MANAGEMENT OF HEPATIC DISEASE

Many types of hepatic disease are managed with specific treatment modalities. Examples of disor­ders with specific treatments are listed in Table 9-2. In addition to specific treatment, many patients with hepatic disease require general supportive care to manage the acute and chronic aspects of the derangements seen with hepatic failure.

Management of Acute Hepatic Failure

The cornerstone of treating acute hepatic failure includes elimination of the inciting cause (such as drugs or toxins), providing optimal conditions for hepatic regeneration, preventing complications, and reversing derangements that occur with

hepatic failure. The important derangements that may be seen include dehydration and hypovolemia, hepatic encephalopathy, hypoglycemia, acid-base and electrolyte abnormalities, coagulopathies, gas­tric ulceration, sepsis, and endotoxemia.

Dehydration, Hypovolemia, and Electrolyte Disturbances

Many patients with severe hepatic disease have vomiting, diarrhea, and anorexia.

To manage these derangements, aggressive intravenous fluid therapy is often needed. The fluid of choice may be determined by measure­ment of serum electrolyte and arterial blood gas levels. If arterial blood testing is not available, the serum bicarbonate concentration can be esti­mated from the serum total CO2 concentration. However, these values are usually not available immediately. In general the fluid of choice is half­strength saline (0.45%) with 2.5% dextrose, sup­plemented with potassium chloride. Potassium chloride should be added at the rate of 30 mEq/L of fluids until serum potassium concentration is known, at which time the concentration can be adjusted. Ringer's solution or normal saline (0.9%) are acceptable alternatives, but their higher sodium content makes them less desirable because many patients with hepatic disease have excessive sodium retention and their administration can exacerbate ascites. Lactated Ringer's solution should be avoided because lactate must be con­verted to bicarbonate in the liver.

Acute Hepatic Encephalopathy

The approach to managing acute hepatic encephalopathy involves reducing the formation and absorption of encephalopathic toxins from the intestinal tract, avoidance of drugs that exacerbate encephalopathy (e.g., tranquilizers, anticonvul­sants, anesthetics), controlling GI hemorrhage, and appropriate dietary management. Factors that pre­cipitate metabolic changes that can lead to encephalopathy are listed in Box 9-14. These factors must be avoided or treated if possible.

Decreasing Encephalopathic Toxins

The therapeutic efforts designed to reduce forma­tion and absorption of encephalopathic toxins are primarily directed towards reducing ammonia absorption, although other encephalopathic toxins are also important, including benzodiazepine-like

BOX 9-14

Factors That Precipitate Metabolic Changes Leading to Hepatic Encephalopathy

Increased dietary protein intake Gastrointestinal hemorrhage Diuretic administration

Sedative or barbiturate administration

Uremia

Infection or endotoxemia

Constipation

Large intestinal bacterial overgrowth Methionine administration substances, mercaptans, short-chain fatty acids, and aromatic amino acids. Because ammonia is pro­duced primarily in the colon from bacterial action on dietary amines (proteins) and urea (which dif­fuses from the systemic circulation into the colon), efforts at lowering blood ammonia concentration are aimed at interrupting this process. This can be done in several ways. First, food is withheld initially to prevent dietary proteins from reaching the colon. In addition, large-volume (25 ml/lb body weight) cleansing enemas are used to decrease bacterial numbers.

Lactulose (Cephulac) administration is another useful adjunct to decrease ammonia absorption. Lactulose is a disaccharide that undergoes minimal absorption in the stomach and small intestine, reaching the colon unchanged. There it is metab­olized by bacteria, resulting in the formation of low molecular weight acids that acidify the colonic contents. This has the effect of converting ammonia (NH₃) to the ammonium ion (NH₄⁺), thus trapping it in the colon and preventing its absorption. In addition, the metabolic by-products of lactulose induce an osmotic catharsis and there­fore lower colonic bacterial numbers. The initial dose of lactulose is 0.5 ml/lb body weight. It can be given by several routes. The oral route is pre­ferred. In stuporous patients it can be administered via orogastric tube. Alternatively, it can be given mixed with a saline enema. In conscious patients the liquid is given orally by syringe. In the acute situation it can be given up to every 2 to 4 hours. In the long-term management of chronic hepatic encephalopathy, it is given at the above dose orally three times a day. The dose can be titrated by not­ing the consistency of the feces, because excessive amounts of lactulose will cause diarrhea. Ideally the feces should be loose to slightly liquid.

