Recognizing and treating common liver diseases (Proceedings)

Reactive Hepatopathies

The so-called "reactive hepatopathies" which occur secondary to non-hepatic disease can result in increased serum biochemical hepatic tests and histomorphologic abnormalities. Most of the reactive hepatopathies cause increases in laboratory tests that evaluate hepatocellular integrity (ALT, AST) and tests of hepatic cholestasis (ALP, GGT). In most cases there are little if any changes in tests that evaluate hepatic function (bilirubin, albumin, glucose, and BUN). Most of the animals with secondary liver disease also retain normal serum bile acid concentrations, which again supports a concept that there is generally minimal hepatocellular dysfunction in most of these disease conditions.

This group is characterized by nonspecific hepatocellular degeneration or necrotic changes without evidence of significant chronic progressive inflammation. Again, these changes are usually secondary to manifestations of a primary non-hepatic disease. The reason the liver often undergoes these changes revolves from the fact that the liver is involved in many metabolic and detoxification functions. Endogenous toxins, anoxia, metabolic changes, nutritional changes and endogenous stress related glucocorticoid release are examples of conditions responsible for the majority of these changes. Non-specific mild liver changes routinely also occur following general anesthesia.

A good example that helps explain this concept is inflammatory bowel disease in which it is not unusual to observe mild inflammatory changes around portal triads presumed to be the result of abnormal portal uptake of gastrointestinal "toxins". Throughout the liver and closely associated with portal areas are Kupffer cells (fixed macrophages) that function to filter the blood of injurious toxins, inflammatory mediators and bacteria. When this macrophage system is abnormally insulted Kupffer cells release their own inflammatory mediators that in turn insult the hepatocytes.

Another example could be the sick septic dog having vacuolar change thought to be due to endogenous cortisol release for endogenous stress and hepatic cholestasis from presumed endotoxin or cytokine alteration of bilirubin metabolism.

Histological findings associated with secondary reactive changes include descriptors such as vacuolar degeneration, hydropic degeneration, swollen hepatocytes, lipidosis, intracellular or intrahepatic cholestasis, mild multifocal hepatitis and periportal or variable hepatic necrosis. These changes are devoid of the typical progressive chronic inflammatory cell infiltrates characteristic of chronic hepatitis.

In a review of consecutive liver biopsies at Colorado State University histology grouped as non-specific reactive changes made up the largest category of abnormalities (approximately 25%) In this group we were able to identify an associated disease in many that could explain the likely cause for the hepatic enzyme increases and histological changes observed. Concurrent diseases identified included neoplasia, gastrointestinal, renal, autoimmune, dermatologic, dental, infectious and cardiac disease as a few examples. In some cases an underlying disease is not identified. The ALT values on the average are 1-2 X normal and the ALP values 1-3 X normal. It is interesting to note that in a series of 32 dogs having reactive hepatopathies, 8/8 cases in which serum bile acids were run, all were within the normal reference range again suggesting hepatic function remains intact.

This category appears to be the most common histological change to occur in dogs and is by far the most common cause of elevated liver enzymes. Based on this fact, dogs presented with elevations in ALT and ALP should always have primary non-hepatic disease ruled out first. These changes are usually very reversible and no specific hepatic therapy is required short of treating the primary disease. The liver changes resolve once the primary etiology is successfully treated. Therapy providing good liver support such as antioxidants may be warranted.

Vacuolar Hepatopathies

The histological reports of diffuse vacuolar hepatopathy are often very frustrating in determining the underlying etiology. 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 (edema) or other metabolic wastes or intermediates. Vacuolar hepatopathies may occur in conjunction with hydropic degeneration in which there is cytosolic swelling but devoid of distinct vacuoles. A number of conditions discussed above causing reactive hepatopathies can be responsible for vacuolar hepatopathies or lesions may develop as a result of secondary chronic stress (presumed to be endogenous steroid induced) resulting from concurrent disease.

Glucocorticoid (steroid) hepatopathies occur in the dog secondary to exogenous or endogenous glucocorticoids. On histology the vacuolar lesions contain glycogen that is not easily differentiated from other vacuolar contents without specialized histopathology processing. The development of steroid hepatopathies is linked with marked increases in ALP. The glucocorticoid associated ALP (G-ALP) is unique to the dog and dogs having steroid hepatopathies are associated with a large component of G-ALP. Experimentally when steroids are administered to dogs there is initially an increase in ALP but latter G-ALP increases and may comprise the majority of ALP concentration. Determining the G-ALP portion of ALP has been suggested as a screening test for hyperadrenocorticism but unfortunately many other conditions are also associated with increased G-ALP which is most likely secondary to chronic stress of the disease. Hence, many will question the diagnostic usefulness of G-ALP.

