Fatty liver disease is a consequence of negative energy balance at the onset of lactation in dairy cows. Liver lipid accumulation occurs when body fat stores are mobilized and release nonesterified long chain fatty acids (NEFAs) into blood, which to a considerable part reach the liver. If the amount of NEFAs reaching the liver exceeds the liver's capacity to process these, NEFAs are re-esterified and deposited inside the hepatocyte as triacylglycerol (TAG), a process termed liver lipid accumulation. A mild increase in liver TAG content is to be considered normal in high-yielding dairy cows, but larger amounts of TAG deposited inside the hepatocyte may disturb liver function and further exacerbate the negative energy balance.
Fatty liver disease is one of the important metabolic diseases of postparturient dairy cows. Although often considered a postpartum disorder, it usually develops before and during parturition. Periparturient depression of feed intake, and endocrine changes associated with parturition and lactogenesis contribute to development of fatty liver. Cows that are overconditioned at calving are at highest risk. Fatty liver can develop whenever there is a decrease in feed intake and may occur secondary to the onset of another disorder. Fatty liver at calving is commonly associated with ketosis Ketosis in Cattle Ketosis is an elevated concentration of ketone bodies (acetone, acetoacetate, beta-hydroxybutyrate) in all body fluids. Key clinical signs of ketosis are vague but include anorexia, decreased... read more .
Etiology of Fatty Liver Disease in Cattle
Mobilization of body fat reserves that is triggered by hormonal cues in states of negative energy balance results in the release of NEFAs from adipose tissue. The liver retains ~15%–20% of the NEFAs circulating in blood and thus accumulates increased amounts during periods when blood NEFA concentrations are increased. The most pronounced increase occurs at calving, when plasma NEFA concentrations can exceed 1,000 mcM/L.
NEFAs taken up by the liver can either be oxidized or esterified. The primary esterification product is TAG, which can either be exported as part of a very low density lipoprotein (VLDL) or be stored in liver cells. In ruminants, export occurs at a very slow rate relative to many other species because of impaired VLDL synthesis. Therefore, under conditions of increased hepatic NEFA uptake and esterification, triglycerides accumulate. Oxidation of NEFAs leads either to the production of ATP in the tricarboxylic acid cycle or to the formation of ketones through peroxisomal or beta-oxidation. Ketone formation is favored when blood glucose concentrations are low. Conditions that lead to low blood glucose and insulin concentrations also contribute to fatty liver, because insulin suppresses fat mobilization from adipose tissue.
The greatest increase in liver TAG typically occurs in the first weeks of lactation. The extent of negative energy balance around calving or during disease in combination with the available amount of body fat determine the degree of TAG accumulation in the liver. Excessive TAG accumulation in liver cells results in disturbed liver function and cell damage.
Increases of the liver TAG content from <10 g/kg liver wet weight in late gestation to 20–30 g/kg over the first 4 weeks of lactation are common in highly productive dairy cows and are not associated with clinical disease. Clinical signs related to fatty liver disease tend to become apparent with liver TAG contents of 150 g/kg liver wet weight and above. Although lipid accumulation in the liver is a reversible process, the slow rate of TAG export as lipoprotein causes the disorder to persist for an extended period. Depletion of the liver lipid content usually begins when the cow reaches positive energy balance and may take several weeks to fully subside.
Clinical Findings of Fatty Liver Disease in Cattle
The clinical presentation of fatty liver disease can vary from mild ketosis to liver coma, with fatal outcome depending on the severity of liver TAG accumulation. Mild clinical signs become apparent with liver TAG contents in the range of 100 g/kg liver wet weight, whereas liver coma is observed with values approaching or exceeding 300 g/kg.
There are no pathognomonic clinical signs of fatty liver disease in cattle. The condition is often associated with feed intake depression, decreased milk production, and ketosis. Increased blood NEFA concentration has been associated with impaired immune function and a proinflammatory effect, presumably reflecting in increased incidence of clinical mastitis Mastitis in Cattle With few exceptions, mastitis occurs when microbes enter the teat via the teat canal. Almost any microbe can opportunistically invade the teat canal and cause mastitis. However, most infections... read more , metritis Cows: Several specific diseases are associated with metritis or endometritis. These include brucellosis ( see Brucellosis in Large Animals), leptospirosis ( see Leptospirosis), campylobacteriosis... read more , and other periparturient infectious diseases. However, cause and effect has not been established. Metabolic consequences of TAG accumulation in the liver include reduced gluconeogenesis, ureagenesis, hormone clearance, and hormone responsiveness. Consequently, hypoglycemia, hyperammonemia, and altered endocrine profiles may accompany fatty liver.
