Steroid Hepatopathy

Steroid hepatopathy is a well-recognized, non-inflammatory hepatic disorder characterized by diffuse vacuolar hepatocyte degeneration and swelling, primarily resulting from chronic exposure to endogenous or exogenous glucocorticoids. The condition is most commonly described in dogs, where it is a frequent cause of elevated liver enzymes and hepatomegaly. In cats, steroid hepatopathy is less common and often presents with a different histologic pattern, including glycogen accumulation and lipid vacuolation. The disease is generally considered reversible upon withdrawal of the steroid source, but severe or prolonged cases may lead to progressive hepatic dysfunction, portal hypertension, and fibrosis. Steroid hepatopathy is not a primary inflammatory or neoplastic process, but rather a metabolic adaptation to glucocorticoid excess, which alters hepatic carbohydrate, lipid, and protein metabolism. The clinical significance lies in its mimicry of primary liver disease, its potential to complicate diagnostic interpretation, and its role in the pathogenesis of more severe hepatic lesions, such as vacuolar hepatopathy with secondary nodular regeneration or hepatic fibrosis.

The primary etiology of steroid hepatopathy is excessive glucocorticoid activity, either from endogenous overproduction (e.g., hyperadrenocorticism or Cushing's syndrome) or from exogenous administration of glucocorticoids (e.g., prednisone, prednisolone, dexamethasone, triamcinolone, or methylprednisolone). Endogenous hypercortisolism is most commonly due to a functional pituitary adenoma (pituitary-dependent hyperadrenocorticism, PDH) or an adrenal cortical tumor (adrenal-dependent hyperadrenocorticism, ADH). Exogenous causes include chronic or high-dose glucocorticoid therapy for various inflammatory, immune-mediated, or neoplastic conditions. The development and severity of steroid hepatopathy depend on the dose, potency, duration, and route of administration of the glucocorticoid. Oral and injectable forms are more likely to cause hepatopathy than topical or inhaled forms, but systemic absorption can still occur. In dogs, the condition is particularly common with prednisone or prednisolone at immunosuppressive doses (≥2 mg/kg/day) for extended periods. In cats, exogenous glucocorticoids are less frequently associated with severe hepatopathy, but chronic administration can lead to similar changes. Other iatrogenic sources include depot formulations (e.g., methylprednisolone acetate) and ophthalmic or otic preparations that are systemically absorbed. The molecular trigger involves glucocorticoid receptor-mediated transcriptional changes in hepatocytes, leading to increased glycogen synthesis, gluconeogenesis, and lipid accumulation.

Steroid hepatopathy is most commonly diagnosed in dogs, with a higher prevalence in middle-aged to older animals, reflecting the age distribution of hyperadrenocorticism. No strong breed predisposition is reported for steroid hepatopathy itself, but breeds predisposed to hyperadrenocorticism, such as Poodles, Dachshunds, Boxers, and Boston Terriers, are overrepresented. In cats, steroid hepatopathy is less common and often associated with iatrogenic glucocorticoid use or, rarely, hyperadrenocorticism (feline Cushing's syndrome), which is typically due to a functional adrenal tumor. The condition is seen equally in males and females, although some studies suggest a slight female predominance in dogs with PDH. The incidence of steroid hepatopathy is difficult to estimate because many cases are subclinical and only detected incidentally on routine blood work or abdominal imaging. In a referral population, vacuolar hepatopathy is found in up to 20% of liver biopsies from dogs with elevated liver enzymes. The prevalence of iatrogenic steroid hepatopathy is directly related to the widespread use of glucocorticoids in veterinary medicine. Geographic variation is minimal, but the condition is more commonly recognized in regions with higher rates of hyperadrenocorticism diagnosis. There is no known seasonality, but the use of glucocorticoids for allergic or immune-mediated diseases may increase during certain seasons (e.g., flea allergy dermatitis in summer).

