the_sundog (![[info]](http://l-stat.livejournal.com/img/userinfo.gif){kind=small} the_sundog) wrote,@ 2007-10-05 14:56:00 |
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an article on hepatitis, for my own reference
Volume 18, Issue 4, Pages 239-244 (November 2003)
Current concepts in the treatment of canine chronic hepatitis
Adam Honeckman, DVM, Diplomate ACVIM (Internal Medicine)Corresponding Author Informationa
Abstract
Chronic hepatitis is a common disorder in dogs seen by general practitioners. Several new drugs have been marketed for treating this disease. Unfortunately, there are few controlled studies that examine the efficacy of these medications for the treatment of canine chronic hepatitis. A rational therapeutic approach can be implemented based on histopathologic findings of a liver biopsy. A liver biopsy is essential for establishing a definitive diagnosis and guiding the optimal therapy. The biopsy allows characterizing the inflammatory process, quantitating hepatic copper concentrations, and determining if fibrosis is present. Copper associated hepatopathy is treated with zinc and copper chelators. Idiopathic chronic hepatitis is thought to be immune mediated. The treatment of idiopathic chronic hepatitis consists of controlling inflammation (prednisone, azathioprine), reversing fibrosis (colchicine), and protecting against oxidant damage (vitamin E, ursodeoxycholic acid, S-adenosylmethionine). The prognosis for chronic hepatitis is quite variable. Dogs with end-stage disease have a poor prognosis, while dogs diagnosed earlier can have a mean survival of years. Early diagnosis and intervention are key to the successful treatment of dogs with chronic hepatitis.
Article Outline
Canine chronic hepatitis is commonly seen by general practitioners. The majority of cases are seen in middle-aged dogs, with females being overrepresented. Breeds predisposed to chronic hepatitis include Doberman pinschers, cocker spaniels, Labrador retrievers, and standard poodles.1, 2, 3
Clinical signs may include polyuria, polydipsia, weight loss, anorexia, vomiting, diarrhea, icterus, ascites, coagulopathies, or hepatic encephalopathy. Other animals may be asymptomatic and found to have abnormal liver enzyme increases on routine blood screening that is followed by a liver biopsy for diagnosis. Increased serum liver enzymes are found in almost all dogs with chronic hepatitis. Increased serum bilirubin, hypoalbuminemia, and increased serum bile acids are also common.1, 2 It is noteworthy that there is no need to run a serum bile acids on a dog that has hyperbilirubinemia.4
Over the last few years, several new medications have been advocated for use in treating this disease. Developing an appropriate treatment plan depends on establishing a definitive diagnosis, as well as understanding the etiology and pathophysiology of this disorder.
By definition, chronic hepatitis is an inflammatory process involving the liver that is chronic in duration. Thus, the diagnosis relies on the histopathology of a liver biopsy specimen. A liver biopsy can be used to characterize the inflammatory infiltrate, measure hepatic copper concentrations, and determine if fibrosis is present.
Liver biopsies can be obtained by ultrasound guidance, laparoscopy, or laparotomy. The advantages and disadvantages of each technique have been discussed elsewhere and are beyond the scope of this article.5, 6 But the importance of obtaining a liver biopsy to confirm the diagnosis and guide the optimum treatment of canine chronic hepatitis cannot be overemphasized.
The treatment of chronic hepatitis can be divided into 3 categories: (1) treatment of any identified underlying etiology, (2) supportive therapy to reverse liver pathology, and (3) symptomatic therapy of any complications of liver failure.3, 7
Treatment of underlying etiology
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Some possible etiologies of chronic hepatitis can be identified and specifically treated. Leptospirosis can be treated with appropriate antibiotic therapy. Hepatotoxic drugs, such as carprofen and phenobarbital, should be discontinued and replaced by nonhepatotoxic drugs if possible. Potassium bromide, for instance, should be used as an anticonvulsant instead of phenobarbital.2, 3, 8
Excessive accumulation of copper is another cause of chronic hepatitis. Hepatic copper concentrations can be subjectively evaluated with special histochemical stains, such as rhodanine or rubeanic acid. However, the quantitative analysis of hepatic biopsy tissue is preferred for diagnosing and monitoring copper associated hepatopathy.2, 3
Abnormal hepatic copper concentrations can occur as a primary defect of hepatic copper metabolism or secondary to decreased copper excretion from hepatic dysfunction. Typically, primary defects result in concentrations of more than 2,000 μg/g, while concentrations are typically 800 to 1500 μg/g if copper accumulation is secondary to decreased hepatic function.2, 3
Bedlington terriers are well known for their copper storage hepatopathy. They have an autosomal recessive defect in biliary copper excretion that results in excessive copper accumulation in hepatic lysosomes. Hepatic copper concentrations are usually 1,000 to 12,000 μg/g of tissue; normal is <400 μg/g. The hepatic copper concentrations tend to parallel the degree of hepatic damage. Treatment is usually recommended if hepatic copper levels exceed 750 μg/g.2 Other breeds that have been identified with excessive hepatic copper concentration and concurrent chronic hepatitis include the Doberman pinscher, West Highland white terrier, Skye terrier, and Dalmatian (Fig 1). 1, 2, 9
View full-size image.
Fig 1. Icteric mucous membranes in a Dalmatian with copper associated chronic hepatitis.
Dogs with copper storage hepatopathy can be treated with zinc and copper chelators. The dose of zinc is calculated based on the elemental zinc content, which varies for each salt. Zinc is available as zinc acetate (35% elemental zinc), zinc sulfate (23% elemental zinc), zinc methionine, and zinc gluconate (14.3% elemental zinc). Zinc acetate is generally preferred because its efficacy has been studied, and it is less likely to cause gastrointestinal side effects.10 In one study with Bedlington and West Highland White Terriers, the use of zinc acetate resulted in the improvement of hepatic copper concentrations and reduction in hepatitis.11
Zinc induces intestinal metallothionein, which binds to copper and decreases intestinal copper absorption. Zinc has some antifibrotic and antioxidant effects as well. The initial recommended dose is 5 to 10 mg/kg of elemental zinc orally, twice per day for the first 3 to 6 months, then the dose is decreased by 50%. Zinc should be given separate from meals to improve absorption. It also needs to be given separately from copper chelators because they also can bind to zinc. Side effects of zinc include anorexia, vomiting, and hemolytic anemia.2, 12, 13, 14 Plasma levels should be monitored every 2 to 3 months to avoid toxic levels. The recommended therapeutic level is 200 to 400 μg/dL. Zinc levels exceeding 1,000 μg/dL result in hemolysis.3
Copper chelators, such as D-penicillamine or trientene, are recommended if hepatic copper levels are higher than 2,000 μg/g of tissue. The recommended dose for either drug is 10 to 15 mg/kg orally, twice per day, given 1 to 2 hours before meals. D-penicillamine is used more commonly. However, trientene may be useful for those dogs that are vomiting from D-penicillamine therapy.2, 3, 15
Unfortunately, most cases of chronic hepatitis do not have an underlying etiology that can be readily diagnosed. Many cases of chronic hepatitis seem to be idiopathic. Therefore, treatment depends on addressing pathology findings on the liver biopsy, such as inflammation and fibrosis.
