Malabsorption Syndromes in Small Animals

The dietary history is particularly important, because it may suggest specific dietary intolerance, indiscretion, or sensitivity. Weight loss may indicate malabsorption or protein-losing enteropathy (PLE) but may also be due to anorexia, vomiting, or extra-intestinal disease. Small- and large-intestinal diarrhea may be distinguished by a number of features ( see Table: Differentiation of Small-Intestinal from Large-Intestinal Diarrhea). This distinction is helpful in identifying differential diagnoses and deciding where to take biopsies. Suspected large-intestinal disease in dogs may be evaluated by colonoscopic biopsy. However, diffuse disease is more common, and if signs of large-intestinal disease are accompanied by weight loss, large volumes of feces, or hypocobalaminemia, then there is almost certainly concurrent small-intestinal disease.

A thorough physical examination should be performed. Abdominal palpation is essential to identify abnormalities, and rectal examination is required even when no large-intestinal disease is suspected, both to provide a fecal sample and also to identify previously unreported GI bleeding. In older cats, the thyroid should be palpated carefully (and serum T₄ assayed), because signs of hyperthyroidism can closely mimic those of primary intestinal malabsorption.

Initial evaluation should include a minimum database (CBC, biochemical profile, urinalysis, fecal examination) to rule out non-GI disease Hematologic findings in small-intestinal disease sometimes include:

• anemia of chronic blood loss (microcytic, hypochromic) or chronic inflammation (normocytic, normochromic)

• neutrophilia and/or monocytosis associated with intestinal inflammation, infectious enteropathies, or neoplasia

• eosinophilia associated with parasitism and eosinophilic enteritis

• lymphopenia associated with intestinal lymphangiectasia in dogs

• lymphocytosis in a sick dog raises the suspicion of hypoadrenocorticism

Biochemical tests and urinalysis help to exclude systemic diseases that cause chronic diarrhea, most notably hypoadrenocorticism, protein-losing nephropathies, chronic kidney disease, and liver disease. Hypoproteinemia is frequently secondary to PLE and is seen more commonly in dogs than cats. In most cases of PLE, serum albumin and globulin are both low, but a low albumin alone does not exclude it; inflammatory bowel disease (IBD) and neoplasia are occasionally associated with hyperglobulinemia as well as hypoalbuminemia. Hepatocellular enzymes (ALT, AST) may be increased 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. However, in cats, there may be concurrent IBD and cholangitis (triaditis). Cholestatic enzymes (ALP, GGT) tend to be increased in biliary and pancreatic disease. Urinalysis is important to exclude renal causes of hypoalbuminemia and/or renal disease. However, sometimes both may be seen together (eg, the familial PLE and protein-losing nephropathy of Soft-coated Wheaten Terriers). Hypocholesterolemia may develop with fat malabsorption and is most notable in lymphangiectasia.

Fecal analysis may reveal fat, undigested muscle fibers, or starch. They are indirect evidence for malabsorption, but are nonspecific findings. Fecal analysis is primarily indicated for the identification of infectious agents:

• Feces should be examined for endoparasitic ova and oocysts (especially hookworms and Giardia in dogs and Tritrichomonas and Giardia in cats). Giardia oocysts can be detected using serial zinc sulfate fecal flotations or a commercially available SNAP or ELISA test; the latter is easier to perform, and its sensitivity is better than fecal flotation performed by inexperienced personnel. Tritrichomonas typically causes colitis in cats rather than malabsorption and is best diagnosed by pouch culture or PCR. Cytology of rectal scrapings may reveal Histoplasma organisms. Cryptosporidium is a rare cause of malabsorption and is best identified in feces by immunofluorescence.

• Potentially pathogenic bacteria (including Salmonella and Campylobacter) can be isolated by stool culture. However, isolation of pathogenic bacteria is not conclusive proof of causation because such organisms can be found in the stool of clinically healthy animals. Speciation of Campylobacter isolates by PCR allows distinction of the pathogenic C jejuni from the more common and probable commensal C upsaliensis. Some Escherichia coli are potential pathogens, but molecular techniques to identify genes encoding pathogenicity determinants are required for diagnosis.

• Bacteriologic culture of duodenal fluid obtained endoscopically or at laparotomy has been used to make a diagnosis of SIBO. However, the exact cut-off point at which small intestinal bacterial numbers are considered excessive is a matter of debate, because numbers >10⁵ total or >10⁴ obligate anaerobic colony-forming units (CFU)/mL may be found in apparently clinically healthy dogs, depending on circumstances, including environment, diet, scavenging, and coprophagia.