The pathophysiology of steroid hepatopathy involves glucocorticoid-induced alterations in hepatocyte metabolism. Glucocorticoids bind to intracellular glucocorticoid receptors, which then translocate to the nucleus and modulate gene transcription. In the liver, this leads to increased expression of enzymes involved in gluconeogenesis (e.g., phosphoenolpyruvate carboxykinase, glucose-6-phosphatase) and glycogen synthesis (e.g., glycogen synthase). The net effect is increased hepatic glycogen accumulation, which appears as vacuolated hepatocytes on histopathology. Additionally, glucocorticoids stimulate lipolysis in peripheral adipose tissue, increasing free fatty acid delivery to the liver, which promotes hepatic lipid accumulation. This is particularly prominent in cats, where lipid vacuolation may be more severe. Glucocorticoids also inhibit the release of arachidonic acid from membrane phospholipids, reducing prostaglandin and leukotriene synthesis, which contributes to the anti-inflammatory effects but also alters hepatic blood flow and sinusoidal perfusion. Chronic glucocorticoid excess can lead to hepatocellular swelling, which compresses sinusoids and impairs bile flow, resulting in elevated serum alkaline phosphatase (ALP) activity, particularly in dogs. The increase in ALP is due to the induction of a specific corticosteroid-induced isoenzyme. In addition, glucocorticoids can cause insulin resistance, leading to hyperinsulinemia and further hepatic lipid accumulation. Over time, chronic vacuolar hepatopathy may progress to hepatocellular degeneration, apoptosis, and necrosis, with subsequent activation of hepatic stellate cells and fibrosis. In some dogs, the condition is associated with the development of vacuolar hepatopathy with nodular regeneration, which can lead to portal hypertension and acquired portosystemic shunts. The reversibility of the lesion depends on the duration and severity of glucocorticoid exposure; early changes are reversible upon withdrawal, but chronic fibrosis may be irreversible.

Predisposing factors for steroid hepatopathy include any condition that leads to chronic endogenous or exogenous glucocorticoid excess. Endogenous factors include hyperadrenocorticism (pituitary or adrenal dependent), which is more common in dogs than cats. Exogenous factors include chronic glucocorticoid therapy for immune-mediated diseases (e.g., immune-mediated hemolytic anemia, inflammatory bowel disease, atopic dermatitis), neoplasia (e.g., lymphoma), or orthopedic conditions. The risk increases with higher doses, longer duration, and use of potent or long-acting formulations. Concurrent diseases that cause stress or inflammation may also increase endogenous cortisol production, contributing to the development of hepatopathy. Age is a predisposing factor, as older animals are more likely to receive glucocorticoid therapy or develop hyperadrenocorticism. Breed predispositions to hyperadrenocorticism indirectly increase the risk. Obesity and insulin resistance may exacerbate the metabolic effects of glucocorticoids on the liver. In cats, concurrent diabetes mellitus or hepatic lipidosis may worsen the vacuolar changes. Additionally, individual variation in glucocorticoid receptor sensitivity or metabolism may influence susceptibility. The use of drugs that inhibit cortisol metabolism (e.g., ketoconazole) or that have glucocorticoid-like effects (e.g., progestins) can also predispose to the condition. Finally, the presence of underlying liver disease may make the liver more vulnerable to glucocorticoid-induced injury.

Clinical signs of steroid hepatopathy are often nonspecific and may be absent in mild cases. When present, they are largely attributable to the underlying glucocorticoid excess rather than the hepatic changes per se. Common signs include polyuria, polydipsia, polyphagia, weight gain, abdominal distension (due to hepatomegaly and fat redistribution), muscle weakness, lethargy, and panting. Dermatologic signs such as alopecia, thin skin, and calcinosis cutis may be seen in hyperadrenocorticism. In iatrogenic cases, the history of glucocorticoid administration is key. Hepatomegaly may be detected on physical examination. In severe or chronic cases, signs of hepatic dysfunction may develop, including jaundice, ascites, and hepatic encephalopathy, although these are uncommon. In cats, signs may include poor coat quality, weight loss, and lethargy, but polyuria and polydipsia are less prominent. The clinical stage can be categorized as: (1) subclinical, where only laboratory abnormalities are present; (2) mild, with nonspecific signs such as lethargy and mild PU/PD; (3) moderate, with more pronounced signs of hypercortisolism and hepatomegaly; and (4) severe, with hepatic failure or complications such as portal hypertension. The onset is typically insidious in endogenous cases, but may be more rapid with high-dose exogenous steroids. Physical examination may reveal a palpable liver extending beyond the costal arch, and in some cases, a pendulous abdomen due to muscle wasting and fat redistribution.