Supportive therapy to reverse liver pathology
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The treatment of idiopathic chronic hepatitis involves reversing inflammation (Table 1), slowing progression of fibrosis (Table 2), protecting against damage by hydrophobic bile acids, and protection against oxidant damage (Table 3). 1, 8, 16
TABLE 1.
Anti-inflammatory/Immunomodulating Drugs
Prednisone
Azathioprine
Ursodeoxycholic acid
SAMe
Metronidazole
TABLE 2.
Anti-Fibrotic Drugs
Colchicine
Prednisone
Azathioprine
Zinc
Penicillamine
Ursodeoxycholic acid
TABLE 3.
Antioxidants
Vitamin E
SAMe
Milk thistle
Zinc
Ursodeoxycholic acid
An immune-mediated mechanism for the inflammation in chronic hepatitis has been implicated in several studies. One study of 21 dogs with chronic hepatitis revealed that antiliver membrane protein antibodies were commonly detected.17 Mononuclear cells from the blood of dogs with chronic hepatitis also have a higher proliferative response to liver membrane protein antigen and pokeweed mitogen.18 Both of these studies suggest an immune-mediated process involved in chronic hepatitis. However, it could not be determined if this was primary or secondary.
The inflammation can be treated with a variety of medications. Prednisone or prednisolone at an initial dose of 1 to 2 mg/kg/d and then tapered to 0.5 mg/kg q 48 h is most often recommended. The dose is generally decreased by 50% every 3 to 4 weeks.2, 16 A retrospective study suggested that dogs with chronic hepatitis treated with steroids lived longer than those that were not.19 Because dogs were allowed to be treated with other drugs, this was not considered a controlled study. Despite the lack of controlled prospective trials, prednisone therapy seems rational given the inflammatory, and possible autoimmune, nature of the disease. Prednisone also has some antifibrotic effects.14 In animals with ascites, dexamethasone is preferred over prednisone because it lacks mineralocorticoid effects.8
Some clinicians will also use azathioprine at a dose of 0.5 to 2 mg/kg orally, q 24 h for 1 to 2 weeks, then taper to q 48 h in conjunction with prednisone therapy.3, 20 Azathioprine is used commonly in people with autoimmune hepatitis,21, 22 so its use in dogs seems reasonable if chronic hepatitis is also an immune-mediated disease. Azathioprine also has the benefit of having some antifibrotic effects.14 It must be used with caution in cases of chronic hepatitis for several reasons. First, azathioprine is converted to its active form, 6-mercaptopurine, in the liver.23 Second, it can occasionally cause an acute hepatopathy.2, 20 In addition, there are no controlled studies that show dogs treated with combination therapy of prednisone and azathioprine respond better than those treated with prednisone alone. If azathioprine is used, careful monitoring of the complete blood count (CBC) and serum chemistry panel should be performed.
Metronidazole, in addition to its usefulness as an antibiotic for anaerobic infections and hepatic encephalopathy, may also have beneficial immunosuppressive effects in dogs with chronic hepatitis. When using metronidazole in dogs with liver disease, a reduced dose of 7.5 mg/kg PO q 12 hrs is recommended.
Other immunosuppressive drugs that may be considered for dogs with chronic hepatitis include cyclosporine, methotrexate, and chlorambucil.8, 13 There are currently no data on the use of any of these immunosuppressive medications for canine hepatitis, so they cannot be recommended for routine use at this time.
Colchicine at a dose of 0.03 mg/kg PO q 24 hrs, has been recommended for fibrosis. Colchicine stimulates collagenase activity, and also decreases collagen synthesis and secretion by inhibiting microtubule assembly. Colchicine also has some anti-inflammatory effects by inhibiting leukocyte migration.1, 13 The most common side effects are vomiting and diarrhea, but bone marrow suppression has also been reported.3, 20 A case report has been published describing the use of colchicine in decreasing hepatic fibrosis in a dog.24 To the author’s knowledge, there are no controlled studies on the use of colchicine in dogs with chronic hepatitis at this time.
Theoretically, D-penicillamine would be useful as an antifibrotic by binding to copper and inhibiting lysyl oxidase, an enzyme important for the cross-linking of collagen. However, studies of its efficacy as an antifibrotic in humans and dogs have been disappointing.14
Ursodeoxycholic acid (Actigall, Watson Pharmaceuticals Inc., Corona, CA) is a hydrophilic bile acid with anti-inflammatory, immunomodulating, and choleretic properties. It displaces hydrophobic bile acids that can cause oxidative injury to hepatocytes. Ursodeoxycholic acid may have direct antioxidant effects by increasing glutathione and metallothionein.12, 13 Ursodeoxycholic acid may also decrease collagen formation.15, 20 It is useful in humans with primary biliary cirrhosis.25 The recommended dose for dogs is 10 to 15 mg/kg/d. In one case report, the use of ursodeoxycholic acid resulted in clinical and biochemical improvement over a 6-month period in a dog with chronic hepatitis.26 Future studies are needed to confirm its efficacy for treating chronic hepatitis in dogs. It appears to be well tolerated but is contraindicated in dogs with biliary obstruction.3, 7, 16
Zinc is not only useful for copper associated hepatopathy but may also be helpful in other forms of chronic hepatitis in dogs because of its antioxidant and antifibrotic effects.13, 14 The dose recommended for chronic hepatitis (not associated with copper storage disease) is 2 to 3 mg/kg of elemental zinc per day.12, 13
Vitamin E is an antioxidant that is recommended at a dose of 50 to 600 IU per day.3, 12 Oxidant injury to hepatic mitochondria has been reported in Bedlington terriers with copper storage hepatopathy.27 There is in vitro evidence suggesting that vitamin E may be useful in preventing oxidative damage to hepatocytes exposed to copper or hydrophobic bile acids.12, 13 In human studies, vitamin E was helpful in treating patients with chronic hepatitis B.28 Although there are no controlled studies of its use in canine chronic hepatitis, the use of vitamin E seems reasonable based on experimental studies. Because absorption of fat soluble vitamins may be reduced in cholestatic liver disease, a water soluble form (ie, Nutr-E-Sol, Advanced Nutritional Technologies, Dublin, CA or Liqui E, Twinlab, Hauppauge, NY) may be preferred.12, 16, 29
S-adenosylmethionine (SAMe) (Denosyl, Nutramax Laboratories Inc., Edgewood, MD) is a nutraceutical that has recently been marketed for use in dogs with liver problems. It has anti-inflammatory and antioxidant effects, as well as plays a role in cellular replication and protein synthesis.12, 13 It has been useful for the treatment of acetaminophen toxicity,30 but there are no controlled studies in its use in canine chronic hepatitis. The recommended dose is 20 mg/kg/d, and it is better absorbed if the animal is fasted.1 The Denosyl brand is generally preferred because the bioavailability of the over-the-counter products can vary.20
Silymarin, extracted from milk thistle, is an antioxidant that has also been recommended for chronic hepatitis.12, 29 Although silibinin (the main isomer in silmaryin) has been proven to be useful for treating Amanita mushroom toxicity in dogs and humans,31, 32 there are currently no controlled studies on its use in canine chronic hepatitis. Most studies of milk thistle in humans have shown little or no improvement in biochemical markers, histology of liver biopsies, or survival.33 The recommended dose in dogs is 50 to 250 mg/kg orally, twice per day.12, 13 Due to the lack of standardization of milk thistle preparations12, 13 and possible lack of efficacy, the author does not use milk thistle routinely for chronic hepatitis except in cases when clients specifically request it.
