Ketotic patients

In known metabolic states and disorders, the nature of metabolites excreted at abnormal levels has been identified by GC-MS. Examples of this are adipic and suberic acids found in urine from ketotic patients [347], 2-hydroxybutyric acid from patients with lactic acidosis [348], and methylcitric acid (2-hydroxybutan-l,2,3-tricarboxylic acid) [349] in a case of propionic acidemia [350,351]. In the latter instance, the methylcitric acid is thought to be due to the condensation of accumulated propionyl CoA with oxaloacetate [349]. Increased amounts of odd-numbered fatty acids present in the tissues of these patients due to the involvement of the propionyl CoA in fatty acid synthesis, have also been characterised [278]. A deficiency in a-methylacetoacetyl CoA thiolase enzyme in the isoleucine pathway prevents the conversion of a-methylacetoacetyl CoA to propionyl CoA and acetyl CoA [352,353]. The resultant urinary excretion of large amounts of 2-hydroxy-3-methylbutanoic acid (a-methyl-/3-hydroxybutyric acid) and an excess of a-methylacetoacetate and often tiglyl glycine are readily detected and identified by GC-MS. 

El54 Gerard, S. and Khayam-Bashi, H. (1984). Comparison of Ektachem-400 with alkaline picrate methods for the measurement of creatinine in ketotic patients. Clin. Chem. 30, 968, Abstr. 143. 

E200 Gerard, S.K. and Khayam-Bashi, H. (1985). Characterization of creatinine error in ketotic patients. A prospective comparison of alkaline picrate methods with an enzymatic method. Am. J. Clin. Pathol. 84, 659-664. 

Detection of a volatile compound in blood does not always indicate VSA or occupational/environ-mental exposure to solvent vapor. Acetone and some of its homologs may occur in high concentrations in ketotic patients. Large amounts of acetone and... 

Fatty acids undergo 3-oxidation, producing acetyl CoA, NADH and FADH2. The NADH and FADH2 are oxidised by the respiratory chain to form ATP which is used for gluconeogenesis (Chapter 34) and for urea synthesis (Chapter 44). The acetyl CoA forms the ketoacids acetoacetate and P-hydroxybutyrate, known as the ketone bodies . Acetone, formed in small amounts from acetoacetate, causes the fruity smell of the breath in ketotic patients or people on low carbohydrate diets (e.g. the Atkins diet ). NB When the ratio of NADH NAD is high, as in diabetic ketoacidosis (DKA), the equilibrium of the P-... 

Fig. 14.2 b. Diagnostic approach for ketotic patients. MCAD deficiency may either lead to hypoketotic or ketotic hypoglycemia... 

Pettersen, J.E., Jellum, E. and Eldjarn, L. (1972), The occurrence of adipic and suberic acid in urine from ketotic patients. Clin. Chim. Acta, 38,17. 

Like other diuretics etacrynic acid can impair glucose tolerance in patients with type 2 diabetes mellitus (384). Non-ketotic hyperglycemia has also been reported (385). However, hypoglycemia has also been reported in two patients with uremia (386). 

Most diabetics are in this category. Genetic factors rather than viruses or autoimmune antibodies are apparently causal. The metabolic alterations observed are milder than those described for IDDM (for example, NIDDM patients typically are not ketotic), but the long-term clinical consequences can be just as devastating (for example, vascular complications and subsequent infection can lead to amputation of the lower limbs). 

The patient discussed in the illustrative case presented with orthostatic hypotension, poor skin turgor, dry mucous membrane, a ketotic odor to the breath, elevations in BUN and creatinine, and ketoacidosis. She had severe extracellular volume depletion, which can be estimated using the following clinical criteria ... 

The patient is diagnosed with hyperosmolar non-ketotic (HONK) syndrome secondary to infection of a diabetic foot ulcer and the treatment plan is as follows ... 

