Dietas Com Baixo Teor de Carboidratos, Com Alto Consumo de Proteínas, A Cetose Não É Observada.
Dietas Com Baixo Teor de Carboidratos, Com Alto Consumo de Proteínas, A Cetose Não É Observada.
Dietas Com Baixo Teor de Carboidratos, Com Alto Consumo de Proteínas, A Cetose Não É Observada.
Ketones were rst discovered in the urine of dia- tone—suffered the stigma so often in icted on those
betic patients in the mid-19th century; for almost 50 discovered in bad company. When ketones rst came to
very low in carbohydrate, ketosis varies inversely with glucose. Therefore, to obtain a degree of hyperketonemia
the quantity of protein eaten. This occurs because ap- (approximately 2–7 mM/L) believed to be therapeuti-
proximately 48 to 58% of the amino acids in most dietary cally effective in certain important medical conditions
proteins are glucogenic.35,36 For every 2 grams of protein such as epilepsy, patients must rigorously restrict protein
consumed in a carbohydrate-free diet, somewhere be- as well as carbohydrate intake37 and, when possible,
tween 1.0 and 1.2 grams are potentially convertible to increase their level of physical activity.23
Figure 1. Hepatic formation and peripheral utilization of ketone bodies. Mobilization of non-esteri ed fatty acids (NEFA) from
adipose tissue fat stores by the activation of hormone-sensitive lipase is an initial step that provides ample substrate for the hepatic
production of ketone bodies (b-hydroxybutyrate and acetoacetate). Once fatty acids enter the hepatocyte from the blood circulation,
they are activated to CoA esters by the family of membrane-bound fatty acid acyl-CoA synthetases. The action of one of these
synthetases (long-chain acyl CoA synthetase) is identi ed as (3). After CoA esteri cation, the metabolic paths diverge based on the
fatty acid (acyl) chain length. Short- and medium-chain acyl-CoAs readily cross the outer and inner mitochondrial membranes and
undergo b-oxidation into acetyl-CoA and acetoacetate (the terminal 4-carbon fragment). Long-chain acyl-CoAs readily cross the
outer mitochondrial membrane, after which they must be converted to long-chain acylcarnitine by membrane-bound carnitine
palmitoyltransferaseI, or CPT-1 (1), for subsequent transport across the inner mitochondrial membrane. The inner membrane– bound
enzyme, carnitine acylcarnitine translocase (4), exchanges one long-chain acyl-CoA from the intermembrane space with one free
(unacylated) carnitine from the matrix, thereby permitting carnitine’s return to the intermembrane space. The inner membrane– bound
enzyme carnitine palmitoyltransferase II, or CPT-II (2), converts the fatty acid back into its CoA ester for subsequent b-oxidation,
freeing carnitine for recycling. Very long– chain acyl-CoAs and unsaturated fatty acids of various lengths are transported into
peroxisomes, along with long- and medium-chain acyl-CoAs, for chain-length reduction via b-oxidation. Unlike mitochondrial
b-oxidation, peroxisomal b-oxidation does not proceed to completion. This results in peroxisomal export of medium-chain acyl and
acylcarnitine compounds to the mitochondria for further oxidation. Mitochondrial b-oxidation produces acetyl-CoA, which enters the
TCA cycle for further oxidation to produce ATP. Ketogenesis occurs when hepatic energy requirements are met allowing excess
acetyl-CoA to be acted upon by thiolase, which condenses two acetyl-CoAs to form acetoacetyl-CoA. Hydroxymethylglutyaryl-CoA
synthase (HMG-CoA synthase) condenses acetoacetyl-CoA with acetyl-CoA to form hydroxymethylglutaryl-CoA, which is then
dissociated into acetoacetate and acetyl-CoA by hydroxymethylglutaryl-CoA lyase (HMG-CoA lyase). The action of the
enzyme b-hydroxybutyrate dehydrogenase (5) reduces much of the acetoacetate to b-hydroxybutyrate using NADH as a
reductant. Both acetoacetate and b-hydroxybutyrate are transported back through the mitochondrial membranes for export into
the blood circulation. The pathway of lipogenesis, illustrated by dashed lines, becomes activated in the fed state and results in
the synthesis of fatty acids and their esteri cation into triacylglycerol (triglycerides). The rst committed intermediary in fatty
acid synthesis is malonyl-CoA, which inhibits CPT-1 (enzyme 1). This inhibition is illustrated as a thin dashed line pointing
to CPT-1. Inhibition of CPT-1 prevents mitochondrial uptake of fatty acyl-CoA (and its subsequent b-oxidation), and thereby
blocks ketogenesis. In the fed (non-ketotic) state, triglyceride is exported from the liver as very low– density lipoprotein
(VLDL).
