Hepatic lipidosis (HL), also known as feline fatty liver syndrome, is a serious and potentially life-threatening condition in cats characterized by the accumulation of excessive fat within liver cells. This buildup of fat impairs liver function and can lead to severe complications if left untreated. Cats with HL often present with oxidative stress, indicated by low circulating and hepatic glutathione (GSH) levels and increased risk of Heinz body hemolysis, suggesting an underlying primary disease linked to oxidative injury or systemic redox imbalance. Prompt and appropriate intervention is crucial for successful management and recovery.
Initial Management: Addressing Oxidative Stress with N-acetylcysteine (NAC)
In the acute presentation of hepatic lipidosis, N-acetylcysteine (NAC) plays a vital role as an initial therapeutic agent. Administered intravenously (IV), NAC acts as a thiol donor, supporting the body’s antioxidant defenses. NAC, an acetylated form of L-cysteine, not only boosts glutathione (GSH) synthesis by providing cysteine, a crucial precursor, but also transforms into other antioxidant metabolites. Furthermore, it functions as a direct scavenger of circulating free radicals, mitigating oxidative damage.
During the first 2–3 days of treatment, NAC is typically administered intravenously at a dosage of 140 mg/kg, delivered slowly over 20 minutes. This initial dose is followed by 70 mg/kg every 6–8 hours, diluted to a 10% solution for IV infusion. If using a non-intravenous formulation, it is essential to filter the NAC solution through a 0.25 mcm filter before IV administration. The intravenous route is preferred to ensure optimal absorption and efficacy.
It is critical to avoid prolonged NAC infusions exceeding one hour, as this can potentially lead to hyperammonemia. This adverse effect occurs because NAC can interfere with the urea cycle by impairing carbamyl phosphate synthetase 1 activity, an enzyme essential for ammonia detoxification. Intravenous NAC therapy is continued until the cat can tolerate oral medication, specifically S-adenosylmethionine (SAMe). Oral administration of NAC is generally discouraged due to its unpleasant taste, which can induce nausea and vomiting in cats. While rare, NAC can cause urticaria and hyperemia, signs of an allergic reaction that necessitate immediate discontinuation of the treatment.
Transitioning to Oral Therapy: The Role of S-adenosylmethionine (SAMe)
Once the cat’s electrolyte and hydration imbalances are corrected and oral medication is feasible, bioavailable S-adenosylmethionine (SAMe) should be introduced. SAMe is administered orally at a dosage of 20–40 mg/kg every 24 hours, ideally on an empty stomach to enhance absorption. It is important to understand that NAC and SAMe are not interchangeable. NAC primarily serves to replenish cysteine for immediate GSH synthesis, addressing the limiting amino acid in this process. In contrast, SAMe has a much broader range of metabolic functions that are crucial for liver health and overall well-being.
SAMe acts as a thiol donor, similar to NAC, but its roles extend far beyond antioxidant support. It is a critical methyl donor involved in numerous essential metabolic, synthetic, and detoxification pathways. SAMe is also vital for nucleoprotein synthesis and function, including gene transcription and B12 activation. Furthermore, SAMe generates methylthioadenosine and polyamines, compounds with significant biological activities.
Methylthioadenosine, derived from SAMe, plays a crucial role in regenerating adenosine and methionine. It modulates gene expression, cell proliferation, differentiation, and apoptosis. It also influences protein and DNA methylation, thereby impacting gene expression, and exhibits immunomodulatory effects by suppressing pro-inflammatory cytokines and enhancing anti-inflammatory cytokine production through interaction with the nuclear factor kappa B pathway. Studies in healthy cats have shown that oral SAMe supplementation at 20 mg/kg daily improves hepatic and circulating antioxidant GSH levels. However, specific research on the therapeutic response of SAMe in cats with HL is still needed.
Cornerstone of Recovery: Nutritional Support for Cats with Hepatic Lipidosis
Nutritional support is the cornerstone of recovery for cats with hepatic lipidosis. Initiating feeding is paramount, but only after the cat is adequately rehydrated and electrolyte imbalances are reasonably corrected. The initial approach involves offering a highly palatable and odiferous food to stimulate the cat’s appetite. If the cat shows signs of food aversion, such as salivation, withdrawal, or repeatedly turning its head away from the food, all food should be removed from the vicinity to prevent the development of food aversion syndrome. Syringe feeding small amounts of a palatable, calorie-rich liquid feline formula or chicken or other meat-based baby food can be explored as an initial feeding strategy. Importantly, immediate insertion of a feeding tube is not the first critical step.
