Malabsorption Syndromes - The Merck Veterinary Manual

Malabsorption Syndromes

Malabsorption implies defective absorption of a dietary constituent resulting from interference with its digestion or absorption. Interference with food digestion in small animals is typically due to exocrine pancreatic insufficiency (EPI), whereas most cases of absorption failure are caused by small intestinal disease.

The primary functions of the small intestine include mixing and propulsion of luminal contents, absorption of water and ions, digestion and absorption of nutrients, and secretion of hormones. Digestion and absorption of nutrients occur in 3 sequential phases: intraluminal digestion, mucosal digestion and absorption, and delivery of nutrients to the circulation. Many GI diseases cause chronic malabsorption by interfering with these processes. Malabsorptive syndromes in dogs have been studied in more detail; however, basic diagnostic and therapeutic principles are relevant to other species.

Physiology:

The normal digestive processes convert dietary nutrients into forms that can cross the brush border of intestinal absorptive epithelial cells, or enterocytes. The majority of digestive enzymes are secreted by the pancreas; EPI is thus a major cause of malabsorption. Some terminal digestion prior to absorption can be performed by brush border enzymes.

Main dietary carbohydrates are starch, glycogen, sucrose, and lactose. Starch and glycogen are first hydrolyzed by pancreatic amylase to the oligosaccharides maltose, maltotriose, and α-limit dextrins. Oligosaccharides and ingested disaccharides (sucrose, lactose) are further hydrolyzed to monosaccharides by enzymes located on the brush border of the intestinal epithelial cell. Brush border lactase declines after weaning, especially in cats, and animals may become lactose-intolerant. The final products of mucosal hydrolysis (glucose, galactose, and fructose) are actively transported into the enterocyte by a protein-carrier-mediated process. Once in the cell, monosaccharides diffuse down a concentration gradient through the lamina propria and into the portal venous circulation.

Protein digestion and absorption follow a similar pattern. Proteolytic enzymes from the stomach and pancreas degrade protein into a mixture of short-chain oligopeptides, dipeptides, and amino acids. Oligopeptides are further hydrolyzed by brush-border peptidases to dipeptides and amino acids that cross the brush-border membrane on specific carrier proteins.

Fat-soluble molecules do not need specific carriers to cross the phospholipid barrier of the brush border. However, intraluminal degradation of large lipids is essential. Fat in the duodenum stimulates release of cholecystokinin, which, in turn, stimulates secretion of pancreatic lipase. After solubilization by bile salt micelles, triglycerides are digested by pancreatic lipase to monoglycerides and free fatty acids. At the cell membrane, the monoglycerides and free fatty acids disaggregate from the micelle and are passively absorbed into the cell. Released bile acids remain within the lumen and are ultimately reabsorbed by the ileum. Once inside the cell, the monoglycerides and free fatty acids are re-esterified to triglycerides and incorporated into chylomicrons, which subsequently enter the central lacteals of the villus and are delivered to the venous circulation via the thoracic duct. However, medium-chain triglycerides can be absorbed directly into the portal blood, thus providing an alternative route for fat uptake in case of lymphatic obstruction.

Etiology and Pathophysiology:

Malabsorption is a consequence of interference with mechanisms responsible for either the degradation or absorption of dietary constituents (Table: Mechanisms of Malabsorption).

Diseases that disrupt the synthesis or secretion of digestive pancreatic enzymes cause maldigestion with subsequent malabsorption. An important cause is EPI ( Exocrine Pancreatic Insufficiency), which occurs if there is a loss of ~85-90% of exocrine pancreatic mass. EPI is characterized by severe maldigestion-malabsorption of starch, protein, and most notably, fat. In dogs, EPI is most commonly due to acinar atrophy; chronic pancreatitis is less common, and pancreatic hypoplasia is a rare cause. EPI in dogs is often complicated by small-intestinal bacterial overgrowth (SIBO), which further disrupts nutrient digestion and absorption. EPI is relatively uncommon in cats and is mostly due to chronic pancreatitis.

Intraluminal effects of bacteria in SIBO can also have important consequences. Bacterial deconjugation of bile salts interferes with micelle formation, which results in malabsorption of lipid. Deconjugated bile salts and hydroxy fatty acids exacerbate diarrhea by stimulation of colonic secretion. The causes of SIBO can include defective gastric acid secretion, interference with normal motility or mechanical obstruction of the intestine, interference with the function of the ileocecal valve, and local immunodeficiency; often, the cause is unknown. SIBO may also develop secondary to diffuse small-intestinal disease. It is not clear whether SIBO is seen in domestic species other than dogs; recent evidence suggests it is not a clinical problem in cats, which normally harbor relatively large numbers of anaerobes in the small intestine.