Dietary management may also be useful in dogs with chronic liver disease. A common misconception is that dogs with liver disease should be fed a protein restricted diet. This is only true in dogs with hepatic encephalopathy that are intolerant of dietary protein. Dogs with chronic liver disease should be fed a diet with highly digestible, high biologic value protein that is low in aromatic amino acids and methionine and high in branched chain amino acids and arginine. The diet should be moderate in fat and high in carbohydrates. Fiber may be beneficial in binding to bile acids and decreasing hepatic encephalopathy.2, 8, 34 A commercially available prescription diet, Hills l/d (Hill’s Pet Nutrition Inc., Topeka, KS), has recently been marketed for use in dogs with chronic liver disease.
Symptomatic therapy of any complications of liver failure
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Other symptomatic therapy may include control of hepatic encephalopathy, coagulopathy, fluid and electrolyte imbalances, ascites, GI ulceration, and infection and/or endotoxemia.2, 3, 8
Hepatic encephalopathy can be exacerbated by hypokalemia, dehydration, alkalosis, GI bleeding, and constipation. Treatment involves reducing ammonia production by decreasing dietary protein, controlling GI bleeding, and administering antibiotics effective against urease producing bacteria. Antibiotics most commonly used include amoxicillin 22 mg/kg PO q 12 hrs, neomycin 22 mg/kg PO q 8–12 hrs, or metronidazole 7.5 mg/kg PO q 12 hrs. Lowering the pH in the colon is also useful by inhibiting bacterial growth and converting ammonia to the nonabsorbable ammonium ion. Lactulose given at 0.25–0.5 mls/kg PO q 8–12 hrs, decreases colonic pH and provides an osmotic laxative effect. In cases of severe hepatic encephalopathy, lactulose can be given as an enema (diluted 1:3 with water).3, 8 Diluted povidone-iodine (Betadine, Purdue Frederick Co., Norwalk, CT) solution can also be used as an enema for treating severe hepatic encephalopathy if lactulose is not available.3, 15
Coagulopathies are common in animals with liver disease. Possible mechanisms include decreased clotting factor synthesis, decreased vitamin K absorption in cholestatic disease, and disseminated intravascular coagulation.4 Parenteral vitamin K (0.5 to 2 mg/kg SQ q 12 h for 2 to 3 doses) may be helpful in correcting coagulopathies.3, 34 If vitamin K is ineffective, then blood products, such as whole blood or plasma, may be necessary to stabilize the coagulopathy before performing invasive procedures, such as a liver biopsy.
Ascites can be treated with diuretics, such as spironolactone and/or furosemide. Furosemide is considered more potent but may cause hypokalemia and metabolic alkalosis, which can exacerbate hepatic encephalopathy. Spironolactone is usually preferred because it is potassium sparing and directly inhibits aldosterone, which is thought to play a role in the production of ascites in dogs with liver disease. The recommended dose of spironolactone is 1–2 mg/kg PO q 12 hrs. If this is ineffective, furosemide can be added at 1–2 mg/kg PO q 12–24 hrs.3, 8
GI ulcers are common in dogs with chronic liver disease. Melena is not usually evident in physical examination, so its absence does not exclude the presence of GI ulcers. GI ulcers should be suspected if there is any anorexia, vomiting, or anemia. GI ulcers may be treated with a variety of medications, such as H2 blockers, sucralfate, or omeprazole. Of the H2 blockers, famotidine (0.5–1 mg/kg PO q 12–24 hrs) is generally preferred because of the lack of cytochrome P450 enzyme inhibition. Cimetidine (5–10 mg/kg PO q 6–8 hrs) and, to a lesser extent, ranitidine (2–3.5 mg/kg PO q 8–12 hrs) suppress the cytochrome P450 enzyme. Omeprazole, a proton pump inhibitor, can be used at a dose of 0.7–2 mg/kg PO once daily. The recommended dose of sucralfate is 0.5–1 gram per dog PO q 8–12 hrs.3, 7, 8, 10, 20
Antibiotics may be useful in some dogs with hepatitis, especially if the inflammation is suppurative, rather than mononuclear, in nature.7 Antibiotics that are most commonly used include amoxicillin, amoxicillin-clavulanic acid (Clavamox, Pfizer Inc, New York, NY) fluoroquinolones, and metronidazole (at a reduced dose of 7.5 mg/kg orally, twice per day). Ideally, the choice of antibiotic should be based on culture and sensitivity results of bile or liver tissue. Antibiotics that should generally be avoided in dogs with liver disease include sulfonamides, erythromycin, lincomycin, chloramphenicol, and tetracycline.8 Dogs with chronic liver disease can also be predisposed to endotoxemia because of decreased hepatic reticuloendothelial system function and GI ulceration.8 Bacteria from the GI tract may play a role in ascending cholangiohepatitis or hepatic encephalopathy.
Monitoring
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Monitoring a patient with chronic hepatitis involves the following (1) rechecking laboratory parameters, (2) assessing drug efficacy, (3) watching for side effects from drug therapy, and (4) measuring drug levels when possible.
Monitoring laboratory parameters can be somewhat misleading in dogs being treated with chronic hepatitis. Glucocorticoids can increase liver enzymes, especially alkaline phosphatase, so monitoring serum liver enzymes may not be accurate. However, an improvement in hyperbilirubinemia or hypoalbuminemia would be significant. Clotting times can be rechecked after vitamin K administration or transfusion therapy to see if they have normalized.