Addressing electrolyte imbalances, particularly hypokalemia, is crucial before attempting to feed. It often takes 1–2 days to stabilize hydration and electrolyte balance before feeding can be safely initiated. Hypokalemia can lead to gastric hypomotility, increasing the risk of vomiting and aspiration pneumonia.
If oral feeding is refused or poorly tolerated, nasoesophageal tube feeding with a liquid diet supplemented with essential nutrients is a cautious first step. Initially, a small volume (5–10 mL) of tepid water should be administered through the tube to assess the cat’s tolerance. If no vomiting or signs of discomfort are observed within a 4-hour observation period, feeding with liquefied food can commence. If nasoesophageal feeding is required for more than a few days, and the cat is deemed a reasonable anesthetic risk, placement of an esophagostomy tube (E-tube) is recommended. The distal tip of the E-tube should be positioned 2–4 cm cranial to the esophageal-gastric junction, and its correct placement must be confirmed with a lateral thoracic radiograph.
E-tube feeding is the preferred method for providing long-term nutritional support. Feedings should be administered slowly over 20 minutes, and the tube should be thoroughly flushed after each feeding to prevent blockages and ensure hygiene.
Dietary Considerations: High-Energy, Protein-Rich Nutrition
It is essential to avoid protein restriction in cats with HL. High-energy, high-calorie diets with balanced feline protein content are optimal for these patients. The calculated resting energy requirement (RER) ([BW(kg) x 30 + 70] or [BW (kg)0.75 x 70]) serves as a general guideline for nutritional support. However, feeding should be initiated at 25% of the calculated RER and gradually increased over 3–5 days to reach the full RER. Individual energy needs can vary, with some cats requiring less and others more than the calculated RER. In some cases, trickle feeding (continuous infusion via pump) or frequent small manual feedings every 2–4 hours may be necessary.
Monitoring feeding tolerance is critical. In some instances, gentle physical activity, such as walking, can aid tolerance by stimulating peristalsis and gastric contractions. This approach should be attempted before resorting to motility-modifying drugs like metoclopramide due to concerns about hepatic drug metabolism in cats with HL.
Protein restriction should only be considered in rare cases where a cat exhibits clinical signs of hyperammonemia. However, even in these situations, protein restriction can exacerbate hepatic lipid accumulation. Instead, strategies such as lactulose administration and oral amoxicillin or low-dose metronidazole (7.5 mg/kg every 12 hours) can improve nitrogen tolerance, allowing for the feeding of a normal feline diet. These interventions modulate enteric flora, alter substrate utilization, and promote colonic catharsis, all of which contribute to ammonia control.
Managing Vomiting: Addressing Underlying Causes and Symptomatic Relief
Recurrent vomiting necessitates a thorough re-evaluation. Electrolyte levels should be rechecked, feeding tube position verified, and factors related to the underlying disease process investigated. Antiemetic medications such as metoclopramide (0.05–0.1 mg/kg IM up to every 8 hours, or 0.25–0.5 mg/kg/day CRI), ondansetron (0.025 mg/kg IV up to every 12 hours), or maropitant (1 mg/kg PO every 24 hours) can be used to manage vomiting. Gentle exercise, such as walking during owner visits, can also stimulate enteric motility and reduce episodic vomiting.
Appetite Stimulants: Generally Contraindicated in Severe HL
Appetite stimulants are generally contraindicated in cats with severe hepatic lipidosis due to metabolic liver failure. These drugs may not be metabolized effectively and could increase the risk of accumulating toxic metabolites. Therefore, diazepam, oxazepam, alprazolam, and cyproheptadine should be avoided. Appetite stimulants are unlikely to be effective in recovering cats with severe HL, who typically require esophageal tube feeding to ensure adequate energy and protein intake. While appetite stimulants might occasionally improve food intake in the early stages of HL, it is crucial to address the underlying cause of inappetence rather than relying solely on these medications.
