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Ketosis – an overview | ScienceDirect Topics

  • November 20, 2020
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D.H. Williamson, in Encyclopedia of Human Nutrition (Third Edition), 2013

Pathological Ketosis

The major example of pathological ketosis is of course insulin-dependent or type 1 diabetes. Essentially the changes in this condition are similar to those that occur during fasting, but they are more pronounced. Insulin is absent or very low in the plasma and therefore there is no antagonistic action to restrain the opposing hormones, adrenaline, noradrenaline, and glucagon. Consequently, lipolysis in adipose tissue is greatly stimulated and plasma fatty acids increase to high levels.

The lack of insulin and the large flux of fatty acids to the liver means that lipognesis is inhibited at the level of acetyl-CoA carboxylase and there is the expected decrease in malonyl-CoA concentration. In addition, the sensitivity of CAT I to inhibition by malonyl-CoA is considerably decreased. The level of expression of hepatic CAT I and II proteins also increases several-fold in diabetes. Thus the liver is in the ideal mode for producing excessive amounts of ketone bodies.

It has been suggested that diversion of oxaloacetate to hepatic glucose synthesis (which is also increased in insulin deficiency) may also play a role in the increased rate of ketogenesis by diverting acetyl-CoA from the tricarboxylate cycle. However, the present evidence suggests that this makes a minor contribution. Although the excessive output of ketone bodies by the liver undoubtedly makes the major contribution to their high levels in the blood, it is likely that there is also a degree of underutilization by peripheral tissues. The net result is ketoacidosis and excretion of large amounts of energy as ketone bodies in the urine.

A rare, but intriguing, example of pathological ketosis (ketone bodies up to 10 mmol l−1) is the inborn error of hepatic glycogen synthase deficiency (Figure 8). Here glycogen is virtually absent from the liver so that after short-term fasting (5–10 h) the glucose falls to hypoglycemic levels, plasma insulin is decreased, plasma fatty acids increase, and ketogenesis is switched on. On consuming a meal the pattern is reversed until the blood glucose falls again. This case illustrates the importance of hepatic glycogen (and its mobilization) in the smooth transition of substrate supply from the fed to the fasted state. Treatment in this case was to recommend the consumption of more frequent high-carbohydrate snacks. It is of interest that this particular child suffered no ill effects from the daily exposure to high concentrations of ketone bodies, underlining their role as normal substrates for the brain when available.

Figure 8. Diurnal blood metabolite profile of a child with glycogen synthetase deficiency.

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Danielle L. Brown, … John M. Cullen, in Pathologic Basis of Veterinary Disease (Sixth Edition), 2017


Ketosis is a metabolic disease that results from impaired metabolism of carbohydrates and volatile fatty acids. In times of energy demand, free fatty acids are released from body fat stores, and the free fatty acids are esterified into fatty acyl CoA in the liver. Ketone bodies (acetoacetic acid and β-hydroxybutyric acid) are derived from fatty acyl CoA by oxidation in the mitochondria. In pregnant and lactating animals, there is a continuous demand for glucose and amino acids, and ketosis results when fat metabolism, which occurs in response to the increased energy demands, becomes excessive. Ketosis is characterized by increased concentrations of ketone bodies in blood (hyperketonemia), hypoglycemia, and low concentrations of hepatic glycogen. Ketosis is common in ruminants and usually occurs during peak lactation, whereas ketosis of sheep usually occurs in late gestation, particularly in ewes carrying twins; this latter disease is known as pregnancy toxemia.

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Wendy J. Underwood DVM, MS, DACVIM, … Adam Schoell DVM, DACLAM, in Laboratory Animal Medicine (Third Edition), 2015


Ketosis is diagnosed by clinical signs; sodium nitroprusside tablets or ketosis dipsticks may be used to identify ketones in the urine or plasma. In dairy cattle, blood glucose is typically less than 40 mg/dl, total blood ketones >30 mg/dl, and milk ketones >10 mg/dl. In small ruminants, blood glucose levels found to be below 25 mg/dl and ketonuria are good diagnostic indicators. Often ketones can be smelled in the cow’s breath and milk. In prepartum cattle and in lactating cows, blood levels of NEFA greater than 1000 uEq/l and 325–400 uEq/l are abnormal (Gerloff and Herdt, 2009). Triglyceride analysis of liver biopsy specimens is useful.