Orally administered antibiotics can also be helpful in decreasing colonic bacterial numbers.

Drugs That Exacerbate Encephalopathy Drugs that can depress the CNS should be avoided because of their potential to exacerbate hepatic encephalopathy because these patients have increased cerebral sensitivity to CNS depressants. In addition, drugs that are cleared by the liver have prolonged activity as a result of decreased hepatic clearance. Analgesics, tranquilizers, sedatives, anes­thetics, and barbiturates should be avoided if possi­ble. If sedation is necessary, these drugs should be used in decreased dosages. If a convulsive state is present, diazepam is the safest drug to use to con­trol seizure activity. If analgesia is required, I have had the fewest problems with meperidine (Demerol). This drug is used at a lower dose than in patients with normal hepatic function.

Controlling Gastrointestinal Hemorrhage GI hemorrhage must also be controlled. Patients with hepatic disease are prone to GI hemorrhage because gastrin concentration may be increased (due to decreased hepatic clearance and increased secretion stimulated by excess bile acids), resulting in gastric hyperacidity, and because microthrombi in the mucosal microcirculation (if DIC is present) result in inability to handle back-diffused hydro­gen ions.

A bland diet with minimal residue is helpful to minimize potential inflammation in the bowel. In addition, specific drug therapy is indicated, includ­ing drugs that inhibit gastric acid secretion. The drugs of choice are histamine H₂-receptor antago­nists. These drugs include ranitidine (Zantac), famotidine (Pepcid), and cimetidine (Tagamet). I prefer using ranitidine parenterally at a dosage of 1.0 mg/lb body weight two times a day subcuta­neously or intramuscularly in the acute stages, whereas the drug can be administered orally at the same dosage and frequency for chronic mainte­nance. For cats oral famotidine (2.5 mg one to two times a day) is the best choice. The dose of cime­tidine is 2.5 mg/lb body weight four times a day intravenously, subcutaneously, intramuscularly, or orally.

I also frequently combine ranitidine with sucralfate (Carafate). The latter drug has local pro­tective effects at sites of GI erosions or ulcers. It forms a complex with proteins in the ulcer crater and provides a barrier to the penetration of gastric acid. In addition, recent evidence has demon­strated it to have protective effects for normal gas­tric mucosa by stimulating the production of the protective prostaglandin E₁ and by stimulat­ing normal epithelial cell turnover (a protective effect). Sucralfate is given at a dosage of 0.5 to 1.0 g orally three to four times a day. It has a very wide safety margin because it is not absorbed. The dose for cats is 0.25 g orally three to four times a day.

Another drug that might have potential for managing GI ulceration is misoprostol (Cytotec), a synthetic prostaglandin E₁ analogue. It has been approved for use in humans and has also under­gone clinical evaluation in veterinary medicine as a prophylactic agent for NSAID-induced ulcers. It acts by stabilizing the protective mucous layer in the stomach, increases epithelial cell turnover, and inhibits gastric acid secretion. I have used it on a limited basis at a dosage of 1 to 2.5 μg∕lb body weight orally three to four times a day in the dog. Therapeutic trials are needed to further define its role in managing GI hemorrhage in animals with hepatic disease.

It is important to note that blood transfusion should be avoided unless absolutely necessary. Red blood cells have a high ammonia content, and, once blood is stored, ammonia is released. Storage of blood for 1 day results in the elaboration of 170 μg ammonia per 100 ml blood; after 4 days, 330 μg per 100 ml; and after 21 days, 900 μg per 100 ml. It is not uncommon to see clinical deteri­oration shortly after blood is administered to patients with hepatic failure. If blood administra­tion is necessary, freshly collected blood must be used. Ideally plastic blood collection bags should be used because platelets stick to glass and glass activates factor XII and can exacerbate DIC.