Once obvious dietary, systemic, parasitic, and infectious causes of chronic small-intestinal diarrhea have been eliminated, the next step is differentiation of specific non-small intestinal causes of malabsorption:

• In dogs, EPI should be ruled out before investigating small intestinal causes of malabsorption. The diagnosis of EPI is relatively straightforward, whereas that of small intestinal disease is more complex. Numerous tests have been used for dogs and cats with suspected EPI, but they are too inaccurate or impractical to be recommended. Assay of serum trypsin-like immunoreactivity (TLI) is a highly sensitive and specific test and should be used for the diagnosis of EPI. This assay measures trypsinogen, some of which normally leaks from the pancreas into the blood, thereby providing an indirect assessment of functional pancreatic tissue. In 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. Species-specific canine and feline TLI tests are available, but EPI is a rare cause of malabsorption in cats.

• Hypoadrenocorticism and atypical hypoadrenocorticism in dogs can be ruled out by finding a basal cortisol >55 nmol/L, or by an ACTH stimulation test.

• Hyperthyroidism in cats should be excluded by measuring serum T₄ concentrations.

• Serologic tests for feline leukemia and feline immunodeficiency viruses should also be performed in cats, not only because both may be associated with secondary, chronic diarrhea but also because they are important prognostic factors.

Radiography and ultrasonography should be considered complementary. When indicated by clinical signs or abnormal abdominal palpation, plain radiography is used to identify surgical conditions and to provide clues as to the nature of any small intestinal disease. Abdominal radiography can identify foreign bodies, intestinal obstructions, and masses, but is most useful when vomiting is present or palpable abnormalities are detected. Computed tomography provides greater detail of all abdominal structures but is often not available.

Ultrasonography is an important part of the investigation of most small intestinal diseases. Changes consistent with pancreatitis may be observed ultrasonographically, but failure to find a pancreas is an unreliable way to diagnose EPI. It can measure intestinal wall thickness, layering, and luminal diameter and detect other intestinal lesions (eg, masses, intussusception), mesenteric lymphadenopathy (in neoplasia and inflammatory enteropathies), and abnormalities in other organs. A thickened small intestinal wall and loss of layering is highly suggestive of neoplasia. Mucosal striations have been associated with lymphatic dilatation.

The 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 SI (ileum). As a result, serum folate concentrations can be decreased in proximal SI diseases, serum cobalamin concentrations can be decreased in distal SI diseases, and both can be decreased in diffuse enteropathies. Other factors such as the severity, extent, and duration of a mucosal abnormality; dietary intake; and vitamin supplementation also influence these concentrations.

Hypocobalaminemia is particularly associated with IBD and alimentary lymphoma and results in metabolic changes, including methylmalonic acidemia, that can lead to anorexia. Subnormal cobalamin concentrations are an indication for parenteral supplementation.

In addition, EPI can affect serum folate and cobalamin concentrations, and changes in serum folate and cobalamin concentrations are unreliable for the diagnosis of ARD and secondary SIBO. The validity of serum folate concentrations as a marker of small-intestinal disease in cats is less clear, but hypocobalaminemia is common in cats and may be found in both small-intestinal disease and EPI and when they occur concurrently.

IV administration of ⁵¹Cr-labeled albumin (or ⁵¹CrCl₃ to label endogenous albumin) has been used historically to document PLE in dogs. Measurement of 3-day fecal excretion of this radioactive marker provides an estimation of labeled albumin and hence protein loss into the intestinal lumen. However, its use is very limited because of the need for a radioactive marker.

An alternative approach is the measurement of alpha-1 proteinase inhibitor in the feces. This plasma protein is lost into the intestinal lumen together with albumin, but unlike albumin it is an antiproteinase and is excreted in the feces essentially intact. Species-specific assays have been developed, but only a canine assay is available and only in the USA. Three fresh fecal samples passed by spontaneous evacuation are required; any GI bleeding invalidates the result.

Intestinal inflammation may be identified indirectly by increases in serum C-reactive protein. A more specific test that measures fecal calprotectin is not readily available.

Intestinal biopsy often identifies chronic inflammatory enteropathies but rarely the cause of the inflammation. Although it may be idiopathic (ie, IBD) and require immunosuppression, parasitic infections, food-responsive enteropathies, and ARD may show similar histologic changes. Therefore, sequential empirical antiparasitic trials (ie, a three-day course of fenbendazole) and diet trials are indicated before biopsy if there are no criteria of concern. To avoid inappropriate use of antibacterials and the development of resistance, empirical antibacterial trials before biopsy are reserved for those patients in whom ARD is suspected (eg, young German Shepherds). The presence of anorexia, abnormal abdominal palpation and/or imaging, severe hypoproteinemia, and GI bleeding are all indications to proceed to biopsy.