Fatty liver is likely to develop concurrently with other diseases such as metritis, mastitis, abomasal displacement, or hypocalcemia, typically disorders that are seen at or shortly after calving. Field observations suggest that response to treatment of concurrent disorders is poor if cows have extensive TAG accumulation in the liver. Cows slow to increase in milk production and feed intake after calving are likely to have fatty liver. However, fatty liver is probably the result rather than the cause of poor feed intake.
Fatty liver is often associated with obese cows and is often seen in downer cows Bovine Secondary Recumbency that have decreased feed intake over prolonged periods of time. Overconditioned cows exhibit more pronounced feed intake depression before and after calving than nonobese cows and, therefore, are susceptible to fatty liver. Although obesity predisposes to fatty liver disease, it is not restricted to obese cows. Similarly, obese cows do not necessarily have fatty liver. Other factors thought to potentially predispose to fatty liver disease are clinical and subclinical periparturient hypocalcemia that is associated with hampered insulin secretion, or lameness Overview of Lameness in Cattle The lesions that cause lameness in dairy cows result in intense pain and are a major animal welfare issue. Lameness also causes stress, which debilitates and reduces productivity. The financial... read more in dry cows that is associated with decreased standing and eating times in late gestation and early lactation.
Diagnosis of Fatty Liver Disease in Cattle
Most commonly done indirectly by assessing severity and duration of negative energy balance
The unequivocal diagnosis of fatty liver disease requires the exact determination of the liver lipid or triglyceride content but is of limited clinical value. Indirect indicators such as the severity of clinical signs, blood biochemical parameters allowing assessment of the severity of negative energy balance, and parameters indicative of liver cell injury or altered liver function are generally used in practice.
Direct diagnostic tools for fatty liver are of limited value. Fatty liver is usually diagnosed after the animal has been off feed or has died because of another disease. A positive diagnosis does not mean that clinical signs of illness are the result of fatty liver, and misinterpretation of a positive diagnosis is common.
Liver biopsy is a minimally invasive procedure that is the only direct and most reliable method to determine severity of fatty liver in dairy cattle. Measurement of total lipid or triglyceride content by gravimetric or chemical methods after extraction from tissue by organic solvents is necessary for quantitative assessment; however, these assays are not routinely conducted in commercial laboratories. Estimation of the total lipid content by flotation characteristics of the tissue in copper sulfate solutions of varying specific gravity is rapid, easy, and available for use under field conditions.
Blood and urine metabolites or blood enzyme activity have been proposed as indirect diagnostic parameters. Blood glucose concentrations are low and blood NEFA and beta-hydroxybutyrate concentrations are high when conditions are conducive to the development of fatty liver. Blood cholesterol concentration is usually low when fatty liver occurs, which may reflect an impaired ability of the liver to secrete lipoproteins but can also be a sign of anorexia. AST, glutamate dehydrogenase, and sorbitol dehydrogenase are enzymes of the liver cell that may show increased activity in serum or plasma with liver TAG accumulation and liver damage. The total bilirubin concentration in blood is often positively associated with the NEFA concentration in blood. Blood metabolites or enzymes are nonetheless unreliable indices of the degree of fatty liver, because normal concentrations vary widely among animals. The same problem exists when attempting to determine liver function by measuring sulfobromophthalein clearance from blood.
With the availability of handheld devices allowing cowside testing, measuring beta-hydroxybutyrate concentration in blood has become a popular way to identify herds that may be at risk of developing fatty liver. Measurement of plasma NEFA concentration is more expensive and requires submission of blood samples to a diagnostic laboratory. In addition to wide variations in plasma NEFA concentrations among animals, there can be wide variation in a single individual, because concentrations increase dramatically immediately before and after calving. Therefore, a large number of animals must be sampled at a consistent time relative to calving. Care must be taken not to excite animals before sampling blood, because NEFAs increase rapidly in response to stress; samples should be drawn at standardized times using standardized procedures.