Because of the difficulties in interpreting serum liver enzymes, drug efficacy can be better assessed by documenting the reversal or slowing the progression of liver pathology. A liver biopsy can be rechecked after 3 to 6 months of therapy to document regression of inflammation, resolution of fibrosis, and decrease in hepatic copper concentrations.3 Amelioration of clinical signs, such as decrease in ascites or resolution of hepatic encephalopathy, can also be used to document drug efficacy.
Besides monitoring for drug efficacy, it is also important for clinicians to monitor for drug side effects. Myelosuppression has been seen with azathioprine and rarely with colchicine therapy.3, 20 A CBC should be monitored every 1 to 2 weeks initially, then every 1 to 2 months. Azathioprine has also been associated with acute pancreatitis and acute hepatopathy,20 so serum chemistries should be monitored periodically as well. GI side effects, such as anorexia, vomiting, or diarrhea, can be seen when administering azathioprine, colchicine, D-penicillamine, or zinc. Side effects are rare with ursodeoxycholic acid, vitamin E, SAMe, and milk thistle.1, 10, 12, 15, 29
Drug toxicity can be minimized with some medications if serum drug concentrations can be measured. Only a few of the drugs commonly used in chronic hepatitis can have therapeutic levels monitored. Zinc levels should be measured every 2 to 3 months. The goal therapeutic range is 200 to 400 μg/dL. Zinc levels >1,000 μg/dL can cause hemolytic anemia.3 If potassium bromide is used to control seizures, serum levels can be monitored. The target serum concentration is 2 to 3 mg/mL when used as monotherapy.35
Prognosis
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The prognosis for dogs with chronic hepatitis is quite variable. Dogs with hypoalbuminemia, hypoglycemia, prolonged clotting times, and bridging fibrosis tend to have shorter survival times.19 In one study, most dogs with cirrhosis died within 1 week of diagnosis.36 The prognosis for cocker spaniels with chronic hepatitis is considered poor, with many dogs dying within 1 month.3 For other types of chronic hepatitis, median survival ranged from 21.1 to 36.4 months.36
Because dogs with end-stage disease have a poor prognosis, early diagnosis and intervention are key to the successful treatment of dogs with chronic hepatitis. Breeds predisposed to chronic hepatitis should have blood tests (CBC and serum chemistry panel) performed periodically. Increased liver enzymes should be followed by bile acid determination and liver biopsy when appropriate.
DRUG FORMULARY
Drug Dose Use/Comments
Penicillamine Capsules 125 mg, 250 mg Tablets 250 mg 10–15 mg/kg PO BID Given separately from meals and zinc Copper associated hepatopathy, may cause vomiting
Trientene Capsules 250 mg 10–15 mg/kg PO BID Given separately from meals and zinc Copper associated hepatopathy, better tolerated than penicillamine
Zinc Copper hepatopathy 5–10 mg elemental Zn/kg divided BID × 3–6 months, then decrease by 50% Chronic hepatitis 2–3 mg/kg/day elemental zinc Antifibrotic Antioxidant Monitor Zn levels Goal 200–400 mcg/dl, May cause anorexia, vomiting, hemolysis, Give separately from meals and copper chelators
Prednisone Tablets 5 mg, 20 mg 1–2 mg/kg/day, then decrease 50% q 3–4 weeks Mononuclear inflammation, antifibrotic
Azathioprine Tablets 50 mg 0.5–2 mg/kg SID 1–2 wks, then EOD Immunosuppressive Antifibrotic May cause myelosuppression, pancreatitis, hepatopathy
Colchicine Tablets 0.5 mg, 0.6 mg 0.03 mg/kg PO SID Anti-fibrotic
Ursodeoxycholic acid Tablets 250 mg Capsules 300 mg 10–15 mg/kg/day Contraindicated in biliary obstruction, anti-inflammatory, antioxidant
SAMe Denosyl tablets 90 mg, 225 mg 20 mg/kg/day fasted Anit-inflammatory Anti-oxidant
Spironolactone Tablets 25 mg, 50 mg 100 mg 1–2 mg/kg PO BID Diuretic for ascites
Famotidine Tablets 10 mg, 20 mg, 40 mg 0.5–1 mg/kg PO SID-BID GI ulcers
Omeprazole Capsules 10 mg, 20 mg, 40 mg 0.7–2 mg/kg PO SID GI ulcers
Potassium Bromide 70–80 mg/kg/day as single agent Anticonvulsant Therapeutic level 2–3 mg/ml
References
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1. 1Richter K. Common Canine Hepatopathies. In: 2002 Proceedings, 20th Annual American College of Veterinary Internal Medicine Forum. Dallas, TX: American College of Veterinary Internal Medicine; 2002;p. 26–28.
2. 2Twedt DC. Chronic hepatitis-Recent advances. In: 2001 Proceedings, 19th Annual American College of Veterinary Internal Medicine. Denver, CO: American College of Veterinary Internal Medicine; 2001;p. 607–609.
3. 3Johnson SE. Chronic hepatic disorders. In: Ettinger SJ, Feldman EC editor. ed 5. Textbook of Veterinary Internal Medicine. vol 2:Philadelphia, PA: Saunders; 2000;p. 1298–1325.
4. 4Leveille-Webster CR. Laboratory diagnosis of hepatobiliary disease. In: Ettinger SJ, Feldman EC editor. ed 5. Textbook of Veterinary Internal Medicine. vol 2:Philadelphia, PA: Saunders; 2000;p. 1277–1293.
5. 5Day DG. Indications and techniques for liver biopsy. In: Ettinger SJ, Feldman EC editor. ed 5. Textbook of Veterinary Internal Medicine. vol 2:Philadelphia, PA: Saunders; 2000;p. 1294–1298.
6. 6Richter K. Liver biopsy methods-Laparoscopy vs. ultrasound vs. FNA. In: 2002 Proceedings, 20th Annual American College of Veterinary Internal Medicine Forum. Dallas, TX: American College of Veterinary Internal Medicine; 2002;p. 23–25.
7. 7Webster CR. Medical management of canine inflammatory hepatic disease. In: 2002 Proceedings, North American Veterinary Conference. Orlando, FL: Eastern States Veterinary Association; 2002;p. 342–344.
8. 8Miller R, Bartges J. Medical and nutritional management of liver disease. In: 2001 Proceedings, 19th Annual American College of Veterinary Internal Medicine Forum. Denver, CO: American College of Veterinary Internal Medicine; 2001;p. 654–656.