Differential diagnoses for steroid hepatopathy include other causes of vacuolar hepatopathy and elevated liver enzymes. Key differentials include: (1) Diabetes mellitus with hepatic lipidosis, which can cause similar vacuolar changes but is distinguished by persistent hyperglycemia and glycosuria. (2) Feline hepatic lipidosis, which is characterized by severe lipid vacuolation and is more common in cats with anorexia; it is differentiated by clinical history and histopathology. (3) Primary hyperlipidemia or hyperlipoproteinemia, which may cause lipid accumulation but is less common. (4) Glycogen storage diseases, which are rare congenital disorders. (5) Chronic hepatitis or cirrhosis, which is inflammatory and fibrotic, with different histologic features. (6) Hepatic neoplasia, such as hepatocellular adenoma or carcinoma, which may present with hepatomegaly and elevated enzymes but is distinguished by imaging and biopsy. (7) Cholangiohepatitis, particularly in cats, which is inflammatory and may have bile duct involvement. (8) Toxic hepatopathy from drugs or plants, which may cause hepatocellular necrosis and elevated enzymes. (9) Congenital portosystemic shunts, which cause hepatic atrophy and elevated bile acids. (10) Extrahepatic bile duct obstruction, which causes marked hyperbilirubinemia and ALP elevation. Definitive differentiation requires a thorough history (especially glucocorticoid exposure), endocrine testing for hyperadrenocorticism, abdominal imaging, and liver biopsy. The presence of corticosteroid-induced ALP isoenzyme in dogs is highly suggestive of steroid hepatopathy but not definitive.

The diagnostic approach to steroid hepatopathy begins with a complete history and physical examination, with special attention to glucocorticoid administration and signs of hyperadrenocorticism. Initial laboratory tests include a complete blood count, serum biochemistry profile, and urinalysis. Typical findings include elevated ALP (often marked), mild to moderate elevations in alanine aminotransferase (ALT), and sometimes increased gamma-glutamyl transferase (GGT). Hypercholesterolemia, hyperglycemia, and low blood urea nitrogen (BUN) may be present. Urinalysis may show low urine specific gravity (<1.020) due to glucocorticoid-induced diuresis. If hyperadrenocorticism is suspected, endocrine testing is performed: the ACTH stimulation test or low-dose dexamethasone suppression test (LDDST) is recommended. A urine cortisol:creatinine ratio can be used as a screening test. If iatrogenic steroid hepatopathy is suspected, the history of glucocorticoid use is sufficient, and withdrawal of the drug should lead to resolution of clinical signs and laboratory abnormalities. Abdominal ultrasonography is useful to assess liver size and echogenicity; the liver may be diffusely hyperechoic and enlarged. If the diagnosis remains uncertain or if the patient does not respond to steroid withdrawal, a liver biopsy is indicated. Histopathology reveals diffuse vacuolar hepatopathy with glycogen and/or lipid accumulation. The diagnostic algorithm should also rule out other causes of hepatomegaly and elevated liver enzymes, such as neoplasia or inflammatory disease. In cases where the underlying cause is not apparent, additional tests such as bile acid stimulation test, coagulation profile, and infectious disease testing (e.g., leptospirosis, infectious canine hepatitis) may be considered.

Hematology: Complete blood count may show a stress leukogram characterized by mature neutrophilia, lymphopenia, and eosinopenia, particularly in endogenous hyperadrenocorticism. In iatrogenic cases, similar changes may be present. Mild erythrocytosis may occur due to increased erythropoietin or dehydration. Serum Biochemistry: The most consistent finding is elevated serum alkaline phosphatase (ALP) activity, often 2- to 10-fold above the reference range, due to induction of the corticosteroid-induced ALP isoenzyme. Alanine aminotransferase (ALT) may be mildly to moderately elevated (1- to 3-fold) due to hepatocellular swelling and leakage. Gamma-glutamyl transferase (GGT) may also be increased. Total bilirubin is usually normal unless severe hepatic dysfunction or concurrent disease is present. Hypercholesterolemia and hypertriglyceridemia are common due to increased lipolysis and hepatic lipid synthesis. Fasting blood glucose may be mildly elevated, but overt diabetes mellitus is uncommon. Total protein and albumin may be normal or slightly decreased. Blood urea nitrogen (BUN) may be low due to increased glomerular filtration rate and polyuria. Urinalysis: Urine specific gravity is often low (<1.020) due to glucocorticoid-induced polyuria. Proteinuria may be present if concurrent glomerular disease exists. Urine cortisol:creatinine ratio is elevated in hyperadrenocorticism. Blood Gas Analysis: Metabolic alkalosis may be present due to hypokalemia and increased renal bicarbonate reabsorption. Specific Biomarkers: Corticosteroid-induced ALP isoenzyme can be measured in dogs and is highly specific for glucocorticoid exposure. Bile acids may be normal or mildly elevated. Endocrine assays: ACTH stimulation test or LDDST are used to diagnose hyperadrenocorticism. In iatrogenic cases, endogenous cortisol is suppressed, and ACTH stimulation shows a blunted response.

