Research Updates: Ascites validated as a powerful prognostic indicator in canine chronic hepatitis

In 2006, a panel of experts assembled by the World Small Animal Veterinary Association (WSAVA) published guidelines for the standardization of clinical and histologic subtypes of liver disease in small animals.1 These guidelines state that a histologic diagnosis of chronic hepatitis requires the presence of hepatocellular apoptosis or necrosis, a mononuclear or mixed inflammatory infiltrate, hepatocyte regeneration, and fibrosis. Primary chronic hepatitis is clinically diagnosed after identification of these characteristic histopathologic findings and exclusion of secondary causes of chronic hepatitis, including associated toxins, infectious agents, and primary metabolic defects (i.e. copper-associated chronic hepatitis).

Erika Meler, DVM, MS

Although previous studies have examined a variety of clinicopathologic and histopathologic variables in dogs with secondary chronic hepatitis or chronic hepatitis of all types, no prognostic factor has been identified as of yet in dogs with primary chronic hepatitis. Because ascites is a well-recognized negative prognostic factor in people with liver disease, the authors' goal was to compare survival times in dogs with primary chronic hepatitis with or without ascites.

Barrak Pressler, DVM, PhD, DACVIM

In this retrospective study, 34 dogs with clinically and histologically confirmed primary chronic hepatitis were identified by medical records review, exclusion of dogs with suspected or confirmed secondary causes of liver disease, and review of original histologic sections of liver by one veterinary pathologist who was blinded to the clinical information. Information collected for each dog included signalment, date of onset of clinical signs, date of liver biopsy acquisition, the presence or absence of ascites at the time of biopsy, drugs administered, patient outcome (survival or death or euthanasia from liver-related or unrelated disease), and date of death.

Free abdominal fluid (ascites) had been noted in 14 of the 34 dogs and was confirmed to be either a pure or modified transudate in the 11 samples submitted for cytologic examination. Kaplan-Meier survival analysis revealed that the mean survival time was significantly different between the two groups regardless of the date of onset of liver-related clinical signs or the date of biopsy. The median survival of patients that died of liver-related causes from the date of biopsy was 24.3 months for dogs without ascites vs. 0.4 months for dogs with ascites (P < 0.001, meaning that this finding was highly statistically significant). In addition, patients in the nonascitic group were more likely to have been prescribed a liver-specific diet, whereas patients in the ascitic group were more likely to have been prescribed spironolactone.

COMMENTARY

This study confirms that in dogs with confirmed primary chronic hepatitis, those patients with ascites at the time of diagnosis will have significantly decreased survival times compared with those without ascites. Although the number of dogs reported in this study is not large, the difference in survival times between these two groups is large enough that statistical analysis confirms that the difference is not due to chance alone.

The association between ascites and earlier death makes intuitive sense. The pathophysiologic mechanisms thought to be necessary for ascites formation include the presence of portal hypertension, an increase in renin-angiotensin-aldosterone system activation, and hypoalbuminemia; all of these parameters imply advanced disease or a globally diseased liver, and each may independently result in ascites. However, veterinarians should be aware that some owners of dogs with asymptomatic ascites may have elected to euthanize rather than wait for diuretics to exert their effects, and inclusion of these dogs in this study may have influenced the reported results. The mean survival time reported for dogs with ascites was shorter than for human patients with the same histologic and clinical findings, which raises suspicion of this "euthanasia option effect."

In a recent retrospective review of canine chronic hepatitis of multiple etiologies, the prognostic factors associated with a significantly decreased survival time were jaundice, presence of an abdominal fluid wave (presumptively due to ascites), small liver size, enlarged portal lymph nodes, and cirrhosis.2 Half the dogs in that study that had a diagnosis of chronic hepatitis had cirrhosis, an advanced and irreversible stage of hepatic fibrosis. This observation may likewise have been a compounding factor in the study discussed here; dogs with ascites likely have a more advanced stage of disease at the time of presentation and, therefore, logically have decreased survival. Unfortunately, the number of dogs with and without ascites that had cirrhosis (as opposed to just occasional fibrosis) was not reported in this study.

The association between administration of spironolactone and presence of ascites was not surprising, given that this diuretic is only prescribed to patients with hepatic disease known to have sufficient fluid accumulation requiring medical intervention. Spironolactone may help slow or prevent ascites via aldosterone antagonism, which results in reduced sodium and water and reabsorption in the distal renal tubule. In theory, other classes of drugs that inhibit the renin-angiotensin-aldosterone system (e.g. angiotensin-converting enzyme inhibitors such as enalapril or benazepril, or angiotensin II receptor antagonists such as losartan) could also be used to decrease ascites formation. However, aldosterone is also pro-fibrotic, and antagonism with spironolactone may provide additional benefits other than an immediate reduction in ascites.

A reason for the association between feeding a diet formulated for dogs with liver disease and absence of ascites is not as clear. It may be that some patients with ascites would not have developed this complication if they had been fed such a diet earlier in their disease progression. Alternatively, the perceived poorer quality of life of dogs with ascites may have caused most owners to preferentially feed more savory or familiar diets to their pets. Or it may be that those disease factors that directly or indirectly cause fibrosis, cirrhosis, or development of ascites are not altered by dietary therapy. Nevertheless, at this time most veterinary hepatologists suggest that dogs with ascites be fed a sodium-reduced diet.

Raffan E, McCallum A, Scase TJ, et al. Ascites is a negative prognostic indicator in chronic hepatitis in dogs. J Vet Intern Med 2009;23(1):63-66.

The information in "Research Updates" was provided by Erika Meler, DVM, MS, and Barrak Pressler, DVM, PhD, DACVIM, Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Purdue University, West Lafayette, IN 47907.

REFERENCES

1. WSAVA Liver Standardization Group. WSAVA standards for clinical and histopathological diagnosis of canine and feline liver diseases. Philadelphia, Pa: Elsevier; 2006.

2. Poldervaart JH, Favier RP, Penning LC, et al. Primary hepatitis in dogs: a retrospective review (2002-2006). J Vet Intern Med 2009;23(1):72-80.