9. 9Webb CB, Twedt DC, Meyer DJ. Copper-associated liver disease in Dalmatians (a review of 10 dogs (1998–2001)). J Vet Intern Med. 2002;16(6):665–668. MEDLINE | CrossRef
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11. 11Brewer GJ, Dick RD, Schall W, et al.. Use of zinc acetate to treat copper toxicosis in dogs. J Am Vet Med Assoc. 1992;201:564–568. MEDLINE
12. 12Twedt DC. Antioxidants and liver disease. In: 2001 Proceedings, 19th Annual American College of Veterinary Internal Medicine Forum. Denver, CO: American College of Veterinary Internal Medicine; 2001;p. 13–15.
13. 13Twedt DC. A review of traditional and not so traditional therapies for liver disease. In: 2001 Proceedings, 19th Annual American College of Veterinary Internal Medicine Forum. Denver, CO: American College of Veterinary Internal Medicine; 2001;p. 610–612.
14. 14Leveille CR, Arias IM. Pathophysiology and pharmacologic modulation of hepatic fibrosis. J Vet Intern Med. 1993;7:73–84. MEDLINE
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16. 16Harkin KR. Canine liver disease II-The chronic liver diseases. In: 2002 Proceedings, North American Veterinary Conference. Orlando, FL: Eastern States Veterinary Association; 2003;p. 332–335.
17. 17Weiss DJ, Armstrong PJ, Mruthyunjaya A. Anti-liver membrane protein antibodies in dogs with chronic hepatitis. J Vet Intern Med. 1995;9:267–271. MEDLINE
18. 18Poitout F, Weiss DJ, Armstrong PJ. Cell-mediated immune response to liver membrane protein in canine chronic hepatitis. Vet Immunol Immunopathol. 1997;57:167–178.
19. 19Strombeck DR, Miller LM, Harrold D. Effects of corticosteroid treatment on survival time in dogs with chronic hepatitis 151 cases (1977–1985). Am Vet Med Assoc. 1988;193:1109–1113.
20. 20Hitt ME. Chronic active hepatitis in dogs-Experiences with aggressive treatment efforts. In: 2001 Proceedings, 19th Annual American College of Veterinary Internal Medicine Forum. Denver, CO: American College of Veterinary Internal Medicine; 2001;p. 775–777.
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23. 23Couto CG. Use and misuse of immunosuppressants. In: 2002 Proceedings, 20th Annual American College of Veterinary Internal Medicine Forum. Dallas, TX: American College of Veterinary Internal Medicine; 2002;p. 599–600.
24. 24Boer HH, Nelson RW, Long GG. Colchicine therapy for hepatic fibrosis in a dog. Am Vet Med Assoc. 1984;185:303–305.
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Current concepts in the treatment of canine chronic hepatitis
Adam Honeckman, DVM, Diplomate ACVIM (Internal Medicine)Corresponding Author Informationa
Abstract
Chronic hepatitis is a common disorder in dogs seen by general practitioners. Several new drugs have been marketed for treating this disease. Unfortunately, there are few controlled studies that examine the efficacy of these medications for the treatment of canine chronic hepatitis. A rational therapeutic approach can be implemented based on histopathologic findings of a liver biopsy. A liver biopsy is essential for establishing a definitive diagnosis and guiding the optimal therapy. The biopsy allows characterizing the inflammatory process, quantitating hepatic copper concentrations, and determining if fibrosis is present. Copper associated hepatopathy is treated with zinc and copper chelators. Idiopathic chronic hepatitis is thought to be immune mediated. The treatment of idiopathic chronic hepatitis consists of controlling inflammation (prednisone, azathioprine), reversing fibrosis (colchicine), and protecting against oxidant damage (vitamin E, ursodeoxycholic acid, S-adenosylmethionine). The prognosis for chronic hepatitis is quite variable. Dogs with end-stage disease have a poor prognosis, while dogs diagnosed earlier can have a mean survival of years. Early diagnosis and intervention are key to the successful treatment of dogs with chronic hepatitis.
Article Outline
Canine chronic hepatitis is commonly seen by general practitioners. The majority of cases are seen in middle-aged dogs, with females being overrepresented. Breeds predisposed to chronic hepatitis include Doberman pinschers, cocker spaniels, Labrador retrievers, and standard poodles.1, 2, 3
Clinical signs may include polyuria, polydipsia, weight loss, anorexia, vomiting, diarrhea, icterus, ascites, coagulopathies, or hepatic encephalopathy. Other animals may be asymptomatic and found to have abnormal liver enzyme increases on routine blood screening that is followed by a liver biopsy for diagnosis. Increased serum liver enzymes are found in almost all dogs with chronic hepatitis. Increased serum bilirubin, hypoalbuminemia, and increased serum bile acids are also common.1, 2 It is noteworthy that there is no need to run a serum bile acids on a dog that has hyperbilirubinemia.4
Over the last few years, several new medications have been advocated for use in treating this disease. Developing an appropriate treatment plan depends on establishing a definitive diagnosis, as well as understanding the etiology and pathophysiology of this disorder.
By definition, chronic hepatitis is an inflammatory process involving the liver that is chronic in duration. Thus, the diagnosis relies on the histopathology of a liver biopsy specimen. A liver biopsy can be used to characterize the inflammatory infiltrate, measure hepatic copper concentrations, and determine if fibrosis is present.
Liver biopsies can be obtained by ultrasound guidance, laparoscopy, or laparotomy. The advantages and disadvantages of each technique have been discussed elsewhere and are beyond the scope of this article.5, 6 But the importance of obtaining a liver biopsy to confirm the diagnosis and guide the optimum treatment of canine chronic hepatitis cannot be overemphasized.
The treatment of chronic hepatitis can be divided into 3 categories: (1) treatment of any identified underlying etiology, (2) supportive therapy to reverse liver pathology, and (3) symptomatic therapy of any complications of liver failure.3, 7
Treatment of underlying etiology
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Some possible etiologies of chronic hepatitis can be identified and specifically treated. Leptospirosis can be treated with appropriate antibiotic therapy. Hepatotoxic drugs, such as carprofen and phenobarbital, should be discontinued and replaced by nonhepatotoxic drugs if possible. Potassium bromide, for instance, should be used as an anticonvulsant instead of phenobarbital.2, 3, 8
Excessive accumulation of copper is another cause of chronic hepatitis. Hepatic copper concentrations can be subjectively evaluated with special histochemical stains, such as rhodanine or rubeanic acid. However, the quantitative analysis of hepatic biopsy tissue is preferred for diagnosing and monitoring copper associated hepatopathy.2, 3
Abnormal hepatic copper concentrations can occur as a primary defect of hepatic copper metabolism or secondary to decreased copper excretion from hepatic dysfunction. Typically, primary defects result in concentrations of more than 2,000 μg/g, while concentrations are typically 800 to 1500 μg/g if copper accumulation is secondary to decreased hepatic function.2, 3
Bedlington terriers are well known for their copper storage hepatopathy. They have an autosomal recessive defect in biliary copper excretion that results in excessive copper accumulation in hepatic lysosomes. Hepatic copper concentrations are usually 1,000 to 12,000 μg/g of tissue; normal is <400 μg/g. The hepatic copper concentrations tend to parallel the degree of hepatic damage. Treatment is usually recommended if hepatic copper levels exceed 750 μg/g.2 Other breeds that have been identified with excessive hepatic copper concentration and concurrent chronic hepatitis include the Doberman pinscher, West Highland white terrier, Skye terrier, and Dalmatian (Fig 1). 1, 2, 9
View full-size image.
