Idiopathic Vacuolar Hepatopathy

Chapter 148

Idiopathic Vacuolar Hepatopathy

Hepatic vacuolar change is a common histologic diagnosis in dogs but not cats. In the author’s review of 150 consecutive liver biopsies performed at Colorado State University approximately 12% of the cases had predominantly a vacuolar hepatopathy (VH) as the major histologic finding. By definition according to the World Small Animal Veterinary Association (WSAVA) Liver Standardization Group, VH refers to a reversible parenchymal change characterized by swollen hepatocytes with clear cytoplasm resulting from glycogen without displacement of the nucleus from the center (Cullen et al, 2006). The distribution and the extent of the lesion can be diffuse or zonal or involve individual cells. VH is a relatively easy histologic diagnosis to make; however, periodic acid-Schiff (PAS) staining with or without diastase can be used to demonstrate glycogen accumulation. Vacuolated hepatocytes also can result from fat accumulation secondary to abnormal fat metabolism and is referred to as hepatic steatosis or lipidosis. Hepatic steatosis is a distinct histologic vacuolar classification associated with abnormal fat metabolism and is not discussed in this chapter.


VH in dogs is associated most often with hyperadrenocorticism (HAC). The dog is particularly sensitive to the effects of glucocorticoids that induce serum alkaline phosphatase (ALP) steroid isoenzyme activity and cause hepatic glycogen accumulation (see Web Chapter 50). Congenital glycogen storage disorders, breed-specific disorders, hepatic nodular hyperplasia, and a variety of stress-associated secondary diseases are conditions that can cause this typical hepatic vacuolar change. A large study of 336 histologic liver specimens having VH (defined as making up greater than 25% of the hepatocytes) were reviewed retrospectively for an underlying etiology (Hill et al, 2006). The authors reported 55% of the cases were associated with either endogenous or exogenous glucocorticoids and 45% had no known glucocorticoid exposure. Most of the dogs with no glucocorticoid exposure had other identifiable concurrent illness. Conditions such as renal, immune-mediated, cardiac, hepatic, or gastrointestinal disease or neoplasia accounted for many cases. The author’s hypothesis was that stress-induced hypercortisolemia associated with acute or chronic illness likely contributed to the development of the VH. A second in vivo study showed that experimentally inducing chronic fourfold to fivefold elevations in plasma cortisol concentrations to simulate a stresslike state in normal dogs resulted in inhibited nonhepatic glucose use and increased hepatic gluconeogenesis and glycogen formation through enhanced substrate delivery to the liver (Goldstein et al, 1993).

A rare cause of VH is glycogen storage disease. These are groups of congenital disorders with deficient or defective activity of the enzymes responsible for metabolizing hepatic glycogen (Specht et al, 2011). Affected dogs are young, exhibit signs of hypoglycemia, and have large livers with marked glycogen accumulation. Hepatic nodular hyperplasia is a common, benign intrahepatic event; it causes an increase in liver enzymes and histologic changes, which include macroscopic or microscopic hepatic nodules that often contain a VH. VH also is observed in the regenerative nodules of dogs with the hepatocutaneous syndrome.

Idiopathic Vacuolar Hepatopathy

However, a subset of dogs have elevations in serum ALP and excessive hepatic glycogen accumulation that do not have evidence of a stress-induced illness or HAC based on cortisol testing, a history of recent glucocorticoid administration, or a specific hepatic disease. These dogs are referred to as having an idiopathic vacuolar hepatopathy (IVH). They generally have no clinical signs and usually are identified during investigation of unexplained elevations in serum ALP found on routine health screens. Several theories have been proposed regarding the cause of IVH. Some believe adrenal progestagens are the cause; most likely increases in 17-hydroxyprogesterone and progesterone are responsible as these abnormalities are frequently identified when using a commercial adrenal steroid panel. However, critical evaluation and validation of adrenal steroid panels (measuring 17-hydroxyprogesterone, progesterone, estradiol, testosterone, and androstenedione) are still lacking, and a direct association to IVH has not been made. To confuse matters further, the author and others have observed similar abnormalities in noncortisol adrenal steroids in dogs without IVH or having increases in serum ALP, which casts doubt on the relationship of these specific progestagens in this condition. Progestagens are reported to bind to glucocorticoid receptors, but whether they can induce a glucocorticoid response is unknown. One in vitro study found that sex hormones do not induce ALP production in isolated hepatocytes (see Chapter 50 for more detail). Some suggest that progestagens may act by increasing the bioavailability of cortisol by competing for the same binding receptors; this results in an increase in endogenous cortisol, which causes the VH. However, IVH dogs by definition have normal serum cortisol concentrations (see Chapter 50). Because the VH changes are typical of glucocorticoid excess, an adrenal steroid yet to be identified could be responsible for the VH. Obviously future research is necessary to delineate this syndrome and the relationship to adrenal steroids.

Scottish terriers also are reported to have a breed-specific syndrome associated with a VH and elevated serum ALP (Zimmerman et al, 2010). These affected dogs generally have no clinical signs. The authors of this study found that the elevated ALP was predominantly the corticosteroid isoform and following ACTH stimulation test in conjunction with an adrenal steroid panel found increases in one or more noncortisol steroid hormones. The authors concluded that affected Scottish terriers have a type of HAC on the basis of exaggerated adrenal hormone response. The author of this chapter also has observed similar noncortisol steroid hormone increases in Scottish terriers but also in Scottish terriers without VH or increases in ALP, adding more confusion to this syndrome. See Chapter 51 for further information on adrenal steroids.

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Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Idiopathic Vacuolar Hepatopathy

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