Vacuolar Hepatopathy in the Scottish Terrier

Remo Lobetti BVSc MMedVet (Med) PhD Dipl ECVIM (Internal Medicine) Bryanston Veterinary Hospital, PO Box 67092, Bryanston, 2021, South Africa, Email: rlobetti@mweb.co.za,                                                                                       Reviewed by Dr Marlies Böhm

Vacuolar hepatopathy (VH) is a common and frustrating diagnosis often without a specific aetiology. When hepatocytes become injured, one response is for them to swell and become vacuolated. Hepatocellular vacuoles distending the cytosolic compartment may contain, fat, glycogen, intracellular water, metabolic waste products or metabolic intermediates.

Vacuolar hepatopathies may occur in conjunction with hydropic degeneration in which there is cytosolic swelling but devoid of distinct vacuoles. Vacuolar hepatopathies can be caused by a number of conditions – or lesions may develop because of secondary chronic stress (presumed to be endogenous steroid induced) resulting from concurrent disease.

In dogs there are several ALP isoenzymes : bone , liver, and steroid induced, specific to dogs, being some. In dogs, elevated serum ALP activity may reflect inflammatory, neoplastic, or cholestatic disorders involving the liver, biliary tree, or pancreas. A common cause for VH in dogs is the endogenous overproduction of steroidogenic hormones or treatment with cortisone2. Increased hepatic production of ALP and its release into the systemic circulation accompanies VH, with the corticosteroid-induced ALP iso-enzyme predominating. Greater than a 3-fold elevation in serum ALP activity is common in dogs with VH.

Traditionally VH is considered a benign lesion, however, progressive VH can lead to diffuse hepatic remodelling resulting in the formation of parenchymal nodules and intra-sinusoidal hypertension secondary to hepatic remodelling. In its extreme manifestation, VH can result in splanchnic hypertension, acquired portosystemic shunts, ascites, and hepatic insufficiency.

Although degenerative VH can develop in any dog, it is recognized as a progressive VH in the Scottish terrier, a breed which also shows a high incidence of hepatic carcinoma. One study in healthy Scottish terriers showed a relationship between elevated serum ALP activity and increased adrenocorticosteroid hormone concentrations following ACTH stimulation as well as a correlative association between older age and concentration of androstenedione.

In a retrospective study, it was shown that VH accompanied by a progressive increase in serum ALP activity was found in the Scottish terrier. These increases are marked – reaching the 2000-3000u/L range . Sequential monitoring over years in individual dogs has confirmed the progressive nature of this syndrome, with increases in serum ALP activity coinciding with development of diffuse increased hepatic parenchymal echogenicity and numerous small hypoechoic parenchymal nodules evident on ultrasonographic examination. Although ultrasonographic detection of features such as hyperechoic or coarse-appearing hepatic parenchyma, hypoechoic nodules contrasting against hyperechoic parenchyma, and discrete mass lesions is common, ultrasound cannot definitively confirm VH. Ultrasonographic features reflect hepatic parenchymal remodelling and progression of non-degenerative to degenerative VH with formation of regenerative nodules sometimes associated with dysplastic hepatocellular foci. It is possible that these foci precede the development of hepatic carcinoma as occurs in humans.

Approximately 40% of Scottish terriers with VH have a broad range of historical, physical, and clinic-pathologic features consistent with typical hyperadrenocorticism. Finding elevated serum ALP activity or VH in a Scottish terrier may thus lead to adrenal function testing that may show an exaggerated adrenal hormone production, which then may be interpreted to represent typical or atypical hyperadrenocorticism. However, one study in 13 Scottish terriers undergoing conventional therapy for hyperadrenocorticism showed no positive outcomes. All treatments were either ineffective or resulted in adverse reactions, such as glucocorticoid insufficiency, hepatotoxicity, and even death. The apparent frailty of the Scottish terrier with VH treated with conventional therapy for hyperadrenocorticism remains unexplained.

As the underlying metabolic abnormality causing VH in the Scottish terrier may be associated with sex hormone–related adrenal gland hyperactivity, treatment with trilostane may thus be ill-advised, considering that studies in dogs have shown that trilostane fosters accumulation of sex hormone precursors, fails to control overproduction of androstenedione, and leads to adrenomegaly. Adrenal gland hyperactivity associated with VH in the Scottish terrier predominantly involves sex hormones (most notably progesterone and androstenedione) and may be accompanied by overt adrenomegaly (unilateral or bilateral). Despite adrenomegaly, various studies have shown that cortisol assessments (baseline and post-ACTH stimulation testing, low-dose dexamethasone suppression test, urine cortisol-to-creatinine ratio) inconsistently verify typical hyperadrenocorticism.

It remains possible that adrenal hyperplasia secondary to chronic stress or illness can account for the increased serum concentrations of cortisol and sex hormones. However, it is plausible that the adrenal gland hyperactivity and associated VH reflect a breed-related genetic disorder affecting adrenal steroid genesis that leads to ALP induction, hepatocellular glycogen accumulation, progressive VH, and ultimately formation of hepatic carcinoma in some dogs. In some Scotties, VH is not always benign, as it may rapidly progress to liver failure with development of small nodular liver, portal hypertension, and ascites. Yet, in other dogs with VH, chronically elevated serum ALP activity (3-20 fold) can persist for > 10 years without apparent clinical deterioration.