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Fiona Carragher, Mike Champion, in Clinical Biochemistry: Metabolic and Clinical Aspects (Third Edition), 2014

Measurement of ketones

Ketosis is a normal response to fasting and, when not associated with either acidosis or hypoglycaemia, should, in infancy and childhood, be considered as physiological. However, as previously mentioned, the presence of ketones in a neonate is abnormal and requires urgent follow-up. Although ketosis is a physiological response, it is likely to be of clinical significance when it is associated with acidosis. The detection of urine ketones, using a simple point-of-care testing device, is therefore the starting point for the investigation of metabolic acidosis (see Box 24.2).

The absence of ketones can also give a clue to the underlying IMD, the most classic example of which is hypoketonuria with hypoglycaemia due to a fatty acid oxidation defect such as MCADD. Patients with this group of disorders are able to mobilize fat stores during periods of fasting or catabolic stress but, owing to enzyme deficiencies, are unable to oxidize the fatty acids completely, leading to a relative deficiency of acyl-CoA required for ketogenesis. Although classically considered to lead to a complete absence of ketone production, it is more common to see some ketones present but at an inappropriately low concentration. The presence of ketonuria in hypoglycaemia should therefore not preclude investigation for fatty acid oxidation defects.

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Samuel T. Henderson PhD, in Diet and Nutrition in Dementia and Cognitive Decline, 2015

Ketosis and AD

Ketosis has also demonstrated potential as an AD therapy. Exposure of cultured hippocampal cells from 18-day embryonic rats to 5 uM Aβ42 results in a 50% decrease in cell number. When cells are simultaneously exposed to 5 uM Aβ42 and 4 mM BHB, a doubling of cell survival is observed [44]. Van der Auwera et al. tested a KD in a mouse model of AD, which exhibits significant levels of Aβ in as little as 3 months of age and extensive plaque deposition by 12–14 months. Sixteen 3-month-old female mice were fed either a ketogenic chow or standard chow for 43 days. Among the animals on the KD, a significant 25% reduction in levels of both Aβ40 and Aβ42 was noted [29].

The cognitive effects of a KD in human AD patients have not been reported. A KD may be difficult to implement in an AD patient due to the shift in food preference toward sweet foods. Mungas et al. examined food preference in 31 AD patients and 43 normal elderly controls. Participants with probable AD showed a preference for both sweet high-fat foods and sweet low-fat foods [49].

To avoid compliance issues, Reger et al. induced ketosis with MCTs without restricting carbohydrate or protein intake. The study utilized a crossover design to examine the effects of acute elevation of serum KB levels on cognitive performance in 20 mild to moderate probable AD subjects (mean age 74.7; mean MMSE score 22.0). A single 40-g dose of MCT induced a 12-fold rise in serum BHB levels after 2 h. Ninety minutes after dosing, subjects were administered the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog), a paragraph recall test, and others. A significant positive correlation between performance on the paragraph recall task and serum BHB concentration was found (P=0.02). In addition, significant improvement was noted in ADAS-Cog scores in subjects who were E4(−) compared to those who were E4(+) (P=0.039) [43].

In a follow-up study, Henderson et al. induced ketosis in mild to moderate AD subjects (mean MMSE of 23) by daily dosing of 20 g of MCTs for 90 days. This study was a randomized, double-blind, placebo-controlled, multicenter trial conducted at 23 clinical sites within the United States. Twenty grams of MCTs successfully induced significant rises in serum BHB levels. After 45 days of treatment, cognitive improvement was noted as a significant 1.9-point difference in mean change from baseline in ADAS-Cog scores between placebo and the MCT groups. Consistent with the earlier acute dosing study, subjects who lacked the E4 allele performed significantly better in ADAS-Cog scores compared to placebo at both days 45 and 90. As with the earlier study, postdose serum BHB levels correlated with improvement in ADAS-Cog scores, suggesting the induction of ketosis may be beneficial to AD patients, particularly if they lack an APOE4 allele (Figure 40.3) [50].

Figure 40.3. Chronic ketosis in AD patients improves cognitive performance.