Fig 1. Icteric mucous membranes in a Dalmatian with copper associated chronic hepatitis.
Dogs with copper storage hepatopathy can be treated with zinc and copper chelators. The dose of zinc is calculated based on the elemental zinc content, which varies for each salt. Zinc is available as zinc acetate (35% elemental zinc), zinc sulfate (23% elemental zinc), zinc methionine, and zinc gluconate (14.3% elemental zinc). Zinc acetate is generally preferred because its efficacy has been studied, and it is less likely to cause gastrointestinal side effects.10 In one study with Bedlington and West Highland White Terriers, the use of zinc acetate resulted in the improvement of hepatic copper concentrations and reduction in hepatitis.11
Zinc induces intestinal metallothionein, which binds to copper and decreases intestinal copper absorption. Zinc has some antifibrotic and antioxidant effects as well. The initial recommended dose is 5 to 10 mg/kg of elemental zinc orally, twice per day for the first 3 to 6 months, then the dose is decreased by 50%. Zinc should be given separate from meals to improve absorption. It also needs to be given separately from copper chelators because they also can bind to zinc. Side effects of zinc include anorexia, vomiting, and hemolytic anemia.2, 12, 13, 14 Plasma levels should be monitored every 2 to 3 months to avoid toxic levels. The recommended therapeutic level is 200 to 400 μg/dL. Zinc levels exceeding 1,000 μg/dL result in hemolysis.3
Copper chelators, such as D-penicillamine or trientene, are recommended if hepatic copper levels are higher than 2,000 μg/g of tissue. The recommended dose for either drug is 10 to 15 mg/kg orally, twice per day, given 1 to 2 hours before meals. D-penicillamine is used more commonly. However, trientene may be useful for those dogs that are vomiting from D-penicillamine therapy.2, 3, 15
Unfortunately, most cases of chronic hepatitis do not have an underlying etiology that can be readily diagnosed. Many cases of chronic hepatitis seem to be idiopathic. Therefore, treatment depends on addressing pathology findings on the liver biopsy, such as inflammation and fibrosis.
Supportive therapy to reverse liver pathology
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The treatment of idiopathic chronic hepatitis involves reversing inflammation (Table 1), slowing progression of fibrosis (Table 2), protecting against damage by hydrophobic bile acids, and protection against oxidant damage (Table 3). 1, 8, 16
TABLE 1.
Anti-inflammatory/Immunomodulating Drugs
Prednisone
Azathioprine
Ursodeoxycholic acid
SAMe
Metronidazole
TABLE 2.
Anti-Fibrotic Drugs
Colchicine
Prednisone
Azathioprine
Zinc
Penicillamine
Ursodeoxycholic acid
TABLE 3.
Antioxidants
Vitamin E
SAMe
Milk thistle
Zinc
Ursodeoxycholic acid
An immune-mediated mechanism for the inflammation in chronic hepatitis has been implicated in several studies. One study of 21 dogs with chronic hepatitis revealed that antiliver membrane protein antibodies were commonly detected.17 Mononuclear cells from the blood of dogs with chronic hepatitis also have a higher proliferative response to liver membrane protein antigen and pokeweed mitogen.18 Both of these studies suggest an immune-mediated process involved in chronic hepatitis. However, it could not be determined if this was primary or secondary.
The inflammation can be treated with a variety of medications. Prednisone or prednisolone at an initial dose of 1 to 2 mg/kg/d and then tapered to 0.5 mg/kg q 48 h is most often recommended. The dose is generally decreased by 50% every 3 to 4 weeks.2, 16 A retrospective study suggested that dogs with chronic hepatitis treated with steroids lived longer than those that were not.19 Because dogs were allowed to be treated with other drugs, this was not considered a controlled study. Despite the lack of controlled prospective trials, prednisone therapy seems rational given the inflammatory, and possible autoimmune, nature of the disease. Prednisone also has some antifibrotic effects.14 In animals with ascites, dexamethasone is preferred over prednisone because it lacks mineralocorticoid effects.8
Some clinicians will also use azathioprine at a dose of 0.5 to 2 mg/kg orally, q 24 h for 1 to 2 weeks, then taper to q 48 h in conjunction with prednisone therapy.3, 20 Azathioprine is used commonly in people with autoimmune hepatitis,21, 22 so its use in dogs seems reasonable if chronic hepatitis is also an immune-mediated disease. Azathioprine also has the benefit of having some antifibrotic effects.14 It must be used with caution in cases of chronic hepatitis for several reasons. First, azathioprine is converted to its active form, 6-mercaptopurine, in the liver.23 Second, it can occasionally cause an acute hepatopathy.2, 20 In addition, there are no controlled studies that show dogs treated with combination therapy of prednisone and azathioprine respond better than those treated with prednisone alone. If azathioprine is used, careful monitoring of the complete blood count (CBC) and serum chemistry panel should be performed.
Metronidazole, in addition to its usefulness as an antibiotic for anaerobic infections and hepatic encephalopathy, may also have beneficial immunosuppressive effects in dogs with chronic hepatitis. When using metronidazole in dogs with liver disease, a reduced dose of 7.5 mg/kg PO q 12 hrs is recommended.
Other immunosuppressive drugs that may be considered for dogs with chronic hepatitis include cyclosporine, methotrexate, and chlorambucil.8, 13 There are currently no data on the use of any of these immunosuppressive medications for canine hepatitis, so they cannot be recommended for routine use at this time.
Colchicine at a dose of 0.03 mg/kg PO q 24 hrs, has been recommended for fibrosis. Colchicine stimulates collagenase activity, and also decreases collagen synthesis and secretion by inhibiting microtubule assembly. Colchicine also has some anti-inflammatory effects by inhibiting leukocyte migration.1, 13 The most common side effects are vomiting and diarrhea, but bone marrow suppression has also been reported.3, 20 A case report has been published describing the use of colchicine in decreasing hepatic fibrosis in a dog.24 To the author’s knowledge, there are no controlled studies on the use of colchicine in dogs with chronic hepatitis at this time.