The plasma NEFA concentrations at which triglyceride accumulates in the liver have not been established but are probably ~600 mcM/L and higher. These concentrations are common within 24–48 hours of parturition. However, prolonged exposure of the liver to concentrations >600 mcM/L will likely lead to fatty liver. Primiparous cows are less susceptible to fatty liver during periods of increased plasma NEFAs. Therefore, mature animals should be sampled when using plasma NEFAs as a predictor of fatty liver. To screen a herd for the prevalence and severity of hepatic lipidosis, determination of plasma NEFAs not earlier than 1 week antepartum is recommended. Even though plasma NEFA concentration is a direct parameter for the lipid mobilization and thus the liver lipid accumulation, after parturition the plasma beta-hydroxybutyrate concentration has been found to more accurately reflect the severity of hepatic lipidosis.
Microscopic evaluation can be used to estimate the volume of the tissue occupied by fat. Estimates obtained by this method agree fairly well with chemical determination of triglyceride when expressed as a percentage of tissue dry weight. Mild, moderate, and severe fatty liver are often defined as <20%, 20%–40%, and >40% fat (percentage of cell volume), respectively, but these values have little meaning relative to impact on physiologic function or clinical signs of the animal. Use of ultrasonography Ultrasonography in Animals Ultrasonography is the second most commonly used imaging format in veterinary practice. It uses ultrasonic sound waves in the frequency range of 1.5–15 megahertz (MHz) to create images of body... read more as an alternative noninvasive procedure is being developed to determine the severity of fatty liver but is not yet routinely available.
Prevention and Treatment of Fatty Liver Disease in Cattle
Prevention is based on identifying at-risk cows and monitoring energy balance.
Treatment of affected cows is primarily supportive.
Prevention of fatty liver disease must focus on optimizing cow animal well-being during the dry period. Crowding, sudden ration changes, limited feed bunk space, heat stress, and lameness all may contribute to the reduction of feed intake in the days and weeks before calving. Excessive body condition at the time of dry-off and factors negatively affecting feed intake in the last weeks of gestation are important risk factors. Cows at increased risk should be identified because they may benefit from individual preventive treatment. Therapy is based on oral administration of gluconeogenic substances, to which parenteral dextrose administration may be added in more severe cases.
Reducing severity and duration of negative energy balance is crucial to prevent fatty liver. This can be achieved by avoiding:
rapid diet changes
Cows within a herd should enter the dry period with an average body condition score (BCS) of 3–3.5 (scale: 1 = thin, 5 = obese). Thin cows (BCS ≤2.5) can be fed additional energy during the dry period to replenish condition without fear of causing fatty liver. Overconditioned cattle (BCS ≥4) should not be feed restricted, because this will promote fat mobilization from adipose tissue and increase blood NEFAs and liver triglyceride.
The critical time for prevention of fatty liver is ~1 week before through 1 week after parturition, when cows are most susceptible. Cows that are candidates for preventive measures are those that are overconditioned or starting to go off feed. Propylene glycol, 300–600 mL/day, given as an oral drench during the final week prepartum, has effectively reduced plasma NEFAs and the severity of fatty liver at calving. Propylene glycol can be fed, but feeding may not be as effective if the full dose is not consumed in a short period of time. Glycerol (up to 1 kg/cow, once daily) has been suggested as a less expensive and more palatable alternative to propylene glycol.
Glucose or glucose precursors are effective for the control of ketosis and fatty liver disease because they trigger an insulin response. Insulin is antilipolytic, ie, it decreases lipid mobilization from adipose tissue. A single 100 IU IM dose of a 24-hour, slow-release insulin immediately after calving may be prophylactic. Higher doses may cause severe hypoglycemia and should not be used without concurrent glucose administration. Glucagon stimulates glycogenolysis, gluconeogenesis, and insulin production. In contrast to that in nonruminants, the lipolytic effect of glucagon in ruminants is negligible. Glucagon (10 mg/day, IV, for 14 days) is effective at reducing liver triglyceride. In most countries, neither insulin nor glucagon are approved for use in food-producing animals. Niacin is an antilipolytic agent that may have potential for prevention of fatty liver, but unequivocal evidence supporting niacin supplementation of animals at risk is not available.
