Hepatic lipidosis (Proceedings)

Feline hepatic lipidosis (HL), a syndrome characterized by hepatocellular accumulation of lipid, intrahepatic cholestasis and hepatic dysfunction, is one of the most common liver disorders of the domestic cat accounting for approximately 50% of biopsy diagnoses. It may be a primary (idiopathic) condition or secondary to another disease process. Despite widespread interest and the numerous studies performed since HL was first described in the veterinary literature in 1977, the causes and pathogenic mechanisms of the disease are still largely unknown. However, even with our relatively limited understanding of HL significant progress has been made in the therapy of this condition, reducing mortality from a value of close to 90% in the original descriptions to approximately 10% in more recent studies utilizing aggressive nutritional support.

This talk is intended to provide some background information about our current understanding of HL. In addition to discussing some of the potential predisposing factors, causes, and mechanisms of the disorder, information and ideas about nutritional support and therapeutic options for HL patients will be discussed in detail.

What causes hepatic lipidosis in cats?

The primary histologic changes in HL are severe lipid accumulation within hepatocytes and canalicular bile stasis. There are numerous specific potential causes and mechanisms for these types of changes, however, it is very likely that the pathogenesis of HL is multifactorial. A better understanding of the unique pathways of hepatic metabolism in felines is needed to provide insight into how derangements and interactions of these pathways can lead to development of clinical disease. Proposed mechanisms for HL development include roles for metabolic changes associated with starvation and/or obesity, protein deficiency, relative carnitine deficiency, essential fatty acid deficiency, dysregulation of hormone-sensitive lipase, and insulin resistance among others.

Lipid buildup is obviously a key part of the pathogenesis of HL and leads to storage of excess lipid within vacuoles in the hepatocytes. When accumulation of these vacuoles becomes excessive, changes in liver function are observed. This is not necessarily true of many other species in which lipid accumulation is less dramatic, but also often relatively innocuous.

An observed increase in the concentration of lipids within the liver may be due to several factors. The concentration will increase after high-fat meals, when fat stores are mobilized (e.g. fasting), during periods of increased hepatic synthesis, or when metabolism, processing, and secretion of lipids within the liver are decreased. Accumulation of lipids occurs when there is an imbalance between delivery of fatty acids to the liver and the ability of the liver to oxidize them for energy or release them in the form of very-low-density lipoproteins (VLDLs).

Increased delivery can occur during mobilization of fat stores for energy during periods of fasting/starvation or deficiency of specific nutrients. In most cats that develop HL there is a period of partial to complete anorexia that precedes the development of clinical signs related to HL by days to weeks. During this period there is protein restriction (which may be a key component of the disease) and release of stored fatty acids from adipose tissue. These fatty acids should be oxidized by the liver for energy, but in cats that develop HL there may be a decreased capacity for hepatic lipid metabolism and/or processing. Electron microscopy of these cats has demonstrated decreased quantities of several of the components of the cellular machinery needed to oxidize lipids. In addition restriction of protein intake (e.g. anorexia) may lead to down regulation of the synthesis of proteins that are required for formation VLDLs. In one study, histologic evidence of HL was apparent in 15/15 fasted obese cats by 2 weeks. Clinical signs of HL were present in 12/15 of these cats by weeks 5-7 and seemed to be associated with a body weight decrease of about 30-35%.

Impaired fatty acid oxidation also appears to be significant in cats with HL. Carnitine, taurine and essential fatty acids have received a lot of attention for their roles in maintaining membrane integrity and functions necessary for utilization of lipids for energy. Carnitine is required for fatty acid transport through hepatic mitochondrial membranes where they can be oxidized. One theory suggests that in HL the demand for carnitine is greater than stores or synthesis can provide for. In one study, cats fed 25% of their caloric requirements had minimal lipid accumulation when carnitine supplementation was provided compared to control cats. However, this benefit was significantly reduced in another study when there was inadequate Ω-3 intake.

There is also some evidence of decreased glucose tolerance and decreased insulin responses to glucose infusions in fasted cats that subsequently developed HL. In addition, the high levels of non-esterified fatty acids found in some studies suggest that there may be inappropriate regulation of hormone sensitive lipase.

It is established that obesity and fasting (although not necessary) appear to be risk factors for HL in cats. Further studies are required to gain a better understanding of the other risk factors and pathophysiologic mechanisms of disease however.

What is the clinical picture of hepatic lipidosis in cats?

Diagnosis of HL should be based upon appropriate historical and physical examination findings, consistent clinical pathology and diagnostic imaging results, and cytologic or histopathologic evaluation of hepatocytes. Definitive diagnosis requires liver biopsy and histopathologic evidence of severe vacuolar lipid accumulation in greater than 50% of the hepatocytes in an acinus.

Most cats with HL are middle-aged to older and are overweight prior to the development of the disease. There is no apparent sex or breed predilection. There is usually a history of partial to complete anorexia for a few weeks before clinical signs of HL are apparent. This may result from a stressful event or environment, refusal of a less palatable food after a change in diet, or a concurrent condition resulting in anorexia. In most cases there will be a weight loss of greater than 25% prior to development of other signs of HL.

Clinical signs of HL in cats include depression, lethargy, weight loss (often with loss of muscle mass as a prominent feature), dehydration, hepatomegaly, icterus, ptyalism, or other signs of hepatic encephalopathy.