Radiography: Abdominal radiographs may reveal hepatomegaly, with the liver extending beyond the costal arch. In chronic cases, mineralization of the adrenal glands may be seen, but this is not specific. Thoracic radiographs may show signs of pulmonary thromboembolism or calcinosis cutis. Ultrasonography: Abdominal ultrasonography is the most useful imaging modality. The liver is typically enlarged and diffusely hyperechoic (bright) compared to the spleen or renal cortex. The echotexture may be coarse, and the hepatic vasculature may be attenuated. In some cases, nodular regeneration may be seen as hypoechoic or hyperechoic nodules. The adrenal glands may be enlarged in hyperadrenocorticism; a cutoff of >7.5 mm in dogs is suggestive. Doppler ultrasound can assess portal blood flow. Computed Tomography (CT): CT is more sensitive for detecting adrenal masses and may be used for surgical planning. It can also quantify liver volume and detect nodular changes. Magnetic Resonance Imaging (MRI): MRI is rarely used for steroid hepatopathy but may be indicated for pituitary imaging in PDH. Endoscopy: Not directly useful for liver evaluation, but may be used to obtain duodenal biopsies if concurrent gastrointestinal disease is suspected. Fluoroscopy: Not typically used. Echocardiography: May be indicated if concurrent cardiac disease is present, but not for liver evaluation.

Fine Needle Aspiration (FNA): Cytology of the liver may show hepatocytes with marked vacuolation, consistent with glycogen or lipid accumulation. However, FNA is not definitive and cannot distinguish steroid hepatopathy from other vacuolar hepatopathies. Histopathology: Liver biopsy is the gold standard for diagnosis. Histologic findings include diffuse hepatocellular vacuolation, with hepatocytes appearing swollen and clear due to glycogen accumulation (best demonstrated with periodic acid-Schiff (PAS) stain, which is digested by diastase) or lipid vacuoles (stained with Oil Red O on frozen sections). The vacuolation is most prominent in the centrilobular (periacinar) region. There is no significant inflammation or necrosis in uncomplicated cases. In chronic or severe cases, there may be hepatocellular atrophy, fibrosis, and nodular regeneration. Special stains: PAS with and without diastase digestion can differentiate glycogen from other vacuoles. Oil Red O or Sudan black stains are used for lipid. Trichrome stain can highlight fibrosis. Electron microscopy may show glycogen particles and lipid droplets. The histopathologic changes are reversible upon withdrawal of glucocorticoids, but fibrosis may persist.

The primary treatment for steroid hepatopathy is to eliminate the source of excess glucocorticoids. In iatrogenic cases, the glucocorticoid dose should be tapered gradually to avoid iatrogenic hypoadrenocorticism. The rate of taper depends on the duration and dose of therapy; for short courses (<2 weeks), abrupt withdrawal may be safe, but for longer courses, a gradual reduction over weeks to months is recommended. In endogenous hyperadrenocorticism, treatment is directed at the underlying cause. For PDH, medical therapy with trilostane (Vetoryl) is the preferred treatment. The initial dose is 1-3 mg/kg orally once daily, with food. The dose is adjusted based on clinical response and ACTH stimulation test results. Alternatively, mitotane (Lysodren) may be used, but it has more side effects. For ADH, surgical adrenalectomy is the treatment of choice if the tumor is resectable and there is no metastasis. In cases where surgery is not possible, medical therapy with trilostane or mitotane may be used. Supportive care for steroid hepatopathy includes a high-quality, easily digestible diet with moderate protein and low fat to reduce hepatic workload. Supplementation with antioxidants such as S-adenosylmethionine (SAMe) and vitamin E may be beneficial, although evidence is limited. Ursodeoxycholic acid (Actigall) at 10-15 mg/kg/day orally may help improve bile flow and reduce hepatocyte injury. If the patient has concurrent diabetes mellitus, insulin therapy is required. In severe cases with hepatic failure, aggressive supportive care including intravenous fluids, antiemetics, and hepatoprotectants is necessary. The prognosis is good if the steroid source is removed before irreversible fibrosis occurs.