For an exclusion diet trial, hydrolyzed diets are preferred: it is easier to feed a novel diet than to choose a single protein to remove from the diet, remission is achieved more frequently, and time to relapse is longer. However, hydrolyzed diets may be less palatable, not balanced for growth in young animals, and not in a palatable formulation (most are dried kibble). Curiously, followup studies after successful clinical resolution with a hydrolyzed diet do not show resolution of the histologic changes.

Definitive diagnosis of chronic small-intestinal disease ultimately includes histologic examination of intestinal biopsies taken by endoscopy or at laparotomy. However, if there is clinical remission with a prior empirical treatment trial, biopsy is not justified. Histologic examination of intestinal biopsy specimens can identify morphologic changes of intestinal inflammation (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 if sequential biopsies are possible, although resolution of changes does not always follow clinical remission. Morphologic abnormalities may also provide prognostic information, because more severe enteropathies tend to be more difficult to manage.

Endoscopy is minimally invasive and allows visualization of the mucosa and targeted biopsy sampling. However, endoscopic mucosal biopsies cannot give an adequate representation of deeper disease and are limited to the parts of the SI small intestine (duodenum and sometimes proximal jejunum and ileum) that can be visualized via gastroscopy and colonoscopy. Endoscopic biopsy is preferred initially because the risk of intestinal surgical wound dehiscence can exceed 10% in debilitated, malnourished, or hypoproteinemic animals.

Surgery is the preferred option when there is a concern about deeper or extraintestinal disease or a focal lesion has been identified. Due to the risks associated with enterotomies, empirical treatment trials are usually performed first unless a surgical condition (eg, a focal lesion, partial obstruction) has been identified by palpation or imaging. If a laparotomy is performed and a gross focal lesion is not present, multiple elliptical, longitudinal biopsy samples should be collected from the duodenum, jejunum, and ileum; mesenteric lymph nodes should be biopsied and other organs examined.

However, there may be minimal or no obvious abnormalities in certain malabsorptive disorders (eg, ARD) despite considerable interference with intestinal function. Nevertheless, histologic descriptions alone provide little information on possible etiology or underlying mechanisms of damage, which would assist effective management and determination of prognosis. Furthermore, inconsistencies in histologic descriptions between pathologists is a recognized problem. However, the World Small Animal Veterinary Association GI Standardization Group has published a descriptive template as a basis for concordance.

Dietary modification is a critical aspect of the management of small-intestinal diseases both in dogs and cats. Diets generally contain moderate levels of limited protein sources and highly digestible carbohydrates (to reduce protein antigenicity and osmolar effects and to improve nutrient availability) and low to moderate levels of fat. In addition, they are lactose and gluten free, may be fiber-restricted, and may contain increased levels of antioxidants, prebiotics (eg, fructo-oligosaccharides), or omega-3 fatty acids. These additives are thought to modulate the inflammatory response and increase the diversity of the microbiome and health of enterocytes. Prebiotics are digestible fibers that encourage the growth of a healthy microbiome.

Treatment with an exclusion diet consisting of a single novel protein source or a hydrolyzed protein should be used as trial therapy when intestinal inflammation or dietary sensitivity is suspected. Boiled white rice, tapioca, and potato are suitable gluten-free carbohydrate sources, while cooked white fish, lamb, or chicken are often used as a protein source, depending on the dietary history. Cottage cheese, duck, horsemeat, rabbit, or venison may be acceptable alternatives.

Home cooking of diets ensures the ingredients that are being fed and a commercial single protein exclusion diet is not essential during a diet trial; however, they are preferred for maintenance to reduce potential longterm nutritional imbalances. However, commercial protein hydrolysates may be the most effective diets to manage inflammatory enteropathies and identify dietary sensitivities. The response to an exclusion diet is often rapid, but the diet must be fed for at least three and, in a few cases, up to ten weeks before being considered a failure.

Probiotics. Evidence for the efficacy of probiotics in chronic enteropathies is largely lacking, but hypothetically they help restore a normal microbiome and reduce intestinal inflammation.

Cobalamin and folate supplementation. Hypocobalaminemia is common in both EPI and chronic enteropathies and leads not only to metabolic changes that suppress appetite, but also to histologic small-intestinal changes; the small intestine needs cobalamin to be healthy. Traditionally cobalamin has been supplemented by weekly SC injections. However, recent studies in dogs and cats have shown that daily oral supplementation bypasses the normal absorption pathway and can restore normal serum cobalamin concentrations and correct any metabolic changes. Oral cobalamin has even been shown to be effective in EPI, despite the secretion by the pancreas of intrinsic factor, a protein linked to cobalamin absorption being impaired.

The effect of hypofolatemia has not been elucidated in dogs and cats but leads to anemia in humans. So whether it is simply a marker of small-intestinal damage or actually needs to be supplemented is not yet known.