ketosis, which is the physiological response to insulin Examples of mechanisms by which diet-induced
deprivation during starvation, was equivalent in meta- hyperketonemia might overcome or circumvent meta-
bolic effects to the actions of insulin . . . (Moreover), bolic impediments to utilization of such substrates as
ketones by-passed the block in glucose transport caused glucose and pyruvate are shown schematically in Fig-
by lack of insulin . . . (and) also by-passed the block in ure 3.
PDH induced by insulin de ciency by providing an
alternative source of mitochondrial acetyl CoA.” The
Use of a “Hyperketogenic” Diet in Treatment
pathway by which ketones are able to achieve this effect
of Seizure Disorders
is shown in Figure 2.
Veech et al.50 pointed out that the gradients of K Fasting has long been acknowledged as a method to
and Na (and Ca ) between the extra- and intracellular prevent or reduce seizures in epileptic individuals.37
phases of the cell are normally in virtual equilibrium Because of the obvious limitations of this treatment, use
with the resting electrical potential between these two of a ketogenic diet to mimic the metabolic effects of food
phases, and with the energy ( G) of ATP hydrolysis, deprivation was proposed in 1921 by both Woodyatt52
which sustains the action of the Na pump. By increas- and Wilder53 at the Mayo Clinic. In 1924, Peterman54
ing metabolic ef ciency and, thereby, the energy pro- (also from Mayo) reported the clinical application and
duced by ATP hydrolysis, BHB augments the potential effectiveness of the regimen suggested by Woodyatt and
between the extra- and intracellular phases, giving rise to Wilder. Peterman’s diet provided (per day) 1 g of pro-
an increase in the energy of the K gradient (ratio of tein/kg body weight (considerably less in adults), 10 to
[K ]out/[K ]in) in muscle and brain. A larger mitochon- 15 g of carbohydrate, and the remainder of the calories as
drial membrane potential would lead to larger energy fat. The Peterman ketogenic diet is sometimes called the
production because it is the mitrochondrial membrane 4:1 diet because it provided a ratio of approximately 4
potential difference that drives the production of ATP. parts (by weight) fat to 1 part (by weight) of a mixture of
Maintenance of a suitable K gradient in the cell is, of protein and carbohydrate. This distribution of the major
course, indispensable to its proper functioning. As will macronutrients is almost identical to that of most anti-
be discussed below, impairment of ion homeostasis convulsant diets used today.37 The term “hyperketogenic
within neuronal cells in certain brain areas might result diet” (HKD) will be used in this review to distinguish the
in a degree of electrical instability suf cient to trigger an 4:1 diet (and certain variations thereof) from the far less
epileptic seizure (or, in the heart, a cardiac arrhythmia). drastic, low-carbohydrate, mildly ketogenic diets that
Studies of blood ow and oxygen consumption in have been advocated for weight control in a succession
the brains of food-deprived obese human subjects re- of popular diet books.