Preventing Refeeding Syndrome: Pre-Feeding Preparations
To prevent the potentially life-threatening refeeding syndrome, several crucial steps must be taken before initiating feeding. Correction of hypokalemia, initiation of intravenous phosphate infusion, and thiamine supplementation are essential. Thiamine is critical for normal pyruvate metabolism and the citric acid cycle, both of which become highly active when feeding resumes after prolonged fasting. Lactic acidosis observed in HL is thought to be partly due to thiamine deficiency and often resolves rapidly with thiamine supplementation and hydration correction.
Phosphate supplementation is necessary to provide phosphate for the surge in ATP utilization and synthesis that occurs with food intake after chronic starvation. Refeeding-induced hypophosphatemia can lead to weakness, hemolysis, metabolic encephalopathy, and other severe complications. Serum phosphorus concentrations should be monitored regularly, and potassium phosphate supplementation adjusted accordingly. Intravenous potassium phosphate supplementation is often administered just before feeding to prevent persistent or feeding-induced hypophosphatemia.
Plasma potassium concentrations also require close monitoring. Water-soluble vitamins are essential at the onset of feeding. Without adequate potassium, phosphate, and thiamine supplementation, refeeding syndrome can rapidly progress, causing patient weakness, collapse, metabolic encephalopathy, hemolytic anemia, enteric atony, bleeding tendencies (due to hyperphosphatemia affecting platelet aggregation), and potentially death.
Adjunctive Therapies: L-carnitine and Taurine
L-carnitine Supplementation: Supporting Fatty Acid Oxidation
L-carnitine (L-CN) is a conditionally essential, vitamin-like nutrient synthesized in the liver and kidneys from SAMe, lysine, vitamin C, vitamin B6 (pyridoxine), and iron. Research in cats supports the benefits of L-CN supplementation in optimizing fatty acid oxidation in overweight cats while preserving lean body mass. Clinical observational data suggest that L-CN supplementation, when combined with appropriate nutritional support and electrolyte and vitamin supplementation, improves recovery rates in cats with HL compared to those receiving only fluids and nutritional support. L-CN supplementation may provide supraphysiologic benefits, or domestic cats may have limited on-demand synthetic capacity despite maintaining a narrow L-CN surplus.
Natural prey of cats contain significantly higher levels of L-carnitine than many commercial feline diets (150–3,000 mg L-CN/kg animal tissue), further supporting its potential importance. L-CN dosing in HL cats is recommended at 250–500 mg/cat daily, using medical-grade liquid L-carnitine that can be administered via E-tube. It is important to note that bioavailability can vary significantly among over-the-counter L-CN products.
Taurine Supplementation: Essential for Bile Acid Conjugation
Taurine, an essential amino acid, is rapidly depleted in cats even with short periods of fasting. One of taurine’s critical functions is its obligatory role in bile acid conjugation. Bile acid conjugation is essential for their water solubility, which facilitates renal and enteric excretion and reduces their cytotoxicity to some extent. Cats with HL exhibit markedly elevated serum bile acid concentrations. Taurine supplementation at a dose of 250–500 mg/cat orally is recommended as soon as possible, particularly during the initial week of management.
Why Ursodeoxycholic Acid (UDCA) Should Be Avoided in Feline Hepatic Lipidosis
There are compelling reasons to avoid ursodeoxycholic acid (UDCA) treatment in cats with hepatic lipidosis:
- Exacerbation of Liver Injury: Bile acids accumulate to extremely high concentrations in cats with HL, similar to levels observed in cats with extrahepatic bile duct obstruction (EHBDO). Studies in EHBDO models have shown that UDCA can worsen liver damage in hepatocytes and small bile ductule cells.
- Lack of Benefit in HL Models: Research in children with kwashiorkor (protein and energy malnutrition) who develop HL (a syndrome resembling feline HL), obese children with HL, and obese rat models of HL has demonstrated no benefit from UDCA administration.
- Potential Taurine Depletion: UDCA supplementation may increase the risk of further reducing plasma taurine concentrations due to increased taurine consumption if dietary taurine intake is insufficient.
Given these concerns, UDCA is not recommended for the treatment of Hepatic Lipidosis In Cats.
In conclusion, managing hepatic lipidosis in cats requires a multi-faceted approach focusing on aggressive nutritional support, addressing oxidative stress, preventing refeeding syndrome, and utilizing adjunctive therapies like L-carnitine and taurine. Understanding the pathophysiology of HL and the rationale behind each therapeutic intervention is crucial for successful outcomes in these critically ill feline patients.