Dietary Management

Dietary management is important in the acute and chronic stages of hepatic failure. In the acute stages, food restriction is important to mini­mize dietary substrates for ammonia production in the colon. Most encephalopathic patients are anorectic, so this is not a problem. Once acute encephalopathy is controlled, dietary management is important. This involves protein restriction, small frequent meals, and the careful selection of ingredients in the diet. These factors will be discussed in detail in the section on management of chronic hepatic disease.

Hypoglycemia

Many patients with severe hepatic failure are hypoglycemic because of inadequate gluco­neogenic enzymes and depletion of glycogen stores. Hypoglycemia can significantly worsen hepatic encephalopathy in addition to its other deleterious effects. It has been shown that hypo­glycemia is an accurate predictor of early death in patients with hepatitis. Glucose supplementa­tion will correct hypoglycemia, prevent cata­bolic processes, and may lower CNS and blood ammonia concentrations. It is usually easy to restore normal blood glucose concentration with intravenous glucose supplementation in patients with hepatic failure, whereas it is more difficult to maintain euglycemia with other causes of hypo­glycemia such as insulin-producing tumors. Glucose can be supplied in the intravenous fluids up to a concentration of 5% to 10%. It is rare that higher glucose concentrations will be necessary to maintain euglycemia.

Coagulopathies

The causes of coagulopathies associated with severe hepatic disease are numerous (see section on pathophysiologic derangements occurring with hepatic disease), and appropriate manage­ment depends on identifying the cause. The most common coagulopathy seen is DIC. Appropriate treatment includes aggressive intravenous fluids to maintain tissue perfusion and treatment of the underlying hepatopathy if possible. Additional treatment measures include inhibition of platelet function with aspirin, and clotting factor and antithrombin III replacement with a fresh whole blood transfusion (collected in a plastic collection bag to prevent activation of factor XII) along with heparin therapy (110 units/lb body weight subcu­taneously three times a day). Heparin can also be added to the transfused blood at a concentration of 125 units/500 ml blood to activate antithrombin III. If there is antithrombin III depletion and it is not supplied in the form of a fresh blood transfusion, heparin therapy will be deleterious.

If the cause of the coagulopathy is from abnor­mal clotting factor production, a fresh whole blood or plasma transfusion is indicated. As men­tioned above, stored blood should be avoided due to its high ammonia content. In some instances, vitamin K deficiency causes abnormal clotting ability. This can be corrected by administering vitamin K₁ orally or subcutaneously. Even if this does not correct abnormal clotting times, it is a therapeutic measure that does little harm and is sometimes worth trying.

Sepsis and Endotoxemia

Patients with severe hepatic disease are prone to systemic and hepatic infection due to abnormal hepatic reticuloendothelial cell function. Because the liver is responsible for clearing bacterial prod­ucts from the portal blood, therapy is directed primarily against intestinal flora. The main con­cern is with gram-negative enteric bacteria and anaerobes, as well as endotoxins. If sepsis is strongly suspected, multiple blood cultures (both aerobic and anaerobic) are indicated. If hepatic biopsy is performed, a culture of the specimen should always be obtained. If an organism can be cultured, appropriate antibiotic therapy can be employed. Otherwise patients should be placed on antibiotics empirically. In most patients with severe hepatic disease, prophylactic antibiotics are indicated.

Appropriate choices for empiric antibiotic use are based on activity against intestinal flora, degree of hepatic clearance, and toxicity. Drugs requiring hepatic inactivation should be avoided, whereas drugs excreted by the liver should be beneficial, although they must be used with caution. Drugs with good activity against anaerobes include metronidazole (2.7 to 4.5 mg/lb body weight two to three times a day), penicillins, and cephalo­sporins. Often these drugs are combined with a quinolone or an aminoglycoside such as genta­micin to combat gram-negative organisms. These drugs can be given systemically for septicemia or orally to kill intestinal bacteria (because aminogly­cosides are not absorbed when given by this route). Oral amoxicillin-clavulanate (Clavamox) is a good broad-spectrum single-agent antibiotic.