The prognosis for steroid hepatopathy is generally good if the underlying cause is identified and treated early. In iatrogenic cases, withdrawal of glucocorticoids typically leads to resolution of clinical signs and normalization of liver enzymes within weeks to months. However, if the liver has undergone significant fibrosis or nodular regeneration, the changes may be irreversible, and the prognosis is guarded. In endogenous hyperadrenocorticism, the prognosis depends on the underlying cause and response to treatment. For PDH treated with trilostane, the median survival time is approximately 2-3 years. For ADH, surgical removal of the tumor can be curative if complete excision is achieved, but the prognosis is poor if the tumor is malignant or has metastasized. Negative prognostic indicators include the presence of hepatic fibrosis, portal hypertension, ascites, or hepatic encephalopathy. The severity of clinical signs and the presence of concurrent diseases (e.g., diabetes mellitus, pancreatitis) also affect the prognosis. Serial monitoring of liver enzymes and clinical signs is essential to assess response to treatment. In most cases, ALP levels decrease within 2-4 weeks after steroid withdrawal, but may take several months to normalize. If ALP remains elevated, further investigation is warranted.

Follow-up for steroid hepatopathy depends on the underlying cause. For iatrogenic cases, after glucocorticoid withdrawal, recheck a serum biochemistry profile (including ALP, ALT, GGT, and bilirubin) every 2-4 weeks until values normalize. Clinical signs should improve within 1-2 weeks. For endogenous hyperadrenocorticism, monitoring is more intensive. For dogs on trilostane, recheck an ACTH stimulation test 10-14 days after starting therapy or after any dose change, and then every 3-6 months. The goal is to maintain post-ACTH cortisol between 2-5 μg/dL (55-138 nmol/L). Clinical signs such as polyuria, polydipsia, and polyphagia should improve within 2-4 weeks. Liver enzymes should be monitored every 3-6 months. For dogs on mitotane, monitoring includes ACTH stimulation tests and clinical signs. For cats with hyperadrenocorticism, treatment is more challenging, and monitoring is similar. In all cases, periodic abdominal ultrasonography may be recommended to assess liver size and adrenal gland size. If the patient develops signs of hepatic failure, more frequent monitoring and supportive care are needed. Long-term management includes dietary modifications and possibly hepatoprotectants. The owner should be educated about the signs of glucocorticoid withdrawal (e.g., lethargy, vomiting, diarrhea) and the need for gradual tapering.

Pearls: (1) Steroid hepatopathy is a common cause of elevated ALP in dogs; the presence of corticosteroid-induced ALP isoenzyme is highly specific. (2) In dogs, a marked increase in ALP (often >1000 U/L) with only mild ALT elevation is classic for steroid hepatopathy. (3) Cats with steroid hepatopathy may have less pronounced ALP elevation; GGT may be more sensitive. (4) Always ask about any glucocorticoid exposure, including topical, ophthalmic, or otic preparations, as these can be systemically absorbed. (5) In iatrogenic cases, gradual withdrawal of glucocorticoids is essential to avoid hypoadrenocorticism. (6) If hyperadrenocorticism is suspected, perform an ACTH stimulation test or LDDST; a urine cortisol:creatinine ratio can be used as a screening test. (7) Liver biopsy is not always necessary if the history and laboratory findings are consistent, but it is indicated if the diagnosis is uncertain or if the patient does not respond to treatment. Pitfalls: (1) Failing to recognize that steroid hepatopathy can coexist with other liver diseases, such as chronic hepatitis or neoplasia. (2) Assuming that elevated liver enzymes are solely due to steroid hepatopathy without ruling out other causes. (3) Abruptly discontinuing glucocorticoids, which can cause iatrogenic hypoadrenocorticism. (4) Overinterpreting the significance of vacuolar hepatopathy on biopsy without considering the clinical context. (5) Not monitoring liver enzymes after steroid withdrawal, leading to missed diagnosis of persistent disease. (6) In cats, not considering other causes of vacuolar hepatopathy, such as hepatic lipidosis or diabetes mellitus.