Summary graph of mean change in ADAS-Cog score from baseline after 90 days of treatment with MCT or placebo. The MCT used in this study was a caprylic triglyceride referred to as AC-1202. Graph shows analysis of different population groups in the study, including the intention-to-treat with last observation carried forward (ITT w/LOCF), per protocol, and dosage compliant groups, each stratified by APOE4 carriage status. Black columns represent subjects receiving AC-1202. White columns represent subjects receiving placebo. Error bars represent standard error of the mean. Table displays mean change from baseline for each group. Mean change from baseline was largest in APOE4(−) subjects who were dosage compliant.

Graph from Henderson et al. [50]; Copyright 2005.

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Kah Ni Tan, … Karin Borges, in Bioactive Nutraceuticals and Dietary Supplements in Neurological and Brain Disease, 2015

The Alternative Metabolic Anticonvulsant Mechanism of the KD

Ketosis causes a shift in the metabolism of substrates in the TCA cycle and both the production and degradation of glutamate. Several reviews by Yudkoff and colleagues outline the details of this process. Briefly, acetoacetate and β-hydroxybutyrate are metabolized by succinyl-CoA transferase to yield acetoacetyl-CoA, which can be further metabolized to acetyl-CoA (Yudkoff et al., 2005). As succinyl-CoA is an inhibitor of citrate synthase activity, its consumption in this reaction promotes citrate formation through the condensation of oxaloacetate and acetyl-CoA (Yudkoff et al., 1997, 2004). A reduction in oxaloacetate amounts will lead to reduced glutamate transamination to produce aspartate via aspartate transaminase, as oxaloacetate is required as a substrate (Yudkoff et al., 2004). The lack of the activity through this pathway may provide higher levels of glutamate that can then be metabolized to glutamine or GABA.

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Michael L. Bruss, in Clinical Biochemistry of Domestic Animals (Sixth Edition), 2008

1 Bovine Ketosis

Bovine ketosis is actually at least three different syndromes that occur in cows during lactation (Kronfeld, 1980; Kronfeld et al., 1983). The syndromes are characterized by anorexia, depression (usually), ketonemia, ketolactia, keton-uria, hypoglycemia, and decreased milk production. The three syndromes are underfeeding ketosis, alimentary ketosis, and spontaneous ketosis.

Underfeeding ketosis occurs when a dairy cow receives insufficient calories to meet lactational demands plus body maintenance. This version of ketosis can be conveniently divided into nutritional underfeeding ketosis and secondary (or complicated) ketosis. The former occurs when the cow has a normal appetite but is given an insufficient quantity of feed or a diet with low metabolic energy density. The latter occurs when a cow has some other disease, such as hypocalcemia, mastitis, and metritis, which suppresses appetite and causes the cow to consume insufficient nutrients. In most respects, underfeeding ketosis resembles starvation ketosis explained earlier, except that there is the additional caloric and glycemic burden of milk production.

Alimentary ketosis occurs when cattle have been fed spoiled silage that contains excessive amounts of butyric acid (Adler et al., 1958; Brouwer and Kijkstra, 1938). As discussed previously, the rumen epithelium has a high capacity to activate butyrate to acetoacetate and 3-hydroxybutyrate. Under conditions where excessive butyrate is presented to the rumen epithelium, large amounts of 3-hydroxybutyrate will be produced and released to the circulation with resulting ketosis. Alimentary ketosis then is really butyrate toxicosis.

Spontaneous ketosis is probably the most common, the most researched, the most controversial, and the least understood form of bovine ketosis. It occurs in high producing dairy cows that are near the peak of lactation, that have access to abundant high-quality feed, and that have no other disease (Baird, 1982; Kronfeld, 1980). The disease is not accompanied by severe acidosis (Sykes et al., 1941), and spontaneous recovery is common although there is a large decrease in milk production (Baird, 1982; Kronfeld, 1980). There are several schemes proposed for the molecular pathogenesis of the syndrome. As these schemes are discussed, it will become evident that they are not necessarily mutually exclusive, and more than one of them may be correct and may be present simultaneously in the same animal.