Tetracycline is concentrated in the bile and may be useful for biliary tract infections. However, it should be used with caution to avoid excessive blood levels and toxicity. Quinolone antibiotics (enrofloxacin, orbifloxacin, marbofloxacin) also have promise for use with hepatic disease because they have excellent activity against aerobic intes­tinal flora and reach high concentrations in the liver.

Antibiotics that should be avoided include chloramphenicol, lincomycin, sulfonamides, eryth­romycin, clindamycin, chlortetracycline, and hetacillin. These drugs are either inactivated by the liver, require hepatic metabolism, or can cause hepatotoxicity.

Methods used to control endotoxin absorption include nonabsorbed orally administered antibi­otics (aminoglycosides) and cholestyramine. The latter drug binds to bile acids and endotoxins and prevents their absorption into the portal circula­tion.

Other Therapeutic Modalities

Additional therapeutic measures to treat acute hepatic coma include the intravenous administration of branched-chain amino acids. Because amino acid derangements (mainly increased aromatic amino acids) contribute to hepatic encephalopathy, nor­malization of amino acid ratios may be helpful. By administering branched-chain amino acids, fewer aromatic amino acids enter the CNS, because they compete for a common carrier to get across the blood-brain barrier. However, there is conflicting evidence as to their effectiveness in managing hepatic coma. The high cost of these solutions will also limit their use. The use of conventional amino acid solutions or protein hydrolysates should be avoided because use of these solutions leads to a high serum ammonia concentration.

The use of the dopamine agonist L-dopa has also been proposed to treat acute hepatic coma. It is thought that this and similar drugs act to favor­ably alter neutrotransmitter concentrations in the brain. The use of benzodiazepine-receptor antag­onists (such as flumazenil) has also been suggested in the management of patients with hepatic encephalopathy. Elevations in the activity of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) seem to be mediated by increased brain concentrations of benzodiazepine-receptor agonists in patients with hepatic encephalopathy. Clinical trials in dogs with hepatic coma are needed before these drugs can be recommended for routine clinical use.

Management of Chronic Hepatic Disease

If a specific disease is identified by hepatic biopsy, specific therapy should be instituted if possible (see Table 9-2). However, supportive care will be nec­essary to treat the patient during the acute and chronic phases of hepatic disease. Often ongoing care is essential because many hepatic diseases cannot be readily reversed and are progressive. In addition, a long time is often required for defini­tive therapy to be effective. The goals of therapy in chronic hepatic disease are to (1) slow the progres­sion of the disease, (2) ameliorate existing clinical signs and hepatic encephalopathy, (3) support hepatic regeneration, and (4) reduce the need for specific hepatic functions.

Nutritional Management

Nutritional therapy represents the cornerstone for long-term management of chronic hepatic disease and is the most effective way to minimize signs of hepatic encephalopathy. The basis for these rec­ommendations stems from knowledge of the pathophysiology of hepatic encephalopathy.

Limitation of dietary protein concentration is one of the most important aspects of an appropri­ate diet. Because ammonia is produced in the colon by bacterial action on dietary peptides, a low-protein diet will decrease substrates for ammonia production. Ideally the protein source should be of high biologic value and of high digestibility. These features will minimize the amount of protein reaching the colon and allow the protein that is absorbed to be used for the body's synthetic functions. It is recommended that 1 g of protein be fed per 20 kcal. If too little pro­tein is fed, there will not be enough nitrogen for the liver's synthetic functions, including synthesis of albumin and clotting factors. In addition, a pro­tein deficiency causes catabolism of body proteins, leading to negative nitrogen balance and a cachec­tic state. This can also result in excess ammonia production. It is also necessary to supply an ade­quate amount of nonprotein calories to support protein synthesis and decrease gluconeogenesis and body protein catabolism.

