Feline Hepatic Lipidosis

Hepatic lipidosis (HL) is an intrahepatic cholestatic syndrome resulting from excessive accumulation of lipid within hepatocytes that can lead to severe hepatic dysfunction. Since the initial description in 1977 (Barsanti et al, 1977), HL has emerged as the most common liver disease diagnosed in cats in North America. It is seen in other parts of the world, although anecdotally not as commonly in some regions (Armstrong and Blanchard, 2009). HL may occur secondary to any disease process that results in protracted partial or complete anorexia. Decreased food intake may be for a period of time as short as 2 days (Center, 2005a). Common concurrent diseases associated with the development of HL include pancreatitis, other hepatic disorders such as cholangitis (see Chapter 150), small intestinal disease, neoplasia, kidney disease, and diabetes mellitus. Concurrent diseases are reported to occur in more than 95% of HL cases (Center, 2005a). HL also occurs less commonly as an idiopathic (primary) condition in an otherwise healthy cat with inadequate food intake. Decreased food intake may occur with forced overly rapid weight loss, unintentional food deprivation, a change to a diet unacceptable to the cat, a sudden change in lifestyle, or stress (e.g., boarding). Early consideration of a diagnosis of HL, identification of any underlying disease process, and prompt initiation of medical and nutritional therapy are essential for the successful management of cats with HL.

Pathogenesis

Prolonged protein and/or calorie malnutrition in cats can result in derangement in all aspects of normal lipid metabolism including mobilization of fatty acids from adipocytes, fatty acid metabolism within hepatocytes, and removal of lipid from hepatocytes. Anorexia is the major clinical aspect of the disease; however, the cause for anorexia in the idiopathic form is undetermined. During a period of anorexia, peripheral lipolysis occurs through the stimulation of hormone-sensitive lipase, resulting in a dramatic increase in the concentration of free fatty acids in the blood. Circulating fatty acids taken up by the liver are either metabolized for energy or converted to triglycerides and stored or secreted back into the circulation as very-low-density lipoproteins (VLDL). If fatty acid delivery exceeds the capacity of the liver to oxidize or secrete them, excessive storage occurs and the clinical syndrome of lipidosis develops. The triglyceride content in the liver of cats with HL averages 43% compared with 1% in the liver of healthy cats (Hall et al, 1997). Although still incompletely understood, the pathogenesis of HL is probably multifactorial, involving factors that affect fatty-acid mobilization to liver, mitochondrial or peroxisomal oxidation of fatty acids in hepatocytes, and the synthesis and possibly secretion of VLDL. Several theories on the pathogenesis of HL have been proposed and have been the topic of some investigations. Hepatic accumulation of fatty acids has been proposed to be due to l-carnitine or apolipoprotein deficiency, but research has failed to substantiate these as primary mechanisms (Armstrong and Blanchard, 2009). Systemic oxidative injury, to which cats are particularly susceptible under normal conditions, also is augmented greatly in cats with HL (Center et al, 2005b) and is reflected by the characteristic presence of Heinz bodies on a complete blood count (CBC).

History and Clinical Signs

Most cats affected with HL are middle-aged, obese, or overweight adults. Although the condition has been reported in a wide age range of cats (Center, 2005a), the median age at presentation is 7 years, which tends to overlap the peak prevalence of obesity. Most reports have failed to show a gender or breed predilection. Most cats are obese or overweight at presentation or historically. Anorexia is the most common and sometimes is the only presenting complaint, with the period of anorexia ranging from 2 days to several weeks. Weight loss is common and can be profound, with concurrent sarcopenia (loss of muscle mass). Other common historical findings are lethargy, jaundice, vomiting, diarrhea or constipation, and an unkempt, poor-quality haircoat. Observant owners may report jaundice. In the absence of signs associated with an underlying disease or complicating factors such as severe hypokalemia or hepatic encephalopathy (HE), HL cats may be bright and alert despite profound anorexia and the presence of marked jaundice.