Fat malabsorption may also be seen with a deficiency of intraluminal bile salts due to cholestatic liver disease, biliary obstruction, or ileal disease, resulting in defective absorption of conjugated bile salts.

Small-intestinal disease can cause malabsorption by reduction of the number or function of individual enterocytes. Diffuse diseases of the mucosa can result in reduced activities of brush border enzymes, decreased carrier-protein function, decreased mucosal absorptive surface area, and interference with final transport of nutrients into the circulation. Weight loss may be seen due to compromised nutrient intake. In addition, malabsorbed nutrients exert strong intraluminal osmotic effects that diminish intestinal and colonic absorption of water and electrolytes, resulting in diarrhea. This may be exacerbated if mucosal damage is accompanied by intestinal inflammation, which can cause secretory and permeability diarrhea.

Potential causes of mucosal damage include inflammatory bowel disease, enteric pathogens (eg, enteric viruses, pathogenic bacteria, giardiasis, histoplasmosis), dietary sensitivity, SIBO, and intestinal neoplasia (lymphosarcoma). Histologic changes such as villous atrophy and infiltration with inflammatory cells indicate intestinal disease but do not identify the underlying cause. For example, lymphocytic-plasmacytic enteritis may be a common response of the intestinal mucosa to more than one provocative agent, particularly microbial and dietary antigens. Definite associations with parasites and pathogenic bacteria, SIBO, and dietary sensitivity have been demonstrated in dogs, but often the underlying cause cannot be identified.

Mucosal damage may also be seen without obvious histologic changes. This is typified by infection with enteropathogenic Escherichia coli (which specifically cause ultrastructural damage to microvilli in an attaching-effacing lesion) and sometimes also by SIBO in the proximal small intestine (which in dogs can cause biochemical damage to the intestinal brush border interfering with enterocyte function).

The main brush border enzyme deficiency reported is a relative lactase deficiency in adult dogs and cats. Acquired brush border defects also may be seen in the course of generalized intestinal disease.

Postmucosal obstruction may be seen with lymphatic obstruction (especially lymphangiectasia) and vascular compromise ( portal hypertension, vasculitis). Intestinal lymphangiectasia causes severe fat malabsorption as well as intestinal protein loss.

Usually there is malabsorption of a number of ingredients with consequent diarrhea; malabsorption of a single ingredient without GI signs is rare (eg, selective cobalamin malabsorption in Giant Schnauzers). Furthermore, the large absorptive capacity of the colon may prevent overt diarrhea despite significant malabsorption (with or without weight loss).

Clinical Findings:

The clinical signs of malabsorption are mainly the result of lack of nutrient uptake and losses in the feces. The duration, severity, and primary cause determine the severity of signs, which typically include chronic diarrhea, weight loss, and altered appetite (anorexia or polyphagia). The absence of diarrhea does not exclude the possibility of severe GI disease. Weight loss may be substantial despite a ravenous appetite, sometimes characterized by coprophagia. Typically, animals with malabsorption are systemically well unless there is severe inflammation or neoplasia. Nonspecific signs may include dehydration, anemia, and ascites or edema in cases of hypoproteinemia. Thickened bowel loops or enlarged mesenteric lymph nodes may be palpable, especially in cats.

Diagnosis:

Chronic diarrhea and weight loss are nonspecific signs common to a variety of systemic and metabolic diseases, as well as malabsorption. A thorough diagnostic approach in dogs and cats with signs suggestive of malabsorption is therefore needed to help exclude association with possible underlying systemic or metabolic disease. A precise diagnosis is also important for determining treatment and prognosis.

The history is particularly important because it may suggest specific dietary intolerance, indiscretion, or sensitivity. Weight loss may indicate malabsorption or protein-losing enteropathy but may also be due to anorexia, vomiting, or extra-GI disease. Small- and large-intestinal diarrhea may be distinguished by a number of features (table 1, Table: Differentiation of Small-intestinal from Large-intestinal Diarrhea). This distinction is more helpful in dogs than in cats, which rarely have exclusively large-intestinal disease. Suspected large-intestinal disease in dogs may be further evaluated by visualizing and taking a biopsy of the mucosa via endoscopic examination. However, if signs of large-intestinal disease are accompanied by weight loss or large volumes of feces, then the small intestine is probably also diseased.