In addition to the quantity of protein, it is help­ful to feed a protein source that is high in branched-chain amino acids and low in aromatic amino acids because amino acid derangements (especially high concentrations of aromatic amino acids) contribute to the pathogenesis of hepatic encephalopathy. Milk proteins are higher in branched-chain amino acids and lower in aromatic amino acids than meat sources and thus are pre­ferred protein sources. Fish proteins are intermedi­ate in amino acid concentrations. Red meat should be avoided because it is the protein source most likely to precipitate encephalopathy (which resulted in the term “meat intoxication” for hepatic encephalopathy). Dogs with experimen­tally produced hepatic failure do better when fed milk proteins than when fed other protein sources. I have also seen clinical improvement with cottage cheese as the main protein source com­pared with commercial low-protein diets (k/d or u/d Prescription Diet [Hill's Pet Products]). Researchers have described two appropriate homemade diets. An additional low-protein diet with cottage cheese as the main protein source is listed in Box 9-15.If a commercial diet is used, dry 1/d Prescription Diet (Hill's Pet Products) is pre­ferred. Alternatively, various diets intended for renal failure are acceptable.

Easily digested carbohydrates should be the major source of energy. Rice is the most highly digestible carbohydrate source and therefore the

BOX 9-15

Low-Protein, Low- Copper, and Low-Salt Diet for Management of Chronic Hepatic Disease[‡‡‡‡‡]

4 oz cottage cheese (or cooked meat if cottage cheese will not be consumed)

1 cup cooked rice (or potato)

1 cup cooked green beans

1 tbsp corn oil

2 tsp calcium phosphate

Salt-free, copper-free, vitamin-mineral supple ment

Ascorbic acid (see text)

Zinc gluconate or sulfate (see text)

Flavor with salt substitute or onion or garlic powder cases of prolonged bile duct obstruction.Vitamin therapy (see following discussion) is often help­ful, however. Finally, fasting will mobilize fatty acids in the body. Therefore frequent meals are helpful.

Certain B vitamins are converted to their active form and stored in the liver. Therefore supple­mentation with a good-quality multiple vitamin preparation is helpful. Fat-soluble vitamins require normal bile secretion for absorption. However, it is rare to get malabsorption of fat-soluble vitamins unless there is prolonged bile duct obstruction. Because intestinal bacteria produce vitamin K, prolonged antibiotic use can result in malabsorp­tion of this vitamin.

Vitamin C (ascorbic acid) supplementation is also recommended. The liver produces an impor­tant part of the dog's daily requirement of ascorbic acid, and dogs with experimentally induced hepatic disease have marked decreases in ascorbic acid concentrations (as low as 10% of normal). Supplementation with ascorbic acid will also increase copper excretion in the urine. Copper will accumulate in hepatocytes with cholestatic disorders and primary copper-storage diseases, and its presence is toxic to hepatocytes. Therefore ascorbic acid should be given at a dosage of 11 mg/lb body weight per day to maintain normal plasma concentrations.

Potassium supplementation is also helpful in some cases of chronic hepatic disease, because many patients are hypokalemic. Signs of hepatic encephalopathy are exacerbated by hypokalemia, and supplementation frequently improves clinical signs. Serum potassium concentration measure­ment is necessary to determine whether supple­mentation is necessary. Potassium chloride tablets or granules (Tumil-K) can be given, or an elixir (1.3 mEq/ml) can be given at a dosage of 0.05 to 0.11 ml/lb body weight three times a day.

Minerals that can be harmful should be avoided. Copper can be hepatotoxic and accu­mulate in the liver in patients with hepatic dis­ease. Therefore a copper-free vitamin preparation should be used. Zinc inhibits the absorption of copper and its deposition in the liver. Therefore supplementation with zinc is recommended for certain hepatic diseases. The dosage is 0.7 to 1.14 mg/lb body weight three times a day of zinc gluconate, and 0.3 mg/lb body weight three times a day of zinc sulfate.

Sodium retention is frequently a problem in chronic hepatic disease, leading to the presence of ascites. Therefore a low-sodium diet is recom­mended (see Box 9-15).

Lipotrophic agents that contain methio­nine should not be administered. This amino acid is a precursor to mercaptans, a group of potent encephalopathic toxins. Methionine administration can significantly worsen signs of encephalopathy. Therefore lipotrophic drugs containing methio­nine have no place in the management of hepatic disease and are contraindicated.

Summary of Nutritional Management

In summary, the nutritional management of chronic hepatic disease should include the follow­ing considerations:

1. Calories from protein should be moderately restricted, and ingredients that are of high bio­logic value and highly digestible should be used.