For iatrogenic steroid hepatopathy, the primary treatment is withdrawal of the glucocorticoid. If the patient has been on long-term therapy, the dose should be tapered gradually. For example, if the patient is on prednisone at 2 mg/kg/day, reduce the dose by 25% every 2-4 weeks until the lowest effective dose is reached, then discontinue. For endogenous hyperadrenocorticism, trilostane (Vetoryl) is the drug of choice for PDH in dogs. The initial dose is 1-3 mg/kg orally once daily, with food. The dose is adjusted based on clinical response and ACTH stimulation test results. The target post-ACTH cortisol is 2-5 μg/dL (55-138 nmol/L). If the cortisol is too high, increase the dose by 10-20% every 2-4 weeks. If the cortisol is too low (<2 μg/dL) or the dog shows signs of hypoadrenocorticism (lethargy, vomiting, diarrhea), reduce the dose and consider temporary withdrawal. Mitotane (Lysodren) is an alternative. For induction, administer 50 mg/kg/day orally in divided doses for 5-7 days, or until the dog shows signs of glucocorticoid deficiency (e.g., decreased appetite, lethargy). Then, for maintenance, administer 50 mg/kg/week in divided doses. Monitoring with ACTH stimulation tests is essential. For ADH, surgical adrenalectomy is preferred. If surgery is not possible, trilostane or mitotane may be used, but the response is less predictable. For supportive care, S-adenosylmethionine (SAMe) is given at 18-20 mg/kg orally once daily on an empty stomach. Vitamin E (tocopherol) is given at 10-20 IU/kg orally once daily. Ursodeoxycholic acid (Actigall) is given at 10-15 mg/kg orally once daily with food. If the patient has concurrent diabetes mellitus, insulin therapy (e.g., NPH insulin at 0.5-1.0 U/kg subcutaneously twice daily) is required. All doses should be adjusted based on renal and hepatic function; in hepatic impairment, reduce doses of drugs metabolized by the liver. Contraindications: Glucocorticoids are contraindicated in patients with systemic fungal infections or known hypersensitivity. Trilostane is contraindicated in patients with primary hepatic disease or renal insufficiency. Drug interactions: Trilostane may interact with potassium-sparing diuretics and ACE inhibitors, leading to hyperkalemia. Mitotane may increase the effects of warfarin and phenytoin.

Several studies have characterized steroid hepatopathy in dogs. A landmark study by DeNovo and Prasse (1983) described the histologic and biochemical changes in dogs treated with prednisone, demonstrating marked ALP elevation and vacuolar hepatopathy. More recent studies have focused on the corticosteroid-induced ALP isoenzyme as a diagnostic marker. A study by Ginel et al. (1998) found that the corticosteroid-induced ALP isoenzyme had high sensitivity and specificity for hyperadrenocorticism. Regarding treatment, the use of trilostane for PDH has been extensively evaluated. A large multicenter study by Braddock et al. (2003) reported that trilostane effectively controlled clinical signs in dogs with PDH, with a median survival time of 662 days. Another study by Vaughan et al. (2008) compared trilostane and mitotane and found similar efficacy but fewer side effects with trilostane. For iatrogenic steroid hepatopathy, a study by Behrend et al. (2006) demonstrated that gradual withdrawal of glucocorticoids led to resolution of clinical signs and normalization of liver enzymes. The ACVIM consensus statement on the diagnosis and treatment of hyperadrenocorticism in dogs (Behrend et al., 2013) provides evidence-based guidelines for diagnosis and management, including the use of ACTH stimulation testing and trilostane therapy. In cats, steroid hepatopathy is less well studied, but a retrospective study by Ferasin et al. (2007) described the clinical and histopathologic features of feline hyperadrenocorticism. Overall, the evidence supports the reversibility of steroid hepatopathy with removal of the steroid source, but emphasizes the need for careful monitoring and management of the underlying condition.