A thorough physical examination should be performed. Abdominal palpation is essential to identify abnormalities, and rectal examination is required even when no lower-intestinal disease is suspected to provide a stool sample and possibly reveal previously unreported melena. In cats, the thyroid should be palpated carefully and serum T₄ assayed, as signs of hyperthyroidism can closely mimic those of malabsorption.

Initial evaluation should include a CBC, biochemical profile, urinalysis, fecal examination, abdominal ultrasonography and, when indicated, radiography. Hematologic correlates of intestinal diseases include anemia of chronic blood loss (microcytic, hypochromic) or chronic inflammation (normocytic, normochromic); neutrophilia and/or monocytosis associated with inflammatory bowel diseases, infectious enteropathies, or neoplasia; eosinophilia associated with parasitism, eosinophilic enteritis, or hypoadrenocorticism; and lymphopenia that may be associated with intestinal lymphangiectasia in dogs.

Biochemical tests and urinalysis help to exclude systemic diseases that cause chronic diarrhea, most notably hypoadrenocorticism, renal failure, and liver disease. Hypoproteinemia frequently is secondary to a protein-losing enteropathy; in most cases, serum albumin and globulin are both low, but a low albumin alone does not rule it out. Inflammatory bowel disease and neoplasia may be associated with hyperglobulinemia as well as hypoalbuminemia. Liver enzymes (ALT, AST) may be elevated as a consequence of increased intestinal permeability allowing more antigens to reach the liver; in such cases, a bile acid stimulation test as well as ultrasonography should be performed to exclude primary liver disease. Hypocholesterolemia may develop with fat malabsorption and is notable in lymphangiectasia. Urinalysis is important to exclude renal causes of hypoalbuminemia and/or renal disease. However, sometimes both may be seen together (eg, the familial protein-losing enteropathy and nephropathy of Soft-coated Wheaten Terriers). In cats, serologic tests for feline leukemia virus and feline immunodeficiency virus should be performed, not only because both may be associated with secondary chronic diarrhea but also because they are important prognostic factors. Feline infectious peritonitis and toxoplasmosis have also been described occasionally as causes of chronic diarrhea in cats. Suspected hyperthyroidism can be excluded by measuring serum T₄ levels.

Feces should be examined for parasites (especially Giardia ) and potentially pathogenic bacteria (including Salmonella and Campylobacter ). Pathogenic Escherichia coli are emerging as a potentially important problem in dogs, but sophisticated molecular techniques to identify genes encoding pathogenicity determinants are required for diagnosis. Giardia can be detected using serial fecal flotations or with a commercially available ELISA; the latter is easier to perform but less reliable. The presence of fat, undigested muscle fibers, or starch may provide indirect evidence for malabsorption but these are unreliable. Detection of excessive leukocytes on fecal cytology may indicate chronic inflammatory bowel disease or presence of enteric pathogens such as Salmonella or Campylobacter . Cytology of colonic scrapings may reveal Histoplasma organisms.

Abdominal radiography is more useful when vomiting is present or palpable abnormalities are detected. Ultrasonography is an important part of the investigation of most small-intestinal diseases. It can be used to measure intestinal wall thickness, layering, and luminal diameter, and to detect other intestinal lesions (masses, intussusception), mesenteric lymphadenopathy (in neoplasia and inflammatory bowel disease), and abnormalities in other organs.

Once obvious dietary, systemic, parasitic, and infectious causes of chronic small-intestinal diarrhea have been eliminated, the next step is differentiation of EPI from intestinal malabsorption while that; the diagnosis of EPI is relatively straightforward, while that of small-intestinal disease is more complicated. Numerous tests of exocrine pancreatic function have been recommended for dogs and cats with suspected EPI, but except for fecal proteolytic activity, they are too inaccurate or impractical to be recommended. Instead, assay of serum trypsin-like immunoreactivity (TLI), which is a highly sensitive and specific test for the diagnosis of EPI in dogs, is used. This assay measures trypsinogen that normally leaks from the pancreas into the blood, thereby providing an indirect assessment of functional pancreatic tissue. In dogs with EPI, functional exocrine tissue is severely depleted and serum TLI concentrations are extremely low, clearly distinguishing EPI from other causes of malabsorption. This test requires a fasted serum sample in dogs but not in cats. In cats, measurement of fecal proteolytic activity was formerly the most reliable widely available test of EPI, but a species-specific feline TLI test has recently been developed and validated.