Dogs having hyperadrenocorticism or those given corticosteroids have considerable individual sensitivity or variation in liver lesions and ALP concentrations. Dogs given 4 mg/kg prednisone will have liver lesions in 2 to 4 days and marked increases in ALP to follow. Rarely if ever total bilirubin increases but bile acid concentrations may become slightly abnormal and possibly as high as 40-50 µmol/L. Topical steroid administration can also cause steroid hepatopathies and may take a month or longer for values to return to normal once medication is discontinued. A single dose of methylprednisolone acetate (Depo-medrol®) can alter adrenocortical function for five weeks or longer.

Dogs having increased ALP and evidence of vacuolar hepatopathy should always be investigated for hyperadrenocorticism. The diagnosis of canine Cushing's disease requires specific testing such as a low dose dexamethasone test or ACTH stimulation test.

Idiopathic vacuolar hepatopathy is a frustrating diagnosis frequently observed in older dog. In all intense purposes they appear typical of steroid hepatopathies based on histology and abnormal ALP but without clinical or laboratory evidence of Cushing's disease. The liver of these dogs contains excess glycogen and they have laboratory finding predominately G-ALP isoenzymes. One is unable to make the diagnosis of Cushing's disease based on lack of typical clinical signs and normal conventional adrenal testing (i.e. ACTH stimulation or LDDS). We have recently investigated several dogs having vacuolar hepatopathy and increased ALP without overt Cushing's disease to have abnormal concentrations in some of the other adrenal steroids (i.e. sex hormones such as progesterone, estradiol, DHEAS or 17a-Hydroxy-progesterone). It has been documented that progestin steroids have been shown to bind to hepatic glucocorticoid receptors and will induce a steroid hepatopathy when given orally to dogs. There is now speculation that increases in progestin steroid hormones may result in the hepatic changes and ALP increase. Clinically we have found many of these dogs fail to have increases in GGT concentrations in spite of significant ALP elevations. It appears those most, if not all of these dogs, live a normal life with out adverse consequences from their liver disease. Obviously further investigation is required into this syndrome. We have observed several dogs following empirical ketoconazole or lysodren therapy to have decreases in ALP supporting aberrant adrenal steroid production. The reason for abnormal progestin levels may be secondary to adrenal adenomas (incidentalomas), adrenal enzyme deficiency converting precursors to cortisol or unapparent adrenal masses. Some adrenal adenomas have been shown to secrete high levels of 17 hydroxyprogesterone in dogs. Some have also suggested administering melatonin (4-6 mg/da) and report improvement in liver enzymes and hepatic changes. More studies are required to confirm this finding.

Recently we have identified a disproportionate number of Scottish terriers suggesting a breed predisposition for this condition. We are currently investigating these and other dogs with ultrasound to rule out hepatic or adrenal masses and an ACTH stimulation test with concurrent adrenal panel that includes progestins. We currently send our samples to the University of Tennessee Diagnostic Laboratory.

Hepatic Nodular Hyperplasia

This is a benign process causing an increase in hepatic values and histomorphologic changes that include macroscopic or microscopic hepatic nodules containing vacuolated hepatocytes. Liver function remains unchanged. Grossly, the appearance may be suggestive of chronic hepatitis or neoplasia. The etiology is unknown but appears to be an aging change in dogs; most of those affected are greater than 10 years of age. Laboratory findings include an ALP increase, but some may have mild increases in ALT and AST concentrations as well. Ultrasound may be normal or may demonstrate larger nodules (many can be only microscopic and not observed on ultrasound). Biopsy confirms the diagnosis, however a wedge section is preferred, as a needle biopsy may not demonstrate the nodules. There is no specific therapy.

Hepatic Neoplasia

In the dog liver tumors can be either metastatic or primary. Metastatic tumors are more common and would include the carcinomas and sarcomas. Hepatocellular ademoma is common in dogs and generally restricted to a single liver lobe. Previous terminology calls these tumors as hepatomas human terminology that is incorrect. These tumors are very slow growing and often are found as an incidental finding on ultrasound as a work up for abnormal liver enzymes. There is no spread to this tumor. Often we will just watch them using ultrasound every several months and if they grow in size rapidly then surgery can be suggested. If they become large they may not lend to resection or may become necrotic and rupture causing abdominal bleeding. Hepatocellular carcinomas are malignant neoplasms that can be either solitary (more slowly growing) or diffuse having a poor prognosis. Sometimes telling the difference from adenoma and carcinoma is difficult FNA or a biopsy sample. It has also been reported that large liver masses may be associated with hypoglycemia due to production of an insulin like factor. The more diffuse cholangiocellular and hepatic carcinomas have poorer prognosis and do not respond well to chemotherapy.