The efficacy of oral monensin, an ionophore antibiotic for prevention of ketosis and thereby also of fatty liver disease, has been studied extensively. Supplementing dry cows with monensin orally for 4 weeks before calving was found to reduce the risk of developing ketosis and hepatic lipidosis in early lactation, particularly in overconditioned and older cows. The relevant mechanism of action appears to be the modulation of rumen fermentation to increase propionate synthesis. Slow-release oral boluses containing monensin for dry cows are available and have become a popular prophylaxis strategy for cows at increased risk of ketosis.
Approaches to treat fatty liver disease are similar to those used to treat ketosis Ketosis in Cattle Ketosis is an elevated concentration of ketone bodies (acetone, acetoacetate, beta-hydroxybutyrate) in all body fluids. Key clinical signs of ketosis are vague but include anorexia, decreased... read more and depend on the severity of the clinical presentation. Mild cases are often treated with oral doses of propylene glycol (250–300 g/cow, twice a day), glycerol (up to 500 g/cow, twice a day) or sodium propionate (200 g/cow, twice a day). The objective with these treatments is to obtain peaks in blood glucose and thereby peaks in insulin secretion. For this purpose, the mentioned doses are best administered as oral boluses rather then mixed into feed. Glycerol as been suggested as a more palatable alternative to propylene glycol, but it does require considerably larger doses and was found to be less beneficial for the treatment of ketosis. Sodium propionate has the disadvantage of being an alkalizing agent, which may be an issue in anorectic cows that frequently develop metabolic alkalosis. Prolonged treatment with sodium propionate of those cows will exacerbate alkalemia and result in dull demeanor and lethargy.
More severe cases of ketosis and fatty liver disease may be treated with a single or repeated IV bolus administration of 500 mL of 50% dextrose solution and can be combined with the administration of propylene glycol (250 mL, PO, twice a day). The intention behind this treatment is to induce one or several peaks of insulin that would interrupt lipomobilization and ketogenesis. Little of the effect is attributed to the energy provided with dextrose, which is mostly excreted through the mammary glands and kidneys.
More complicated cases can be treated by dextrose administration at a continuous infusion rate of up to 60 g/hour/cow, IV, suitable to increase the plasma glucose concentration to 100–150 mg/dL without surpassing the renal threshold for glucose. Drip infusions, however, are not easily administered in the field, limiting this treatment option to a clinical setting. Although this treatment effectively suppresses lipolysis and ketogenesis, treatment-induced hyperglycemia is likely to negatively affect feed intake. It is therefore advisable to reduce the infusion rate after 2–3 days and to determine whether the animal is able to maintain normoglycemia as the parenteral glucose supply decreases.
Use of glucocorticoids in cows with fatty liver is controversial because of their potential lipolytic effect. Recent literature suggests that short-term treatment with dexamethasone does not induce lipolysis in dairy cows. The gluconeogenic effect of glucocorticoids that is well documented in several monogastric species has thus far not been confirmed in cattle. In cattle, increased blood glucose concentrations after parenteral administration of glucocorticoids have primarily been attributed to an impaired glucose uptake by the mammary gland. In addition, glucocorticoids are thought to have a positive effect on feed intake.
In theory, effective treatments would be those that enhance lipoprotein triglyceride export from the liver. However, compounds that are known lipotropic agents in nonruminants have not been proved to be effective in ruminants. IV administration of choline, inositol, methionine, and vitamin B12 are often suggested as treatments. A combination product containing cyanocobalamin and butaphosphan was found to be beneficial when used as complementary therapy for ketosis together with propylene glycol. Parenteral administration of vitamin B12 improved gluconeogenic activity, at least in hypoglycemic cows. Oral administration of these compounds is not effective because they are degraded in the rumen.
Fatty liver disease is a complication of negative energy balance and ketosis in dairy cows occurring in early lactation.
Prevention of fatty liver disease is identical to prevention of ketosis. Paying attention to cow well-being in the dry period is particularly important to prevent avoidable feed-intake depression. In cows at increased risk, such as obese or older highly productive cows, the preventive use of propylene glycol or monensin may be beneficial.
Therapy is based on the oral administration of gluconeogenic substances over several days, to which IV dextrose infusion may be added in more severe cases. The use of glucocorticoids in this context remains an issue of contentious debate.