Theoretically, D-penicillamine would be useful as an antifibrotic by binding to copper and inhibiting lysyl oxidase, an enzyme important for the cross-linking of collagen. However, studies of its efficacy as an antifibrotic in humans and dogs have been disappointing.14
Ursodeoxycholic acid (Actigall, Watson Pharmaceuticals Inc., Corona, CA) is a hydrophilic bile acid with anti-inflammatory, immunomodulating, and choleretic properties. It displaces hydrophobic bile acids that can cause oxidative injury to hepatocytes. Ursodeoxycholic acid may have direct antioxidant effects by increasing glutathione and metallothionein.12, 13 Ursodeoxycholic acid may also decrease collagen formation.15, 20 It is useful in humans with primary biliary cirrhosis.25 The recommended dose for dogs is 10 to 15 mg/kg/d. In one case report, the use of ursodeoxycholic acid resulted in clinical and biochemical improvement over a 6-month period in a dog with chronic hepatitis.26 Future studies are needed to confirm its efficacy for treating chronic hepatitis in dogs. It appears to be well tolerated but is contraindicated in dogs with biliary obstruction.3, 7, 16
Zinc is not only useful for copper associated hepatopathy but may also be helpful in other forms of chronic hepatitis in dogs because of its antioxidant and antifibrotic effects.13, 14 The dose recommended for chronic hepatitis (not associated with copper storage disease) is 2 to 3 mg/kg of elemental zinc per day.12, 13
Vitamin E is an antioxidant that is recommended at a dose of 50 to 600 IU per day.3, 12 Oxidant injury to hepatic mitochondria has been reported in Bedlington terriers with copper storage hepatopathy.27 There is in vitro evidence suggesting that vitamin E may be useful in preventing oxidative damage to hepatocytes exposed to copper or hydrophobic bile acids.12, 13 In human studies, vitamin E was helpful in treating patients with chronic hepatitis B.28 Although there are no controlled studies of its use in canine chronic hepatitis, the use of vitamin E seems reasonable based on experimental studies. Because absorption of fat soluble vitamins may be reduced in cholestatic liver disease, a water soluble form (ie, Nutr-E-Sol, Advanced Nutritional Technologies, Dublin, CA or Liqui E, Twinlab, Hauppauge, NY) may be preferred.12, 16, 29
S-adenosylmethionine (SAMe) (Denosyl, Nutramax Laboratories Inc., Edgewood, MD) is a nutraceutical that has recently been marketed for use in dogs with liver problems. It has anti-inflammatory and antioxidant effects, as well as plays a role in cellular replication and protein synthesis.12, 13 It has been useful for the treatment of acetaminophen toxicity,30 but there are no controlled studies in its use in canine chronic hepatitis. The recommended dose is 20 mg/kg/d, and it is better absorbed if the animal is fasted.1 The Denosyl brand is generally preferred because the bioavailability of the over-the-counter products can vary.20
Silymarin, extracted from milk thistle, is an antioxidant that has also been recommended for chronic hepatitis.12, 29 Although silibinin (the main isomer in silmaryin) has been proven to be useful for treating Amanita mushroom toxicity in dogs and humans,31, 32 there are currently no controlled studies on its use in canine chronic hepatitis. Most studies of milk thistle in humans have shown little or no improvement in biochemical markers, histology of liver biopsies, or survival.33 The recommended dose in dogs is 50 to 250 mg/kg orally, twice per day.12, 13 Due to the lack of standardization of milk thistle preparations12, 13 and possible lack of efficacy, the author does not use milk thistle routinely for chronic hepatitis except in cases when clients specifically request it.
Dietary management may also be useful in dogs with chronic liver disease. A common misconception is that dogs with liver disease should be fed a protein restricted diet. This is only true in dogs with hepatic encephalopathy that are intolerant of dietary protein. Dogs with chronic liver disease should be fed a diet with highly digestible, high biologic value protein that is low in aromatic amino acids and methionine and high in branched chain amino acids and arginine. The diet should be moderate in fat and high in carbohydrates. Fiber may be beneficial in binding to bile acids and decreasing hepatic encephalopathy.2, 8, 34 A commercially available prescription diet, Hills l/d (Hill’s Pet Nutrition Inc., Topeka, KS), has recently been marketed for use in dogs with chronic liver disease.
Symptomatic therapy of any complications of liver failure
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Other symptomatic therapy may include control of hepatic encephalopathy, coagulopathy, fluid and electrolyte imbalances, ascites, GI ulceration, and infection and/or endotoxemia.2, 3, 8
Hepatic encephalopathy can be exacerbated by hypokalemia, dehydration, alkalosis, GI bleeding, and constipation. Treatment involves reducing ammonia production by decreasing dietary protein, controlling GI bleeding, and administering antibiotics effective against urease producing bacteria. Antibiotics most commonly used include amoxicillin 22 mg/kg PO q 12 hrs, neomycin 22 mg/kg PO q 8–12 hrs, or metronidazole 7.5 mg/kg PO q 12 hrs. Lowering the pH in the colon is also useful by inhibiting bacterial growth and converting ammonia to the nonabsorbable ammonium ion. Lactulose given at 0.25–0.5 mls/kg PO q 8–12 hrs, decreases colonic pH and provides an osmotic laxative effect. In cases of severe hepatic encephalopathy, lactulose can be given as an enema (diluted 1:3 with water).3, 8 Diluted povidone-iodine (Betadine, Purdue Frederick Co., Norwalk, CT) solution can also be used as an enema for treating severe hepatic encephalopathy if lactulose is not available.3, 15
Coagulopathies are common in animals with liver disease. Possible mechanisms include decreased clotting factor synthesis, decreased vitamin K absorption in cholestatic disease, and disseminated intravascular coagulation.4 Parenteral vitamin K (0.5 to 2 mg/kg SQ q 12 h for 2 to 3 doses) may be helpful in correcting coagulopathies.3, 34 If vitamin K is ineffective, then blood products, such as whole blood or plasma, may be necessary to stabilize the coagulopathy before performing invasive procedures, such as a liver biopsy.