The most widely accepted theory of bovine ketosis is the hypoglycemia theory (Baird, 1982). In this theory, hypoglycemia is the driving force in the syndrome and ultimately causes the ketonemia. Dairy cows are selected for remaining in the herd more for milk production that for any other factor. Thus, dairy cows have been selected for many generations to have a metabolically aggressive mammary gland. This selection criterion has dictated that the mammary produce a maximum amount of milk with secondary regard for the metabolic consequences for the rest of the animal. It is not surprising, therefore, that occasionally the mammary gland might withdraw glucose from the plasma more rapidly than the liver can resupply it, which leads to hypoglycemia even in a well-fed animal. The hypoglycemia will lead to ketonemia by mechanisms discussed earlier and later in this discussion. The hypoglycemia and ketonemia may cause the cow to be ill enough that she will decrease her feed intake. At this point, the syndrome will resemble underfeeding ketosis.

As explained previously, high milk production equates to a high rate of plasma glucose utilization by the mammary gland, which equates to a high rate of hepatic gluconeogenesis. In a lactating cow, plasma glucose concentration represents the balance point between hepatic glucose production and peripheral glucose utilization, with the mammary gland being the chief user. If peripheral glucose utilization should leap ahead of hepatic glucose production, hypoglycemia will result. In theory, hypoglycemia under these circumstances should lead to a decrease in plasma insulin and an increase in plasma glucagon levels. Lower plasma insulin and higher plasma glucagon should increase the activity of hormone-sensitive lipase in adipose tissue, which will lead to increased plasma levels of LCFA. Consequently, more LCFA will reach the liver and exceed its capacity to oxidize them completely or to reesterify them, and increased ketogenesis will result.

What evidence supports this theory? First, the vast majority of cows with clinical spontaneous ketosis are indeed hypoglycemic (Baird et al., 1968; Gröhn et al., 1983; Schwalm and Schultz, 1976). Second, cows with spontaneous ketosis usually are hypoinsulinemic (Hove, 1974; Schwalm and Schultz, 1976). Third, compared to the prelactation period, postparturient dairy cows have been found to have elevated levels of plasma immunoreactive glucagon (De Boer et al., 1985; Manns, 1972), which is even greater in cows with ketosis (Sakai et al., 1993). Fourth, ketotic cows have elevated levels of plasma LCFA (Baird et al., 1968; Ballard et al., 1968; Schwalm and Schultz, 1976).

Some investigation of molecular mechanisms of ketogenesis in the liver ketotic cows has been performed (Baird et al., 1968; Ballard et al., 1968). In particular, there has been interest in hepatic mitochondrial oxaloacetate levels. In the discussion of ketogenesis presented earlier, it was noted that when increased levels of plasma LCFA occur, the liver can reesterify them or can oxidize them to acetyl-CoA. The acetyl-CoA can be oxidized to carbon dioxide provided there is sufficient oxaloacetate to permit entry into the citric acid cycle as citrate. For the citric acid cycle to operate, there must also be a sufficient amount of ADP available for phosphorylation as well, or accumulation of NADH will slow the cycle. If acetyl-CoA accumulates, the excess will be diverted into ketogenesis.

Two studies have attempted to investigate oxaloacetate concentrations in the livers of ketotic cows (Baird et al., 1968; Ballard et al., 1968). Different methodologies were used to estimate oxaloacetate concentrations; one study (Ballard et al., 1968) concluded that there was no change in oxaloacetate concentration during ketosis, and the other concluded that oxaloacetate concentrations were lower in ketotic than in healthy cows (Baird et al., 1968). Actually, both studies measured total hepatic oxaloacetate rather than mitochondrial oxaloacetate, which may be critical in ketogenic control. However, there has been no evidence to indicate that the ruminant liver should be any different from the nonruminant liver with regard to the concept that if the liver is presented with sufficient LCFA, ketogenesis will result. There has been insufficient research on the control of lipolysis in adipose in ruminants. In particular, there has been insufficient research in differences in plasma levels of lipogenic and lipolytic hormones and sensitivity of adipose to these hormones in cow populations that are susceptible and nonsusceptible to ketosis. No matter how low mitochondrial oxaloacetate levels might be in the liver, ketogenesis will not occur at a significant rate without a sufficient precursor in the form of LCFA, and conversely, ketogenesis could occur with normal oxaloacetate levels if the liver were presented with a sufficiently high concentration of LCFA.