vealed values (45 mL min 1 100 g 1 and 2.7 mL O2 In the 1970s, several investigators55,56 modi ed the
min 1 100 mL 1)44 that were well below the normal Peterman HKD by substituting medium-chain triglycer-
levels for adult human brains of 57 and 3.6, respective- ides (MCT) in varying amounts for long-chain triglycer-
ly.51 Although these data need con rmation, they suggest ides. (MCT’s ketogenic effect is not dependent on con-
an increase in the metabolic ef ciency in human brains current restriction of dietary carbohydrate.57) Although
using ketoacids as their principal energy source in place all such variations of the HKD were approximately equal
of glucose. in reducing seizures, many of the children given MCT-
augmented diets complained of nausea, diarrhea, and 1972, Uhleman and Neims60 demonstrated that mice
occasional vomiting.58 pups fed a high-fat ketogenic diet exhibited signi cantly
Among those patients who adhere to the 4:1 HKD increased thresholds against investigator-applied electro-
for 12 months, 40% experience greater than 90% reduc- shock challenges. This resistance to electroshock disap-
tion in seizures, whereas an additional 40% experience peared promptly after the animals were shifted to a
50 to 90% reduction. Although the precise mechanism of high-carbohydrate diet. Subsequently, a number of stud-
action responsible for the clinical ef cacy of the diet has ies have shown an increase in the electroconvulsive
never been clari ed, it is likely that the hyperketonemia threshold in rats maintained on a high-fat diet or de-
induced by the 4:1 HKD is the key factor responsible for prived of food for 48 hours. De Vivo et al.61 found that
the regimen’s anticonvulsant effect, rather than the ac- the ratios of ATP to adenosine diphosphate (ADP) were
companying metabolic acidosis59 or dehydration.37 In signi cantly increased in the brains of rats fed the high-
fat diet. They concluded “. . . the anticonvulsant property Janigro64 summarized studies indicating that there is
of the ketogenic diet derives from the observed increase a reduction in both glucose uptake and metabolic activity
in cerebral energy reserve, which in turn re ects the in seizure foci in epileptic patients. In his words, “Di-
higher ATP/ADP ratio . . . [this] might provide a reason- minished ion homeostasis together with increased meta-
able explanation for the increased neuronal stability that bolic demand of hyperactive neurons may further aggra-
develops during chronic ketosis.” In 1999, Pan et al.62 vate neuropathological consequences of BBB loss of
carried out 31P magnetic resonance spectroscopic imag- glucose uptake mechanisms.” Therefore, one explanation
ing studies in seven patients with intractable epilepsy for the effectiveness of the 4:1 HKD in preventing
before and after institution of a ketogenic diet. They seizures could be the increased transport of BHB at the
measured signi cant increases ( P , 0.05) in high- BBB and its increased availability as an energy source to
energy phosphates in association with adherence to the the affected neurons. BHB is not only an alternate source
ketogenic diet in these subjects. They concluded that of energy for seizure foci in the brain— bypassing an
enhancement of brain energy metabolism occurs with impairment of carbohydrate utilization such as that
use of the ketogenic diet in humans as in lab animals. which can occur from a block in mitochondrial PDH
Thavendiranathan et al.63 have recently reported activity— but it may actually promote ketone and glu-
studies of the effect of the “classic” ketogenic diet on cose uptake in such foci. In rats, diet-induced ketosis
seizures triggered by two threshold tests—the pentyle- produces an eightfold increase in the activity of the
netetrazol infusion test and the threshold electroconvul- monocarboxylate transporter and increases the level of
sive shock test. These authors observed small but signif- the glucose transporter, GLUT1, in brain endothelial
icant threshold elevations (15–20%) against both cells and neuropil.65 The hypothesis put forth by Janigro
chemically and electrically triggered seizures. Similarly to explain how ketosis might eliminate or reduce seizures
protective effects were not seen when suprathreshold is supported by reports that a suitable ketogenic diet is
stimuli were employed. the treatment of choice for two rare conditions that may