Therapeutics

A combination of drugs are used and needed for the management of chronic hepatitis. Response to therapy is ideally measured by re-biopsing the liver a few months later, however, in many cases, this is not feasible and repeating the liver enzymes 4-6 weeks after initiating therapy may help to monitor response.

• Treat underlying cause if known, for exam­ple, copper toxicity

• Control inflammation and immune modulation

• Antioxidant therapy

• Anti-fibrotic therapy

• Manage hepatic encephalopathy

• Symptomatic therapy.

Copper Chelation

• Penicillamine 10-15 mg/kg BID on an empty stomach. May lead to anorexia and vomiting. Use with caution in cats.

• Trientine can be used as an alternative in patients that do not tolerate penicillamine. Dose 15 mg/kg BID. The drug is not readily available.

• Zinc can be added to help reduce copper levels and avoid accumulation of copper again. Dose is 100 mg q12hrs of elemental zinc. After 2-3 months, the dose can be halved. Zinc should also be administrated on an empty stomach.

Antibiotics

Paramount for infectious hepatitis, but may also help to decrease bacterial colonization in severe chronic hepatitis patients. Amoxicillin, metronidazole, and cephalo­sporins are most commonly used for 2-4 weeks. If using metronidazole lower the dose to 7.5-10 mg/kg BID due to hepatic metabolism.

Choleretic Drugs

Decreasing cholestasis has been shown to improve clinical signs. Increasing levels of bilirubin can cause increase cell permeability and fibrogenesis.

Ursodeoxycholic acid (UDCA) at a dose of 15 mg/kg per day helps to decrease cholesta­sis inflammation and fibrosis. There has been some concern that the use of UDCA in bile duct obstruction may cause rupture but this has been shown not to be the case.

Anti-inflammatories/Immune Modulating Drugs

Prednisolone/Prednisone at 1-2mg/kg/day for 2-4 weeks then gradually tapering to a dose of 0.5 mg/kg every second day. Glucocorticoid treatment is continued for 4-6 months. Ideally, the liver should be re­biopsy 4 months after start of treatment to evaluate if long-term anti-inflammatories are needed. Dexamethasone at 0.2-0.4 mg/kg SID is preferred in patients with portal hyper­tension and/or ascites as it has less mineralo­corticoid effects (Favier et al. 2013).

Other drugs used in this category with var­ying success include azathioprine (1-2 mg/kg SID then taper to every second day) or cyclo­sporine 5 mg/kg SID-BID. Azathioprine has been used with good success in human chronic hepatitis and has shown promise in Labradors with chronic hepatitis. Myco- phenolate can also be considered in severe cases at a dose of 10-20 mg/kg BID. When using long-term drop dose by 25-50%. In cats, chlorambucil at 0.25 mg/kg every third day is used as an add-on after prednisolone if more immunosuppression is required.

Antioxidants

• S-Adenosylmethionine (SAMe) helps with cell replication and has a modulating influ­ence on inflammation. SAMe is a natural metabolite of hepatocytes. Dose of 20 mg/ kg SID on an empty stomach.

• Silymarin (Milk thistle) is a potent free- radical scavenger and has been used for centuries in human medicine as a hepatic antioxidant. Dose: 50-250 mg per day.

• SAMe and silymarin has been shown to have a synergistic effect when used together.

• Vitamin E and C also functions as antioxi­dants. Vitamin E by protecting membrane phospholipids from peri-oxidative damage and vitamin C is a soluble intracellular antioxidant. As dogs and cats normally synthesize them, it is uncertain whether or not supplementation is required.

• Vitamin E: 400-500 units per day. Vitamin C: 30 mg/kg every QID.

• N-acetylcysteine at 70 mg/kg TID are used mostly in drug toxicities.

Antifibrotics

• Corticosteroids, zinc, penicillamine, and colchicine are all used as antifibrotics.

• Corticosteroids are the most commonly used as it also helps with inflammation.

• Colchicine is the only specific anti-fibrotic drug. It stimulates the collagenase activity and has been used to arrest and resolve hepatic fibrosis. It can cause GI signs and should always be started at the lower end of the dose. Dose: 0.03 mg/kg/day. It should be avoided in patients with renal failure and has not been used in cats.

• Zinc dose - 100 mg daily for 4 months then decrease to 50 mg SID. It works best on an empty stomach.

• Losartan (angiotensin II inhibitor) has recently been shown in human medicine to prevent fibrosis. Dose: 0.25-0.5 mg/kg/day.