Antidiarrheals.Oral kaolin and pectin-based suspensions can help solidify diarrhea but are only symptomatic treatments. Similarly, opioids (eg, loperamide) only provide temporary symptomatic relief by modifying motility and decreasing small-intestinal secretion.

Effective treatment of EPI and small-intestinal disease depends on the nature of the disorder, but therapy may be empirical when a specific diagnosis hasn't been made.

Exocrine pancreatic insufficiency. Management of EPI in dogs is relatively straightforward and includes replacing pancreatic enzymes with exogenous enzymes and dietary modification. Feeding a low-fiber diet that contains moderate levels of fat or highly digestible fat, very digestible carbohydrate, and high-quality protein is often recommended. Yet in many dogs and most cats, a standard, good-quality commercial diet is adequate.

Treatment will require lifelong supplementation of each meal with pancreatic extract. Powdered extracts (1 tsp/10 kg body wt) are preferable to tablets, capsules, and most enteric-coated preparations. Fresh or fresh-frozen pancreas can be used as an alternative (100 g/meal for an adult German Shepherd). Treatment of EPI in cats is similar, but cobalamin supplementation is almost invariably required.

The response to pancreatic enzyme replacement therapy may be poor and adjunctive treatments may be necessary:

• Secondary SIBO may be suspected, and the animal should be treated concurrently with oral antibiotics for ≥1 month (see below).

• Acid suppressants (eg, H₂-receptor blockers such as cimetidine or ranitidine; proton pump inhibitors, such as omeprazole) may be given 20 minutes before a meal to inhibit acid secretion and minimize acid degradation of enzymes in the pancreatic extract, but they are expensive and their value is questionable.

• Oral multivitamin supplementation should be considered as supportive therapy, but cobalamin (500–1,000 mcg/week until normalized) should be given.

Dysbiosis and antibiotic-responsive diarrhea. In dogs with ARD, 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 (20–40 mg/kg, PO, every 8 hours for maximum 14 days) has been successful. Metronidazole (10–20 mg/kg, PO, every 12 hours) and tylosin (10–80 mg/kg, PO, every 8–12 hours) are effective alternatives; there is rarely a need to use other antibiotics, and the nontargeted use of fluoroquinolones should be avoided.

Repeated or longterm treatment may be necessary in dogs with idiopathic ARD. Vitamin supplementation may be helpful, particularly for animals with cobalamin deficiency. Secondary ARD usually resolves with appropriate management of the underlying disease (eg, EPI), but idiopathic ARD can be difficult to control, especially in young German Shepherds, which are predisposed to developing the condition.

Inflammatory bowel disease. Treatment of idiopathic inflammatory bowel disease should initially attempt to eliminate or control an underlying antigenic stimulus that may be playing a primary or secondary role in the damage. Treatment should first involve the use of a protein hydrolysate diet. If this is refused by a patient, the diet should comprise digestible carbohydrate (preferably rice, which is most digestible) and a high-quality single 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 prednisone/prednisolone (1 mg/kg, every 12–24 hours for 2–4 weeks, 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, and no evident underlying cause. In more severe cases, it may be necessary to add chlorambucil (2–6 mg/m², PO, every 24 hours until remission, followed by drug tapering) in cats and dogs or ciclosporin (5–10 mg/kg, PO, every 12–24 hours) or azathioprine (2–2.5 mg/kg, PO, every 24–48 hours) in dogs.

Cats are often given adjunctive metronidazole (10 mg/kg, every 12 hours); the beneficial effect of metronidazole may be a result of an inhibition of cell-mediated immune responses as well as anaerobic antibacterial activity. However, the value of metronidazole in combination with prednisolone in the treatment of IBD in dogs has not been shown.

Lymphangiectasia. In lymphangiectasia, a severely fat-restricted, calorie-dense, highly digestible diet that reduces diarrhea has been recommended but tends to exacerbate weight loss. 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 this mechanism is now doubted. Prednisone/prednisolone therapy may be beneficial for its anti-inflammatory and immunosuppressive effects, especially if there is associated lipogranulomatous lymphangitis. The response to treatment is variable; clinical signs may sometimes abate for months or even years, but the longterm prognosis is grave.

Infectious causes. Giardiasis can be treated with metronidazole or fenbendazole, and histoplasmosis treated with itraconazole (cats) or ketoconazole (dogs), with or without amphotericin B.

Intestinal neoplasia. The treatment of alimentary lymphoma involves an appropriate chemotherapy regimen, but response is very poor in dogs and poor in cats with lymphoblastic forms. In cats, treatment of small-cell villous lymphoma with oral prednisone and chlorambucil has been associated with prolonged remission.

Solid tumors of the small intestine (eg, adenocarcinoma) more typically produce signs of intestinal obstruction and bleeding with diarrhea rather than malabsorption. They are managed primarily by surgical resection.