Ascites can be treated with diuretics, such as spironolactone and/or furosemide. Furosemide is considered more potent but may cause hypokalemia and metabolic alkalosis, which can exacerbate hepatic encephalopathy. Spironolactone is usually preferred because it is potassium sparing and directly inhibits aldosterone, which is thought to play a role in the production of ascites in dogs with liver disease. The recommended dose of spironolactone is 1–2 mg/kg PO q 12 hrs. If this is ineffective, furosemide can be added at 1–2 mg/kg PO q 12–24 hrs.3, 8
GI ulcers are common in dogs with chronic liver disease. Melena is not usually evident in physical examination, so its absence does not exclude the presence of GI ulcers. GI ulcers should be suspected if there is any anorexia, vomiting, or anemia. GI ulcers may be treated with a variety of medications, such as H2 blockers, sucralfate, or omeprazole. Of the H2 blockers, famotidine (0.5–1 mg/kg PO q 12–24 hrs) is generally preferred because of the lack of cytochrome P450 enzyme inhibition. Cimetidine (5–10 mg/kg PO q 6–8 hrs) and, to a lesser extent, ranitidine (2–3.5 mg/kg PO q 8–12 hrs) suppress the cytochrome P450 enzyme. Omeprazole, a proton pump inhibitor, can be used at a dose of 0.7–2 mg/kg PO once daily. The recommended dose of sucralfate is 0.5–1 gram per dog PO q 8–12 hrs.3, 7, 8, 10, 20
Antibiotics may be useful in some dogs with hepatitis, especially if the inflammation is suppurative, rather than mononuclear, in nature.7 Antibiotics that are most commonly used include amoxicillin, amoxicillin-clavulanic acid (Clavamox, Pfizer Inc, New York, NY) fluoroquinolones, and metronidazole (at a reduced dose of 7.5 mg/kg orally, twice per day). Ideally, the choice of antibiotic should be based on culture and sensitivity results of bile or liver tissue. Antibiotics that should generally be avoided in dogs with liver disease include sulfonamides, erythromycin, lincomycin, chloramphenicol, and tetracycline.8 Dogs with chronic liver disease can also be predisposed to endotoxemia because of decreased hepatic reticuloendothelial system function and GI ulceration.8 Bacteria from the GI tract may play a role in ascending cholangiohepatitis or hepatic encephalopathy.
Monitoring
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Monitoring a patient with chronic hepatitis involves the following (1) rechecking laboratory parameters, (2) assessing drug efficacy, (3) watching for side effects from drug therapy, and (4) measuring drug levels when possible.
Monitoring laboratory parameters can be somewhat misleading in dogs being treated with chronic hepatitis. Glucocorticoids can increase liver enzymes, especially alkaline phosphatase, so monitoring serum liver enzymes may not be accurate. However, an improvement in hyperbilirubinemia or hypoalbuminemia would be significant. Clotting times can be rechecked after vitamin K administration or transfusion therapy to see if they have normalized.
Because of the difficulties in interpreting serum liver enzymes, drug efficacy can be better assessed by documenting the reversal or slowing the progression of liver pathology. A liver biopsy can be rechecked after 3 to 6 months of therapy to document regression of inflammation, resolution of fibrosis, and decrease in hepatic copper concentrations.3 Amelioration of clinical signs, such as decrease in ascites or resolution of hepatic encephalopathy, can also be used to document drug efficacy.
Besides monitoring for drug efficacy, it is also important for clinicians to monitor for drug side effects. Myelosuppression has been seen with azathioprine and rarely with colchicine therapy.3, 20 A CBC should be monitored every 1 to 2 weeks initially, then every 1 to 2 months. Azathioprine has also been associated with acute pancreatitis and acute hepatopathy,20 so serum chemistries should be monitored periodically as well. GI side effects, such as anorexia, vomiting, or diarrhea, can be seen when administering azathioprine, colchicine, D-penicillamine, or zinc. Side effects are rare with ursodeoxycholic acid, vitamin E, SAMe, and milk thistle.1, 10, 12, 15, 29
Drug toxicity can be minimized with some medications if serum drug concentrations can be measured. Only a few of the drugs commonly used in chronic hepatitis can have therapeutic levels monitored. Zinc levels should be measured every 2 to 3 months. The goal therapeutic range is 200 to 400 μg/dL. Zinc levels >1,000 μg/dL can cause hemolytic anemia.3 If potassium bromide is used to control seizures, serum levels can be monitored. The target serum concentration is 2 to 3 mg/mL when used as monotherapy.35
Prognosis
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The prognosis for dogs with chronic hepatitis is quite variable. Dogs with hypoalbuminemia, hypoglycemia, prolonged clotting times, and bridging fibrosis tend to have shorter survival times.19 In one study, most dogs with cirrhosis died within 1 week of diagnosis.36 The prognosis for cocker spaniels with chronic hepatitis is considered poor, with many dogs dying within 1 month.3 For other types of chronic hepatitis, median survival ranged from 21.1 to 36.4 months.36
Because dogs with end-stage disease have a poor prognosis, early diagnosis and intervention are key to the successful treatment of dogs with chronic hepatitis. Breeds predisposed to chronic hepatitis should have blood tests (CBC and serum chemistry panel) performed periodically. Increased liver enzymes should be followed by bile acid determination and liver biopsy when appropriate.
DRUG FORMULARY
Drug Dose Use/Comments
Penicillamine Capsules 125 mg, 250 mg Tablets 250 mg 10–15 mg/kg PO BID Given separately from meals and zinc Copper associated hepatopathy, may cause vomiting
Trientene Capsules 250 mg 10–15 mg/kg PO BID Given separately from meals and zinc Copper associated hepatopathy, better tolerated than penicillamine
Zinc Copper hepatopathy 5–10 mg elemental Zn/kg divided BID × 3–6 months, then decrease by 50% Chronic hepatitis 2–3 mg/kg/day elemental zinc Antifibrotic Antioxidant Monitor Zn levels Goal 200–400 mcg/dl, May cause anorexia, vomiting, hemolysis, Give separately from meals and copper chelators
Prednisone Tablets 5 mg, 20 mg 1–2 mg/kg/day, then decrease 50% q 3–4 weeks Mononuclear inflammation, antifibrotic
Azathioprine Tablets 50 mg 0.5–2 mg/kg SID 1–2 wks, then EOD Immunosuppressive Antifibrotic May cause myelosuppression, pancreatitis, hepatopathy
Colchicine Tablets 0.5 mg, 0.6 mg 0.03 mg/kg PO SID Anti-fibrotic
Ursodeoxycholic acid Tablets 250 mg Capsules 300 mg 10–15 mg/kg/day Contraindicated in biliary obstruction, anti-inflammatory, antioxidant
SAMe Denosyl tablets 90 mg, 225 mg 20 mg/kg/day fasted Anit-inflammatory Anti-oxidant
Spironolactone Tablets 25 mg, 50 mg 100 mg 1–2 mg/kg PO BID Diuretic for ascites
Famotidine Tablets 10 mg, 20 mg, 40 mg 0.5–1 mg/kg PO SID-BID GI ulcers
Omeprazole Capsules 10 mg, 20 mg, 40 mg 0.7–2 mg/kg PO SID GI ulcers
Potassium Bromide 70–80 mg/kg/day as single agent Anticonvulsant Therapeutic level 2–3 mg/ml
References
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