this usually includes glucocorticoids. However, it seems important to use the lowest effective dose of the corticosteroid. When corticosteroids are used for this disorder, they should typically be used at an anti-inflammatory dose (1 mg prednisolone/kg/day) and then tapered quickly. The steroid treatment should be for relatively short periods of time (i.e., until a week or two after clinical signs substantially diminish or disappear). Severely affected patients and patients that require excessive amounts of corticosteroids may benefit from azathioprine or cyclosporine therapy.
S-adenosyl-L-methionine (20 mg/kg SID) is a nutraceutical that appears to have benefit in some patients with hepatic disease. It increases hepatic glutathione concentrations as well as enabling a variety of important, intermediary metabolism reactions. Milk thistle (silymarin) (4–8 mg/kg/day OR 50–250 mg/day) is an herbal treatment that has proven efficacy in some diseases (e.g., Amanita mushroom poisoning).
Ursodeoxycholic acid (15 mg/kg/day) is beneficial because of its ability to displace more toxic hydrophobic bile acids from the hepatocyte membrane. Like the antioxidants, it generally should not be used as sole supportive therapy. It seems to work best if combined with antioxidants.
Cirrhosis
Cirrhosis is an end-stage hepatic disease that may be caused by various problems, especially chronic hepatitis. In particular, Cocker spaniels seem to have a distinct genetic predisposition to having cirrhosis at inordinately young ages (i.e., < 5 years of age). This may be due to an inherited problem in which they accumulate alpha-1 protease inhibitor in their hepatocytes, which eventually results in cellular death. In general, these dogs are clinically normal until they have completely exhausted all of their hepatic compensatory mechanisms. This means that there is usually little or nothing that can be done when they start showing clinical signs. Unfortunately, many of these dogs have normal serum ALT and SAP activities when they are approaching end stage. Serum albumin and BUN are often decreased, and serum bile acids, if measured, are typically markedly increased (e.g., > 90 µmol/L). However, serum bile acids are not as sensitive or specific as desired. If blood ammonia is increased, that is very specific for hepatic insufficiency, but we are not sure how sensitive it is. Chronic hepatitis may cause the identical scenario in other breeds (especially but in no way limited to the Doberman pincher). There may be ascites due to portal hypertension and salt accumulation in cirrhotic animals. In such animals, there is usually acquired hepatic portal shunting with many tortuous shunts seen in the abdomen, especially around the kidneys. Hypoalbuminemia can make the ascites more likely and more severe if it occurs.
References
1. Bexfield NH, Andres-Abdo C, Scase TJ, et al. Chronic hepatitis in the English springer spaniel: clinical presentation, histological description and outcome. Vet Rec. 2011;169:415–U53.
2. Bexfield NH, Buxton RJ, Vicek TJ, et al. Breed, age and gender distribution of dogs with chronic hepatitis in the United Kingdom. Vet J. 2012;193:124–128.
3. Favier RP, Poldervaart JH, van den Ingh TS, et al. A retrospective study of oral prednisolone treatment in canine chronic hepatitis. Vet Quart. 2013;33:113–120.
4. Hirose N, Uchida K, Kanemoto H, et al. A retrospective histopathological survey on canine and feline liver diseases at the University of Tokyo between 2006 and 2012. J Vet Med Sci. 2014;76:1015–1020.
5. Johnson SE. Parenchymal disorders. In: Washabau RJ, Day MJ, eds. Canine and Feline Gastroenterology. St. Louis, MO: Elsevier; 2013:879–896.
6. Johnston AN, Center SA, McDonough SP, et al. Hepatic copper concentrations in Labrador Retrievers with and without chronic hepatitis: 72 cases (1980–2010). J Am Vet Assoc. 2013;242:372–380.