It has been noticed, however, that dairy cattle can become ketonemic without the presence of significant hypoglycemia (Ballard et al., 1968; Gröhn et al., 1983). This is often the case with subclinical ketosis in which ketonemia exists without other signs of ketosis. It has been postulated that there is a lipolytic signal of unknown identity for lipolysis to meet mammary demand for LCFA, which is independent of plasma glucose concentration (Kronfeld, 1982; Kronfeld et al., 1983). The increased plasma LCFA lead directly to increased hepatic ketogenesis.

When it was first observed that glucocorticoids appeared to be an effective treatment for spontaneous ketosis, it was hypothesized that the disease was due to adrenal cortical insufficiency (Shaw, 1956). This theory has fallen into disfavor because it has been shown that ketotic cows have higher plasma levels of glucocorticoids than healthy cows (Robertson et al., 1957). Glucocorticoids are efficacious and probably have their effect by stimulating proteolysis and inhibiting glucose use in muscle, thereby providing gluconeogenic precursors and glucose (Bassett et al., 1966; Braun et al., 1970; Reilly and Black, 1973; Robertson, 1966; Ryan and Carver, 1963).

The efficacy of glucose or glucose precursors as ketosis treatments favors the hypoglycemic theory. Parenteral glucose provides nearly immediate relief although relapses are common (Kronfeld, 1980). Gluconeogenic precursors, such as propylene glycol, glycerol, and sodium propionate, have been shown to be efficacious (Emery et al., 1964; Kauppinen and Gröhn, 1984; Schultz, 1952; Simesen, 1956). Treatment of cows with bovine somatotropin in one lactation appears to decrease the likelihood of ketosis in the next lactation (Lean et al., 1994). Cows treated with somatotropin appear to have less body fat and more skeletal muscle, so after calving, there is less fat to mobilize to LCFA and more protein to mobilize as a glucose precursor. Therefore, hypoglycemia and subsequent fatty acidemia and ketonemia are less likely to occur.

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John W. Pelley, in Elsevier’s Integrated Review Biochemistry (Second Edition), 2012

Liver Metabolism in the Starvation State

Ketosis resulting from increased hepatic production of ketone bodies is the hallmark of starvation. In the absence of insulin, mobilization of FFAs from adipose tissue continues to increase. Because the only site for regulation of fat oxidation is at the level of adipose tissue, oxidation of fatty acids in the liver continues unabated. Accumulating acetyl-CoA is shunted through ketogenesis to produce the ketone bodies acetoacetate and β-hydroxybutyrate. These substrates, which are water-soluble forms of fat, are metabolized to acetyl-CoA and used for energy production by many tissues (e.g., muscle, brain, kidney) but not by red blood cells or the liver. Acetone, a ketone formed spontaneously by decomposition of acetoacetate, gives a fruity odor to the breath.

Gluconeogenesis slows down as the supply of amino acid carbon skeletons from muscle protein catabolism decreases. However, glycerol released by lipolysis in adipose tissue supports a low level of gluconeogenesis in liver, which is the only tissue that contains glycerol kinase (glycerol → glycerol 3-phosphate →→→ glucose).

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Alexander de Lahunta DVM, PhD, DACVIM, DACVP, Eric Glass MS, DVM, DACVIM (Neurology), in Veterinary Neuroanatomy and Clinical Neurology (Third Edition), 2009


Nervous ketosis is the term used for the occasional occurrence of the encephalopathic form of the metabolic disorder ketosis. The encephalopathy is presumed to be the result of the ketoacidosis and hypoglycemia that interfere with the aerobic metabolism that is critical for normal neuronal function. Nervous ketosis can occur at any time during the first 8 weeks of lactation. These encephalopathic cattle are occasionally blind with normal pupillary size and light responses. They more commonly exhibit bizarre behavior that may include constant licking of one or more sites on their body or inanimate objects in their environment, biting and even breaking off the water cups from the water pipes, and propulsively pushing into their stanchion. If these cattle are loose, they may wander aimlessly or head-press against the fence or wall that confines them. They can act obtunded and demented or be very aggressive. The diagnosis is readily made by determining the presence of ketonuria or ketonemia. These clinical signs will usually resolve with appropriate intravenous therapy with dextrose. However, blindness may persist in a severely affected patient as a result of permanent lesions in the visual neocortex.

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