Diagnosis of small-intestinal disease is difficult due to limitations of routine screening procedures, the need for biopsy, and frequently the absence of diagnostic histologic changes.

Assay of serum folate and cobalamin (vitamin B₁₂) concentrations can be a helpful initial test in the assessment of small-intestinal disease. Folate is absorbed primarily by the proximal small intestine (jejunum), whereas cobalamin is absorbed by the distal small intestine (ileum). As a result, serum folate concentrations can be decreased in proximal small-intestinal diseases, serum cobalamin concentrations can be decreased in distal diseases, and both can be decreased in severe diffuse enteropathies. In addition, SIBO (also called antibiotic-responsive diarrhea) may be suspected by finding increased serum folate or decreased serum cobalamin concentrations, reflecting the ability of many enteric bacteria to synthesize folate (which is subsequently absorbed in the proximal intestine) and to bind cobalamin (which is then unavailable for uptake in the ileum). These tests have a moderate specificity for the detection of SIBO but a low sensitivity, emphasizing that normal serum folate and cobalamin concentrations do not exclude the possibility of small-intestinal disease. Other factors such as the severity, extent, and duration of a mucosal abnormality; the type and numbers of organisms present in SIBO; vitamin supplementation; and dietary intake also influence these concentrations. In addition, EPI can affect serum folate and cobalamin concentrations. The validity of serum folate and cobalamin assays for the investigation of small-intestinal disease in cats is less clear, but low serum cobalamin concentrations may be found with both small-intestinal disease and feline EPI. Measurement of serum folate appears to be of little value in cats, because most cats normally have high serum folate concentrations.

A further indirect approach to the detection of small-intestinal disease is the assessment of intestinal function and permeability by the oral administration of test substances that are subsequently measured in blood or urine samples. Intestinal function has typically been assessed by the xylose absorption test. However, this is an insensitive test; results are frequently normal in dogs with small-intestinal disease, and the test does not appear to work well in cats. As an alternative approach in humans, D-xylose has been given with 3-O-methyl-D-glucose to provide a differential absorption test that exploits the contrasting effect of impaired intestinal absorption on these 2 markers. This appears to be an effective approach in dogs, but the sugar analyses are technically demanding and likely to be available only in specialized laboratories.

Assessment of intestinal permeability provides information about the physical integrity rather than the functional capacity of the mucosa. This new and extremely sensitive approach to the detection of small-intestinal damage involves measurement of urinary or blood concentrations of orally administered probes that cross the intestinal mucosa by unmediated permeation through 2 possible pathways. An intercellular aqueous pathway is represented by a few relatively large “pores.” Damage to the mucosa can open these intercellular pathways and result in enhanced permeability to larger probes such as ⁵¹Cr-EDTA, cellobiose, and lactulose. A second transcellular pathway is thought to consist of a greater number of small “pores,” which act as aqueous channels in enterocytes. These pores are permeable to smaller probe molecules such as mannitol and rhamnose and are reduced in a number of diseases that decrease intestinal surface area. Calculation of the ratio of the urinary excretion of a mixture of 2 probes of different sizes, such as lactulose and rhamnose, has been used successfully not only for the diagnosis of small-intestinal disease in dogs but also to monitor response to treatment (eg, to document dietary sensitivity or SIBO). Unfortunately, this approach does not appear to be useful in cats because intestinal permeability in healthy cats is so high.

IV administration of ⁵¹Cr-labeled albumin, or ⁵¹Cr, involves a different principle and has been used successfully to document protein-losing enteropathy in dogs. Measurement of 3-day fecal excretion of this radioactive marker provides an estimation of albumin and hence protein loss into the intestinal lumen. This test is preferred for diagnosis of intestinal protein loss, but its use is limited to large institutions due to the use of radioactive markers. An alternative approach is the measurement of α-1 protease inhibitor in the feces. This plasma protein is lost into the intestinal lumen together with albumin, but unlike albumin it is excreted in the feces essentially intact. A species-specific canine assay has recently been developed, but further studies are needed to assess its usefulness in the management of protein-losing enteropathy.

Hydrogen breath testing after oral administration of individual sugars has been used extensively in humans to assess bacterial colonization of the small intestine and carbohydrate malabsorption. This test works on the principle that intestinal bacteria ferment intraluminal carbohydrate and produce hydrogen gas, some of which is absorbed into the blood and excreted by the lungs. Increased breath hydrogen concentrations after oral carbohydrate may therefore reflect either bacterial colonization in the proximal small intestine, where carbohydrate concentration is relatively high, or malabsorption of carbohydrate, which then reaches the flora normally present in the distal small intestine and large intestine. This is a promising, simple procedure to detect SIBO in dogs and to assess transit time in cats, but it is likely to be available only at specialist centers.

