In healthy animals, a dynamic relationship exists among the fatty acids that are located in adipose tissue, traveling in the blood, and stored in the liver. Circulating fatty acids are taken up by the liver, where they are either metabolized for energy or converted to triglycerides and secreted back into the circulation. If the supply of fatty acids to the liver exceeds the liver’s capacity to oxidize or secrete them, lipidosis develops. ⁷ Several studies support the theory that the origin of excess hepatic triglycerides in cats with FHL is from fatty acids mobilized from adipose tissue. ^{8.9. and 10.} Metabolic changes that may contribute to hepatic lipidosis include impaired mitochondrial or peroxisomal oxidation of fatty acids in hepatocytes and reduced liver secretion of the very–low-density lipoproteins (VLDLs) that carry triglycerides in the bloodstream. Support for reduced fatty acid oxidation is provided from a study of induced FHL in adult female cats. ¹¹ Cats began to accumulate hepatic lipids during the weight gain phase of the study, and this increase was associated with a reduction in mitochondrial numbers in liver cells. Liver lipid accumulation continued during the weight loss stage of the study, presumably as a result of impaired fatty acid oxidation. Another study reported that overweight cats experiencing rapid weight loss did not demonstrate reduced VLDL transport from the liver, nor was there a pronounced increase in triglyceride synthesis. ¹² Most researchers agree that the pathogenesis of FHL is probably multifactorial, involving factors that affect fatty-acid mobilization to the liver as well as the oxidation of fatty acids or synthesis and, possibly, secretion of VLDLs. ^{3. and 4.}

FHL is relatively common and is usually seen in middle-aged cats with a history of obesity. Females are reported to be twice as likely to be affected as males, but this may reflect a higher incidence of obesity in the females that were studied, rather than a true gender difference. ⁶ There is also evidence that spayed females tend to consume more food, which may predispose them to overweight conditions. ¹³ In the majority of cases, a cat will have experienced a period of stress followed by partial or complete anorexia. Although obesity in cats is not consistently associated with hepatic accumulation of lipids, the metabolic changes caused by prolonged fasting can lead to rapid and severe hepatic fat accumulation and the clinical signs associated with liver disease. For example, when five healthy but obese cats were fasted for a period of 4 to 6 weeks, three of the cats remained healthy and two developed overt clinical and laboratory signs of FHL. ¹⁴ Subsequent studies by the same group reported that voluntary fasting could be induced by changing the diets of obese cats from a highly palatable commercial diet to a less palatable purified diet. ¹⁵ In this study, all of the cats refused to eat the new diet and developed histological signs of hepatic lipidosis over a period of 4 to 7 weeks.

Although prolonged fasting appears to be a consistent finding in cats that develop FHL, the exact metabolic changes responsible for the rapid accumulation of lipid in the liver have not been completely elucidated. Cats diagnosed with FHL typically show signs of protein malnutrition such as muscle wasting, anemia, and hypoalbuminemia. It has been hypothesized that deficiencies of arginine and methionine, secondary to anorexia and protein malnutrition, are involved in the onset of FHL. The cat requires a dietary source of the amino acid arginine for the production of urea in the liver. When the cat stops eating, prolonged anorexia leads to a deficiency of arginine. Urea cycle activity is depressed, and ammonia begins to accumulate in the blood. Byproducts of this disruption in the urea cycle can interfere with lipoprotein synthesis in the liver. ¹⁶ Moreover, a deficiency of one or more essential amino acids may limit the synthesis of the proteins needed for production of lipoproteins by the liver, leading to an accumulation of triglycerides. ¹⁷ For example, methionine contributes to the development of hepatic lipidosis in rats. ¹⁸ In addition, taurine supplementation, which is synthesized from methionine by most species, has been shown to reduce liver lipid concentrations in obese children. ¹⁹ Because taurine is an essential nutrient for cats, it has been speculated that low levels of dietary taurine may contribute to FHL and providing supplemental taurine to the diet may help to prevent its development. ¹¹ Supportive research for the role of protein and essential amino acids has shown that the administration of small amounts of protein to obese cats during fasting helps to prevent the accumulation of hepatic lipids. ²⁰

Carnitine is a compound that is synthesized from methionine and lysine, primarily in the liver. It is necessary for the transport of long-chain fatty acids into cellular mitochondria for oxidation. Human subjects with carnitine deficiency show severe fat accumulation in the liver and other organs and develop signs of liver disease. ²¹ Carnitine concentrations have been shown to be increased in the muscle and liver of obese women and also during periods of starvation in humans and rats. ^{22.23. and 24.} Because of this association in other species and because of evidence of reduced fatty acid oxidation in the liver of obese cats, it had been theorized that a deficiency of carnitine may be a contributing factor to FHL. However, carnitine concentrations in the plasma, liver, and skeletal muscle of cats with hepatic lipidosis have been reported to be normal. ^{25. and 26.} Another study reported increased plasma concentrations of carnitine during a period of weight gain in cats fed a diet containing normal carnitine levels, but liver carnitine did not increase. ²⁷ The change in plasma concentration was attributed to increased food consumption during weight gain. Conversely, liver carnitine levels were not higher in obese cats when compared with lean cats. It is possible that increased liver carnitine is necessary during the overweight condition to support normal fatty acid oxidation in the liver and that insufficient levels may contribute to the onset of FHL during periods of anorexia and rapid weight loss (see p. 433).

Clinical signs of FHL include complete or partial anorexia with a duration of 7 days or longer, depression, jaundice, weight loss, and muscle wasting. ^{28.29. and 30.} Vomiting and/or diarrhea are occasionally reported. Owners usually report that the cat suddenly stopped eating following a period of lifestyle change or stress. Commonly reported stresses include a move to a new house, the arrival of new pets into the household, or a sudden change in diet. Laboratory findings show increased serum activities of liver-associated enzymes, increased serum bilirubin and bile acid concentrations, and, in some cases, increased blood urea nitrogen (BUN) and plasma ammonia concentration. ²⁸ A nonregenerative anemia characterized by irregularly shaped erythrocytes is typically seen. ⁴ The initial diagnosis of FHL is made using medical history, clinical signs, and the results of laboratory tests. The diagnosis is confirmed by a liver biopsy or fine-needle aspirate showing excessive lipid accumulation in the sampled hepatocytes.

Regardless of the metabolic cause of FHL, it is essential for the cat’s recovery that an early diagnosis is made and that supportive fluid and nutritional therapy is started as soon as possible. Aggressive tube feeding is the treatment of choice because afflicted cats will not eat voluntarily. Force-feeding is not recommended because it can further stress the cat and does not provide an accurate measure of the pet’s caloric intake. For these reasons, tube feeding with a nasogastric tube or PEG (percutaneous endoscopic gastrostomy) tube is preferred by most veterinarians. 31. ^{and 32.} The use of a gastrostomy tube involves direct surgical entry into the cat’s stomach. This procedure allows accurate and consistent delivery of nutrients and does not interfere with the cat’s ability to swallow. ^{29. and 31.} Although surgical complications are a risk, most cats tolerate gastrostomy and esophagostomy tubes better than nasogastric tubes.