The magnitude of elevated serum ALP and ALT activities does not differentiate between dogs with VH with and without hepatic carcinoma and does not predict early death from hepatic failure. Consequently, considering the variable age of syndrome onset and rate of progression, it is impossible to predict relative risk for hepatic failure or development of hepatic carcinoma without sequential patient monitoring.

In conclusion, the Scottish terrier has a breed-specific VH containing glycogen and moderately to severely elevated serum ALP activity. Affected dogs generally have no clinical signs; show elevated ALP activity; and increases in one or more non-cortisol steroid hormones can be demonstrated. It is thus recommended that Scottish terriers with elevated serum ALP activity undergo biannual monitoring of serum liver enzyme activities and liver function as well as a yearly hepatic ultrasonographic examination.

Increased surveillance frequency is advised for dogs with sudden marked increases in serum ALP activity or transitioning to a nodular hepatopathy on ultrasonographic evaluation. This strategy would allow early detection of hepatic mass lesions likely to represent surgically excisable hepatic carcinomas and recognition of a subclinical gallbladder mucocele that may allow for uncomplicated cholecystectomy.

In Summary                                                                                                                                                                           From the desk of Dr Marlies Bohm

• Scotties have higher ALP levels than other breeds.

• In Scotties, ALP levels increase with age.

• The pesky bit – Scotties also have a higher prevalence of diseases associated with high ALP levels – Cushing’s, pancreatitis, cholestatic liver disease, diabetes.

• When Scotties have these diseases their ALP levels are much more elevated than that of dogs of other breeds affected with the same disease. But then they also show the typical changes on history, clinical exam and bloods for these diseases.

In your happy high ALP Scotties, ALT levels are typically mildly increased (usually < 3x), urine SG is decreased (typically in the mid teens) and cortisol levels may be increased post ACTH in about 1/3 of dogs.

One retrospective study of 114 Scotties with high ALP showed that 34 eventually developed a hepatocellular carcinoma. But the dogs with a liver tumour lived just as long as the dogs that had just the vacuolar hepatopathy.

In your happy high ALP Scotties, ALT levels are typically mildly increased (usually < 3x), urine SG is decreased (typically in the mid teens) and cortisol levels may be increased post ACTH in about 1/3 of dogs.

So:

• If a Scottie has high ALP levels and is otherwise well, leave him be.

• If you suspect pancreatitis, diabetes or Cushing’s you need to ignore the ALP in your work-up.This is particularly important with Cushing’s.

• If you think he has another hepatobiliary disease you’re going to need more than an elevated ALP to suspect it and a biopsy to prove it.

• Dogs with focal hepatocellular carcinoma can do very well after resection, so if you have a client that would operate on their dog serial ultrasounds could be considered.

REFERENCES

• Badylak SF, Van Vleet JF. 1981. Sequential morphologic and clinicopathologic alterations in dogs with experimentally induced glucocorticoid hepatopathy. American Journal of Veterinary Research; 42:1310–1318.

• Center SA. Interpretation of liver enzymes. 2007. Veterinary Clinics of North America: Small Animal Practice; 37:297– 333.

• Center SA. Breed specific hepatopathies in Scottish terrier and Maltese dogs. 2012. Proceedings of the American College of Veterinary Internal Medicine Forum; 694.

• Cortright CC, Centre SA, Randolph JF, et al. 2014. Clinical features of progressive vacuola hepatopathy in Scottish Terriers with and without hepatocellular carcinoma: 114 cases (1980–2013). Journal of the American Veterinary Medical Association; 245: 797-808.

• Mantis P, Lamb CR, Witt AL, et al. 2003. Changes in ultrasonographic appearance of adrenal glands in dogs with pituitary-dependent hyperadrenocorticism treated with trilostane. Veterinary Radiology and Ultrasound; 44:682– 685.

• Ruckstuhl NS, Nett CS, Reusch CE. 2002. Results of clinical examinations, laboratory tests, and ultrasonography in dogs with pituitary-dependent hyperadrenocorticism treated with trilostane. American Journal of Veterinary Research; 63:506–512.

• Sepesy LM, Center SA, Randolph JF, et al. 2006. Vacuolar hepatopathy in dogs: 336 cases (1993–2005). Journal of the American Veterinary Medical Association; 229:246– 252.

• Sieber-Ruckstuhl NS, Boretti FS, Wenger M, et al. 2006. Cortisol, aldosterone, cortisol precursors, androgen and endogenous ACTH concentrations in dogs with pituitary-dependent hyperadrenocorticism treated with trilostane. Domestic Animal Endocrinology; 31:63–75.

• Zimmerman KL, Panciera DL, Panciera RJ, et al. 2010. Hyperphosphatasemia and concurrent adrenal gland dysfunction in apparently healthy Scottish Terriers. Journal of the American Veterinary Medical Association; 237:178– 186.

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