A new method that can be used to diagnose SIBO in dogs is measurement of serum unconjugated bile acids. Many of the bacterial species that overgrow have the ability to deconjugate bile acids, which then readily diffuse across the mucosa and can be found in the blood. The test is technically difficult, but studies suggest it may be useful.

Definitive diagnosis of chronic small-intestinal disease typically includes histologic examination of intestinal biopsies taken by endoscopy or at laparotomy. Endoscopy is noninvasive and allows visualization of the mucosa and targeted biopsy sampling. However, endoscopic mucosal biopsies may not always give an adequate representation of deeper disease and are limited to the part of the duodenum that can be visualized. Surgery is the preferred option when there is a concern about deeper and extraintestinal disease or a focal lesion. If a laparotomy is performed, multiple thin, longitudinal biopsy samples should be collected from at least the duodenum, jejunum, and ileum; mesenteric lymph nodes should be biopsied and other organs examined.

Histologic examination of intestinal biopsy specimens can identify morphologic changes in inflammatory bowel diseases, including lymphocytic-plasmacytic enteritis and eosinophilic enteritis, intestinal lymphangiectasia, villous atrophy, and intestinal neoplasia. The description of morphologic abnormalities can provide a baseline to evaluate response to treatment, although indirect assessments such as intestinal permeability are clearly more practical than sequential intestinal biopsies. Morphologic abnormalities also provide some indication of prognosis because the more severe enteropathies tend to be more difficult to manage. However, there may be minimal or no obvious abnormalities in certain disorders despite considerable interference with intestinal function. Furthermore, histologic descriptions alone provide little information on possible etiology or underlying mechanisms of damage, which would clearly assist effective management.

Bacteriologic culture of duodenal juice obtained endoscopically or at laparotomy is needed for a definitive diagnosis of SIBO. The exact cut-off point when small-intestinal bacterial numbers are considered excessive is still a matter of debate. An association between >10⁵ total or >10⁴ obligate anaerobic colony-forming units (CFU)/mL, clinical disease, and mucosal damage has been established in dogs. However, higher numbers may be found in apparently clinically healthy dogs, depending on circumstances including environment, diet, scavenging, and coprophagia. The most frequent isolates typically include enterococci and E coli in dogs with aerobic overgrowth and Clostridium in dogs with anaerobic overgrowth. High numbers of anaerobic bacteria are most likely to be pathogenic.

Treatment:

Treatment of malabsorption involves dietary therapy, management of complications, and treatment of the primary cause (if identified). Management of EPI in dogs is relatively straightforward (see Exocrine Pancreatic Insufficiency). It should include feeding a low-fiber diet that contains moderate levels of fat or highly digestible fat, very digestible carbohydrate, and high-quality protein. Specific treatment involves lifelong supplementation of each meal with pancreatic extract. Powdered extracts (2 tsp/20 kg body wt) are preferable to tablets, capsules, and enteric-coated preparations. Fresh or frozen pancreas can be used as an alternative (100 g/meal for an adult German Shepherd). If response to pancreatic replacement therapy is poor, SIBO may be suspected, and the animal treated with oral antibiotics for ≥1 mo (see below). H₂-receptor blockers, such as cimetidine at 5-10 mg/kg or ranitidine at 2 mg/kg, may be given 20 min before a meal to inhibit acid secretion and to minimize degradation of enzymes in the pancreatic extract, but their efficacy is questionable. Oral multivitamin supplementation should be considered as supportive therapy, but cobalamin (500 mg/mo) should be given parenterally. Dietary requirements of cats with EPI can generally be met by conventional commercial diets, but pancreatic replacement therapy is still needed, as well as parenteral cobalamin supplementation in cats with low serum cobalamin levels.

Effective treatment of small-intestinal disease depends on the nature of the disorder, but therapy may be empirical when a specific diagnosis cannot be made. In dogs with SIBO, a low-fat diet may help by minimizing secretory diarrhea due to bacterial metabolism of fatty acids and bile salts. Oral broad-spectrum antibiotic therapy with oxytetracycline (10-20 mg/kg, tid for 28 days) has been successful. Metronidazole (10-20 mg/kg, bid) and tylosin (20 mg/kg, tid) are effective alternatives. Repeated or longterm treatment may be necessary in dogs with idiopathic SIBO. Vitamin supplementation may be helpful, particularly cobalamin by injection (eg, 500 mg/mo for 6 mo) for dogs with cobalamin deficiency. Secondary SIBO usually resolves with appropriate management of the underlying disease, but idiopathic SIBO can be difficult to control, especially in German Shepherds, which are predisposed to developing the condition.