Evaluation of serum chemistries usually reveals at least a two-fold increase in alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). The ALP elevation will generally be greater in magnitude than the ALT or AST elevations. In contrast, γ-glutamyltransferase (GGT) activity is often normal. Hyperbilirubinemia and hyperbilirubinuria are frequent findings but may develop later than the enzyme elevations. Abnormalities of other indirect markers of liver function (e.g. blood urea nitrogen, cholesterol, glucose, albumin) may be present in severe disease. Unlike many other hepatobiliary disorders in the cat, globulin levels are often normal in HL. Cats with HL often develop a nonregenerative anemia and commonly display red blood cell poikilocytosis. Almost ½ of HL cases have a coagulation test abnormality and up to 20% may have evidence of clinical bleeding tendencies. Radiographs may reveal hepatomegaly and the presence of lipid within the liver causes it to appear diffusely hyperechoic on ultrasound evaluation. This is not a sensitive or specific finding however. The main function of diagnostic imaging in these cases is to rule out other disease processes.

Fine needle aspiration of the liver for cytologic evaluation may be helpful in establishing a preliminary diagnosis of HL. Caution is needed when interpreting the results, however, due to the potential for missing concurrent disease or focal lesions.

Biopsy can be used to establish a definitive diagnosis. This can be accomplished by several means including percutaneous needle biopsy (blind or ultrasound-guided), laparoscopy, or surgical intervention (exploratory celiotomy with biopsies). There are advantages and disadvantages to each technique that must be weighed carefully for each individual case. Another consideration is the stability of the patient. For example, if a fine needle aspirate reveals changes consistent with HL in a very sick patient, we may elect to attempt to treat empirically and forego the biopsy until the patient is more stable.

Between1/2 and 2/3 of HL is secondary. The most commonly recognized conditions include cholangiohepatitis, inflammatory bowel disease, and acute or chronic pancreatitis. In one study, about 1/3 of cats with HL had concurrent pancreatitis. These cats had a significantly worse prognosis and the presence of concurrent pancreatitis may significantly impact therapeutic decisions these cases. Because of the large number of cases with concurrent disease, a thorough diagnostic approach is warranted in cases of HL.

What can be done about hepatic lipidosis in cats?

Given how little we know about the underlying mechanisms of HL development in cats, it is somewhat surprising that we are able to make much of a difference in survival. With aggressive nutritional support as the key, however, the mortality rate for HL is only about 10- 30%, versus 75-90% without aggressive treatment. There are numerous other mediations and specific nutritional supplements that may be useful in treating this disease, but further studies are needed to prove their efficacy.

Nutrition

Providing adequate nutrition to patients with HL is the single most important therapy we know of for this condition and is key to providing the best chance for recovery. The best results are likely to be obtained by providing adequate caloric intake in the form of a balanced diet with a moderate to high protein content.

Using commercially prepared feline diets will ensure that the food is nutritionally balanced and complete. Ideally, a high-protein diet should be used (35-45%), but if the animal is showing clinical signs of hepatic encephalopathy, reducing the protein content is appropriate. Try to maintain at least 20% of the calories from protein, however.

When clinical signs are severe, the treatment period may be thought of as comprising two parts: stabilization for the first few days, and long-term recovery for the following weeks to months. During the initial stabilization period there are often electrolyte and fluid imbalances that must be corrected prior to providing nutritional support, and any therapy should be provided in a minimally invasive manner. During this time, many cats will actually appear clinically worse than at presentation. This is also the period during which the most adverse effects are noted and appropriate monitoring for adverse reactions to the refeeding process is necessary.

In almost all cases, cats with HL are not eating and often they are nauseous and/or vomiting. For this reason, assisted feeding is generally necessary and a decision must be made about whether to administer nutrients enterally or parenterally. This decision must be based upon the status of the individual patient, but I often use parenteral nutrition and/or nasoesophageal feeding during the initial period and switch to an esophagostomy or gastrostomy tube once the patient is more stable.

Feeding tubes can be very helpful in managing these patients, particularly since the recovery period can be quite prolonged and a feeding tube will allow the owner to provide appropriate nutritional support for the patient at home. Many of these animals due have decreased motility or delayed gastric emptying due to prolonged anorexia and illness, so antiemetics and/or prokinetics may be helpful. It also helps to use multiple small meals and to start with small amounts and gradually (over the first few days) work up to the full feeding amounts that will supply adequate calories.

It is also important to recognize that there are consequences and possible complications that arise when calories are re-introduced to a chronically malnourished individual. Re-feeding syndrome can be a significant source of morbidity in cats with HL, especially if it is not recognized early. Decreases in several electrolytes (esp. magnesium, phosphorus, and potassium) may have serious consequences and supplementation and alteration of the feeding plan may be necessary.

Other therapies

Other medications and supplements have been used or recommended for managing HL in cats, but none appear to be as critical for success as adequate nutritional support. Treatment to provide liver "support", supplementation of specific nutrients, supportive care for hepatic encephalopathy, and symptomatic therapy may all have a role in certain case/situations.

Summary

Overall, hepatic lipidosis remains one of the most common liver diseases in domestic cats. It is also important to remember, however, that in the majority of cases it is likely a secondary condition and therefore vigilance in pursuing underlying disease is critical. Being aware of some of the risk factors can help us to prevent many of these cases by creating appropriate nutritional plans early in the course of any period of anorexia in cats. In those cases that do develop HL understanding the importance of an aggressive nutritional support and other available supportive therapies has been key in reducing the mortality of this condition.