This report describes successful treatment of chronic refractory diarrhoea with a BA sequestrant in two dogs. Recent studies have reported faecal BA dysmetabolism and decreased expression of ASBT in the ileum of dogs with CE [6,7,8,9]. Dogs with CE had significantly lower amount of total secondary BAs, and increased percentage of primary BAs compared to healthy dogs [7,8,9]. Similar BA dysmetabolism has been shown in people with inflammatory bowel disease too . In another recent study, the serum concentration of 7α-hydroxy-4- cholesten-3-one (C4), a serum biomarkers of hepatic BA synthesis, was compared between healthy dogs and dogs with chronic diarrhoea . Three of 17 dogs with chronic diarrhoea had serum C4 concentrations significantly above the calculated upper limit of the reference interval. These dogs were all partly or fully refractory to conventional therapy. Based on these previous studies it is likely that bile acid diarrhoea is a disease entity in dogs too, but reports on the clinical course and treatment of BAD in dogs are lacking.
It is estimated that 5–27% of dogs with CE have non-responsive enteropathy (NRE), if studies including only dogs with protein-losing enteropathy are excluded [15,16,17,18,19,20,21,22,23]. If dogs with food responsive enteropathy were excluded, the odds ratio (OR) of becoming refractory to treatment was significantly higher in steroid-responsive dogs compared to food-responsive dogs . Potentially, some dogs with NRE may have BAD.
Bile acid diarrhoea is prevalent in humans with Crohn’s disease and IBS-D. Recent recommendations state that BAD should be considered early in patients with chronic diarrhoea . Still, BAD remains an underrecognized and undertreated condition [5, 24]. There are several pathogenetic mechanisms described that lead to BAD in humans with gastrointestinal disorders, the most common of which is malabsorption of BAs in patients with ileal disease, and dysbiosis, which is associated with a decreased ability to convert primary BAs to secondary BAs. Clostridium hiranonis is a bacterial species that plays a prominent role in converting primary BAs to secondary BAs . Decreased abundance of C. hiranonis has been reported in dogs with CE [9, 25]. However, one of the dogs in this report had a normal dysbiosis index and faecal C. hiranonis abundance, leaving malabsorption the most likely reason for BAD.
Treatment with glucocorticoids in rodent models and healthy human volunteers is associated with increased expression of ASBT, which likely increases BA reabsorptive capacity in the ileum [26, 27]. This positive effect on BA transport might have affected one of the case dogs as well, since diarrhoea ceased with higher doses of corticosteroids. However, this may also have been due to the anti-inflammatory and immune-suppressive properties of corticosteroids.
Cholestyramine is a sequestrant with a high affinity for BAs. When binding to BAs, an insoluble complex is formed that is excreted in the feces. Cholestyramine is recommended for use in dogs at an oral dose of 0.5–2.0 g/dog q 12 h for reduction of idiopathic hypercholesterolaemia . Furthermore, cholestyramine has successfully been used to treat cyanobacterial toxicosis in a dog at a dose of 172 mg/kg for 17 days . Several drugs and toxins must be bound to BAs to undergo enterohepatic circulation. Therefore, the irreversible binding of BAs to cholestyramine inhibits systemic toxin absorption and increases faecal excretion. In healthy laboratory Beagle dogs, the elimination rate of the non-steroidal anti-inflammatory drug (NSAID) tenoxicam was drastically accelerated when multiple doses of oral cholestyramine were given following tenoxicam injection, in contrast to both placebo and charcoal administration . In Plumb’s Veterinary Drugs, cholestyramine is recommended to treat cyanotoxin exposure, NSAID toxicosis and vincristine overdose .
One recent study reported that a cholestyramine dose of 0.7 g/kg q 24 h administered for 14 days to 12 healthy Beagle dogs appeared to be clinically safe . No side effects or weight loss were noted. The faecal dry matter content increased with cholestyramine treatment, but the number of bowel movements did not increase and faecal scores were still in the normal range. Macro- nutrient apparent total tract digestibility decreased after cholestyramine treatment, but remained in the normal range. It should be noted that the dose used in these studies was 7 times higher than the doses used in this case report (0.058 g/kg q 12 h and 0.059 g/kg q 12 h, respectively). However, the long term consequences of cholestyramine treatment in dogs need to be studied.
In people, first-line treatment of BAD is cholestyramine, but gastrointestinal side effects, such as constipation, bloating, nausea, flatulence, abdominal pain and worsening diarrhoea are common . This could affect compliance and make it difficult to titrate dosages to clinical effect. Side effects were less prominent and compliance was better when using newer and more expensive BA sequestrants such as colesevelam or colestipol. Besides gastrointestinal side effects, an over 3-fold increase in alanine aminotransferase (ALT) was noted in 11/67 healthy volunteers . This increase was considered benign, and was not documented in any of the case dogs at follow-up visits. A few cases of vitamin K malabsorption and spontaneous bleeding have been reported in people treated long term with cholestyramine [34,35,36,37]. No negative effect on vitamin K absorption was noted in healthy laboratory Beagle dogs treated with dicumarol and Vitamin K when cholestyramine was given at a dose of 200 mg/kg q 24 h . When the cholestyramine dose was increased to 1.0 g/kg, vitamin K absorption was somewhat delayed, but normalized within 24 h. A massive dose of 3.0 g/kg q 24 h of cholestyramine was associated with decreased absorption of vitamin K if the vitamin and cholestyramine was given at the same time, but not if cholestyramine was given 17 h prior to vitamin K.
In people, 3 categories of tests are available to confirm the diagnosis of BAD . The SeHCAT test measures loss of fecal BAs and is considered the gold standard test, but is only available in very few laboratories worldwide . Alternately, serum levels of of bile acid synthesis, including 7α-hydroxy-4-cholesten-3-one (C4) or the ileal regulatory hormone, fibroblast growth factor 19 (FGF19), can be measured by high-performance liquid chromatography (HPLC). These tests have good specificity and negative predictive value for BA malabsorption in patients with IBS-D or functional diarrhoea, but a lower sensitivity for other types of BA malabsorption. The C4 test is regarded as a good screening test to rule out BA malabsorption, but both C4 and FGF 19 have diurnal variation, which can cause false positive results [3, 40]. Measurement of faecal BAs can be performed using HPLC, but requires a 48 h stool collection period, which is not popular among patients . These diagnostic tests are not widely available. Hence, clinical response to cholestyramine is often used to diagnose BAD in people . This approach can be problematic, as a failed empiric trial with cholestyramine, often due to side effects, does not exclude BAD as a diagnosis . However, the lack of tests to diagnose BAD should not exclude patients with chronic diarrhoea from empiric treatment.
In dogs, analysis of faecal BAs has been described, but a reference interval from a larger population of healthy dogs is lacking [6,7,8,9]. Until tools to diagnose BAD in veterinary medicine are validated and available, we hypothesize that, as in people, empirical treatment with BA sequestrants can be tried in dogs with chronic refractory diarrhoea. This treatment saved the two case dogs from euthanasia.