Dietary modification is an important aspect of the management of small intestinal disease in both dogs and cats. Diets generally contain moderate levels of limited protein sources and highly digestible carbohydrates (to reduce protein antigenicity, reduce osmolar effects, and improve nutrient availability), and low to moderate levels of fat (to reduce steatorrhea and decrease secretogogues). In addition, they are lactose and gluten free, may be fiber-restricted, and may contain increased levels of antioxidants, prebiotics (fructo-oligosaccharides), or omega-3 fatty acids. These additives are thought to modulate the inflammatory response and increase the health of the bacterial gut flora. Treatment with an exclusion diet consisting of a single novel protein source should be used as trial therapy when dietary sensitivity is suspected. In addition, intestinal inflammation is sometimes a manifestation of dietary sensitivity, and an exclusion food trial is also indicated in mild cases of inflammatory bowel disease. Boiled white rice and potato are suitable carbohydrate sources, while lamb or chicken are often used as a protein source, depending on the dietary history. Cottage cheese, horsemeat, rabbit, venison, or fish may be acceptable alternatives. Commercial exclusion diets may be generally less suitable than home-cooked diets for diagnosing food hypersensitivity in dogs, although not necessarily in cats; however, they are preferred for maintenance to reduce dietary imbalances. Protein hydrolysate diets may be most effective in eliminating dietary sensitivity. The exclusion diet generally does not need to be fed for >3 wk. Oral prednisolone (0.5 mg/kg, bid for 2-4 wk, followed by a reducing dose) may be useful in some animals with dietary sensitivity if the initial response to the exclusion diet is disappointing.

Treatment of idiopathic intestinal disease in dogs should initially attempt to eliminate or control an underlying antigenic stimulus that may be playing a primary or secondary role in the damage. This is particularly important if there is evidence of intestinal inflammation. Treatment should first involve the use of an exclusion or protein hydrolysate diet for suspected dietary sensitivity as described above. The diet should comprise digestible carbohydrate, (preferably rice, which is most digestible) and high-quality protein. Restriction of fat content may also be valuable and can minimize the secretory diarrhea that is a consequence of bacterial metabolism of fatty acids and bile salts. Oral prednisolone (0.5 mg/kg, bid for 1 mo, followed by a reducing dose) is indicated in cases of intestinal disease with an obvious inflammatory component, such as lymphocytic-plasmacytic enteritis and eosinophilic enteritis. Higher dosages (1-2 mg/kg, bid) may be indicated in more severe cases. In rare severe cases, it may be necessary to use azathioprine (2-2.5 mg/kg, sid).

Cats with inflammatory bowel disease have a higher incidence of dietary sensitivity than dogs, emphasizing the importance of a dietary trial with an exclusion diet. If this fails, treatment may be needed with oral prednisolone at a dosage of 1-2 mg/kg, daily for 2-4 wk, gradually decreasing until clinical signs resolve. Severe cases often require higher dosages and longterm therapy. Cats that do not respond may be given adjunct metronidazole (10 mg/kg, bid). The beneficial effect of metronidazole might be due to an inhibition of cell-mediated immune responses as well as to its anaerobic antibacterial activity. If remission is not maintained on this combination, other immunosuppressive drugs such as chlorambucil or azathioprine can be attempted, although the latter has many side effects in cats.

For treatment of cases of idiopathic villous atrophy, prednisolone, antibiotics, and an exclusion diet can be considered. In lymphangiectasia, a severely fat-restricted, calorie-dense, highly digestible diet is essential. Supplementation with fat-soluble vitamins is advised, and additional medium-chain triglycerides have been recommended as an easily absorbable fat source that bypasses the lymphatics, although their efficacy has recently been questioned. Prednisone therapy may be beneficial for its anti-inflammatory and immunosuppressive effects, especially if there are associated lymphangitis and lipogranulomas. The response to treatment is variable; clinical signs may sometimes abate for months or even years, but the longterm prognosis is grave. Giardiasis can be treated with metronidazole or fenbendazole, and histoplasmosis with itraconazole (cats) or ketoconazole (dogs), with or without amphotericin B. In cases of lymphosarcoma, treatment involves an appropriate chemotherapy regimen.