2. Protein sources with high branched-chain/aro- matic amino acid ratios are preferred. Cottage cheese is an ideal protein source in this regard.

3. A palatable energy-dense diet in amounts suffi­cient to meet energy needs is necessary to avoid negative energy balance.

4. Carbohydrates supply most nonprotein calories but should be from highly digestible sources.

5. Sodium and copper should be restricted.

6. Supplementation with zinc, ascorbic acid, and a salt- and copper-free vitamin-mineral supple­ment may be helpful.

7. These considerations must be present in a highly digestible, low-residue diet and should be fed in small, frequent meals.

Other Drugs to Manage Chronic Hepatic Encephalopathy

As previously discussed, lactulose is effective in decreasing ammonia absorption by decreasing colonic bacterial numbers and lowering colonic pH. For chronic administration, lactulose is given at an initial dosage of 0.5 ml/lb body weight three times a day. The dosage is titrated to yield two to three loose to slightly liquid bowel movements per day. Oral antibiotics will also decrease ammonia absorption by decreasing colonic bacterial num­bers.

Inflammation and Fibrosis

The presence of active inflammation and fibrosis in patients with hepatic disease may justify the use of glucocorticoids and antifibrotic drugs such as colchicine and D-Penicillamine. See the section on treatment of chronic active hepatitis for a detailed discussion of these drugs.

Ascites

Ascites can be an important complication of chronic hepatic disease. See the section on patho­physiologic derangements occurring with hepatic disease for a detailed discussion of the pathogene­sis of ascites.

Emergency treatment of ascites is rarely neces­sary. Occasionally, however, the volume of ascitic fluid is high enough to result in respiratory distress because of compression of the diaphragm, limiting inspiratory efforts. In these patients, paracentesis may be helpful. The only other reasons to with­draw fluid from the abdominal cavity are to make it easier to perform percutaneous hepatic biopsy, laparoscopy, abdominal radiographs, and for diag­nostic fluid analysis and cytologic examination. Otherwise, paracentesis is of no therapeutic value. The risks of paracentesis are hypovolemic shock, iatrogenic infection, protein depletion, and perfo­ration of abdominal viscera. Patients with ascites are already using their maximum cardiac and cir­culatory reserve to maintain tissue perfusion. When a large volume of fluid is rapidly removed, fluid shifts from the intravascular to extravascular compartment and can precipitate hypovolemic shock. Although this is rare in my experience, it is recommended that if paracentesis is necessary, fluid should be withdrawn slowly and intravenous fluid support should be available if necessary.

Dietary salt restriction, diuretics, and aldosterone- inhibiting drugs are used in the long-term control of ascites. Diuretics should be administered with caution to avoid dehydration. Patients with hepatic failure are already using their maximum circulatory and cardiac reserve to maintain perfu­sion when ascites is present. Because one of the main causes of sodium retention in patients with hepatic disease is excessive aldosterone activity, aldosterone-inhibiting drugs are used first. I rec­ommend spironolactone at a dosage of 0.5 mg/lb body weight two times a day initially. If this dose is ineffective, it is doubled to 1 mg/lb body weight two times a day. Spironolactone will also not exacerbate hypokalemia. Loop diuretics such as furosemide (Lasix) are also effective. Furosemide should be used with caution because it can cause excessive urinary fluid loss that will result in hypo­volemia before it improves ascites and also exacer­bate hypokalemia and alkalosis. Furosemide is used at a dosage of 0.5 to 1 mg/lb body weight two to three times a day. Serum electrolytes must be measured periodically in addition to clinical assessment.

If ascites persists, enalapril or benazepril is added at a dosage of 0.125 to 0.25 mg/lb one to two times a day. These drugs are angiotensin­converting enzyme (ACE) inhibitors that decrease activity of the renin-angiotensin-aldosterone sys­tem. Dietary salt restriction is of prime importance to minimize sodium retention. Appropriate low- salt diets include those listed in Box 9-15, in the References, and Prescription Diet 1/d (Hill's Pet Products).