Physical examination commonly reveals lethargy, dehydration, and jaundice (about 70% of cases). Nonpainful smooth hepatomegaly is common but not always present. Loss of muscle mass despite retention of fat stores can make assigning a BCS difficult. The falciform and inguinal fat pads characteristically are retained and can be seen radiographically and ultrasonographically. Severe electrolyte abnormalities, especially hypokalemia and/or hypophosphatemia, and potentially thiamine deficiency, can result in marked muscle weakness and ventroflexion of the neck. Although spontaneous bleeding is uncommon, bruising or hemorrhage from venipuncture or cystocentesis sites may reflect an underlying coagulopathy. Signs of HE, most notably ptyalism and mental dullness, occur in a minority (<5%) of cases (Center, 2005a). Ptyalism also may reflect nausea. Any concurrent disease resulting in anorexia, especially in an overweight cat, can trigger secondary HL. With this in mind any clinical findings related to a concurrent disease can be superimposed on the above clinical signs of HL (e.g., weakness, abdominal pain, or mass).

Diagnostic Evaluation

The diagnostic goal in cats with HL is twofold: establishing a diagnosis of lipidosis and a simultaneous workup for the presence of an underlying disease process. The diagnosis of HL is based on a compatible history, clinical signs, and biochemical and ultrasonographic abnormalities with cytologic or histopathologic confirmation. Additional tests to identify concurrent disease processes include feline pancreatic lipase immunoreactivity (Spec fPL, Snap fPL) and thoracic radiographs. A total T₄ and testing for feline leukemia virus antigen and feline immunodeficiency virus antibody also may be advisable.

Clinicopathologic Findings

The CBC is most commonly within normal limits with primary HL. There may be nonspecific abnormalities such as mild to moderate normocytic, normochromic nonregenerative anemia, poikilocytosis (erythrocytes with an abnormal shape), large numbers of Heinz bodies, lymphopenia, and a mild leukocytosis. The clinician should be aware that because of susceptibility to oxidative stress that occurs with HL poikilocytosis, Heinz bodies and anemia may develop during treatment. The presence of an inflammatory leukogram is uncommon in the idiopathic form of HL and when present should trigger a search for an underlying disorder.

Serum biochemical abnormalities in HL are typical of an intrahepatic cholestatic disorder. The most consistent abnormalities are an increase in serum bilirubin concentration and increased liver enzyme activities. Serum alkaline phosphatase (ALP) activity is increased more consistently than alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities. Increased γ-glutamyltransferase (GGT) activity is elevated inconsistently. Although the magnitude of increase in GGT tends to parallel the magnitude of increase in ALP in other forms of liver disease with HL, the GGT tends to be minimally increased or remains within the reference range (Center et al, 1993). Hypokalemia, hypophosphatemia, and/or hypomagnesemia are seen in some cases at presentation or may develop during treatment. Hypokalemia has been reported to be a negative prognostic indicator along with advanced age and lower PCV (Center et al, 1993). Hypertriglyceridemia, hypercholesterolemia, and transient hyperglycemia also may be observed. Hypoglycemia, hypoalbuminemia, and low blood urea nitrogen may occur and are indicators of significant altered hepatic dysfunction.

The urine of cats with HL commonly reveals bilirubinuria, and lipiduria may be noted on sediment examination or during sonographic evaluation (Armstrong and Blanchard, 2009).

Abnormalities in coagulation tests are reported to be common but resulted in clinically recognized bleeding in less than 4% of cats with severe HL. One or more coagulation abnormalities occurred in 45% of cats with severe HL, with the most common being a prolongation of the prothrombin time (PT) (Center et al, 1993). Response to vitamin K supplementation in cats with HL suggests that the coagulopathy is the result of vitamin K deficiency rather than decreased coagulation factor production because of hepatocellular failure. Intrahepatic cholestasis leading to reduced enterohepatic circulation of bile acids resulting in reduced absorption of fat-soluble vitamins is the suspected mechanism. Although the PIVKA test (proteins invoked by vitamin K antagonism or absence, Thrombotest) may be a more sensitive indicator of prolonged clotting times in cats with HL, this test is not always readily available. Specific liver function testing is not necessary in most cases of HL. Bile acid testing is not indicated if the cat is bilirubinuric or hyperbilirubinemic. Although HE is an uncommon metabolic consequence in HL, if HE is suspected, fasting ammonia measurement can help support the diagnosis of HE and guide therapeutic intervention.