Young patients with Type 1 diabetes are often underweight and need insulin to restore normal weight. Calorie restriction is not initially required in these patients. The blood of these yoxmg diabetics contains negligible insulin and they readily become ketotic. 

Glycerol can increase plasma insulin concentrations and thereby worsen diabetes it can particularly cause hyperosmolar non-ketotic hyperglycemia in patients with tjrpe 2 diabetes (10,11). 

Hyperosmolar non-ketotic hyperglycemia occurred in a 61-year-old patient 6 days after a first cycle of cisplatin therapy (161). The patient recovered with conventional conservative management. 

A case of non-ketotic hyperosmolar syndrome has been reported in a non-diabetic patient taking olanzapine, lithium and valproic acid. Symptoms began only 5 days after the olanzapine was started. Priapism, which was reversed by surgical detumescence, occurred when a 30-year-old man took olanzapine with lithium. ... 

The significance of other hormones in bile acid metabolism is not known. Most of the obese and triglyceridemic patients presented in Table II had latent diabetes and, as obese patients in general, apparently a marked hyper-insulinemia. Since hyperinsulinemia markedly stimulates hepatic lipogenesis in man (166), it is logical to infer that insulin causes in these patients an augmented cholesterol production and an indirectly increased bile acid synthesis. The metabolism of bile acids in insulin-dependent diabetes and in hyperlipidemia of ketotic diabetes is not known. 

Fig. 14.2 a. Diagnostic approach for patients with defects of fatty acid -oxidation associated with non-ketotic presentation. Instead of plasma acylcarnitines, similar results may be obtained by analyzing plasma organic acids... 

In some patients with non-ketotic glycinaemia (including one patient shown to lack serine hydroxymethyltransferase) hypo-oxaluria has been found [98] though oxalic acid excretion is normal in others and, in some cases, hypo-oxaluria is intermittent. 

In ketotic glycinaemia, propionyl-CoA carboxylase is absent or inactive and, in consequence, propionic acid cannot be converted to D-methylmalonic acid [112]. Patients do not accumulate propionic acid, except in traces, but the concentration of glycine in the blood rises to 70 mg per 100 ml and that in the urine to 6,000 mg per g creatinine. No methylmalonic acid is detectable in blood or urine. 

A hyperosmolar non-ketotic coma developed in a 29-year-oId diabetic patient with chronic renal failure after repeated oral use of 120 ml 50% glycerol solution, given every 12 hours for a neovascular glaucoma, in addition to 250 mg Diamox per os every 6 hours for 24 hours. Hyperosmolar non-ketotic coma is a serious disorder having a mortality rate between 20 and 70%. By applying i.v. hypotonic saline, albumin, packed red blood cells together with insulin and bicarbonate, the coma could be treated successfully (47 ). 

Concentrations of amino acids and sugars in blood were normal during ketotic attacks and remission, although concentrations of lactate and pyruvate were increased during keto acidosis. The frequency of the ketotic attacks (every 4-6 weeks) diminished as the patients grew older, but slight mental deficiency occurred in both patients (Tanaka, 1975). 

The earlier reports on patients with chronic propionic acidaemia associated with ketotic hyperglycinaemia tended to concentrate on the occurrence, origin and possible significance of individual metabolites, thereby tending to impart... 

Keto acidosis may occur in infants as a result of specific genetic defects, in addition to its occurrence in association with several other organic acidurias, for example propionic acidaemia (ketotic hyperglycinaemia). Chapter 10, Section 10.4.1 on 2-methylacetoacetyl-CoA thiolase deficiency also discussed a report by Robinson et al. (1979) of a patient with apparent combined deficiencies of this enzyme and of 3-oxoacyl-CoA thiolase, which they considered to be identical enzymes. A report of a case of specific 3-oxoacyl-CoA thiolase deficiency has increased interest in these enzymes as causes of congenital keto acidosis, and these are discussed further below, as are patients with a different cause of a similar biochemical condition, succinyl-CoA 3-keto acid-CoA transferase deficiency. 

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