Diet

Palatability is paramount and a special diet should not be used at the cost of loss of appe­tite. There is a misconception that all liver patients should be on a low-protein diet; however, a low-protein diet is only advised in patients with hepatic encephalopathy. Adequate protein is important for hepato­cyte regeneration. The protein should be of high quality and digestibility. Dairy and plant protein are better tolerated than animal protein in patients with hepatic encephalop­athy. A high carbohydrate and moderate fat content diet can be considered, especially if the patient is prone to hypoglycemia or hyperammonemia.

Feeding smaller meals frequently helps to reduce fasting hypoglycemia and serves to increase protein tolerance.

Including moderate amount of dietary fiber has been shown to be advantageous as soluble fiber reduces availability and produc­tion of nitrogenous waste products by the gut. Insoluble fiber on the other hand helps bind toxic substances.

Commercial liver diets are low in copper and recommended for patients with copper toxicity. Avoid liver, shellfish, organs, and cereal in home-cooked meals, as all of these are high in copper.

Symptomatic Therapy

Clinical signs of nausea, vomiting, diarrhea, and gastrointestinal bleeding are relatively common in patients with chronic hepatitis. As the disease progress and in severe cases hepatic encephalopathy manifests and ascites (due to low protein levels and portal hyper­tension) may occur.

Anti-nausea Drugs

• Metoclopramide 0.5-1 mg/kg TID, if in hos­pital then a continuous rate infusion (CRI) works best at a dose of 1-2 mg/kg/day.

• Ondansetron 0.1-1 mg/kg SID-TID.

• Maropitant - NOT recommended in cases with liver disease.

Appetite Stimulants

Appetite stimulants that can be considered include cyproheptadine (0.2 mg/kg BID or 1-2 mg total dose for cats BID) and mirtazapine (0.5 mg/kg per day).

Gastro-Intestinal Bleeding

• Protein-pump inhibitors such as omepra­zole at 1 mg/kg BID other dosages shown not to work.

• H2-blockers such as famotidine at 0.5-1 mg/kg per os or 0.5 mg/kg slow IV or sc SID-BID can also be used. Avoid the use of cimetidine in these patients due to its powerful P450 microsomal enzyme inhibition.

• Sucralfate at 0.25-1 gram BID-TID. Stagger medication, as sucralfate is more active in an acid environment and can bind other medications.

Ascites

Ascites can be managed with diuretics. The most commonly used diuretics include furo­semide (2-4mg∕kg∕day) and/or spironolac­tone (1-4 mg/kg/day). If the ascites is severe then abdominocentesis can be performed to make the patient more comfortable.

Hepatic Encephalopathy

• Enemas play a big role in managing cases with hepatic encephalopathy (HE). Enemas help to rid the patient of ammonia produc­ing substrates (bacteria and protein). Slightly acidic enemas works best as they ionize the ammonia and prevents further absorption, for example, povidone iodine as a 10% solution.

• Antibiotics (metronidazole/amoxicillin) will help to decrease ammonia-producing bacteria.

• Lactulose helps to decrease the pH in the colon and converts ammonia to ammo­nium, which is poorly absorbed.

Management of Coagulopathies

Patients with advanced chronic hepatitis may suffer from coagulopathies due to vitamin K deficiency. Vitamin K1 can be supplemented at 0.5-2 mg/kg sc or per os SID. If actively bleeding then a plasma transfusion or whole blood transfusion should be considered. Fresh whole blood is preferred above stored blood as ammonia accumulates in stored blood.

Which Therapy is Best for the Patient?

Histopathology results can help choose the combination of treatment that may be needed. The severity of inflammation as well as presence of fibrosis would indicate that anti-inflammatories and antifibrotics are needed as well as other supportive care.

As maintenance therapy, most clinicians will use UDCA and an antioxidant (Vitamin E, SAMe or silymarin) in chronic hepatitis cases. If inflammation persists then low-dose prednisolone may be needed.

If severe clinical signs return or liver enzymes continue to increase then restart a course of antibiotics. Use a combination of anti-oxidants (they have a synergistic effect) and start anti-inflammatories if patient is not on any at time of relapse. If patient is already on prednisolone or other anti-inflammato­ries consider adding another immunosup­pressive drug.

Expected Outcome/Adverse Reactions

Improvement is usually seen within 24­48 hours after start/change of treatment. Possible side effects may include vomiting and diarrhea with certain drugs (colchicine). Alkaline phosphatase levels will potentially increase if prednisolone is used and thus may make interpretation of response to therapy difficult.