J Clin Pathol: first published as 10.1136/jcp.s1-2.1.57 on 1 January 1969. Downloaded from J. clin. Path., 22, suppl. (Ass. clin. Path.), 2, 57-65 Diabetic ketosis and coma D. A. PYKE From the Diabetic Department, King's College Hospital, London This paper is a review of selected aspects of ketosis used for rough estimates of plasma aceto-acetate and coma in diabetes. The two terms are not synony- concentration. The enzyme method of Williamson, mous and indeed part of this review is concerned Mellanby, and Krebs (1962) is much more satis- with distinguishing between them. Diabetic coma factory than the older methods and has permitted is defined here as depression or loss of consciousness accurate measurement of aceto-acetate and ,-hydro- due to uncontrolled diabetes whether or not associ- xybutyrate in blood at low concentrations. Williams, ated with severe ketosis. Berry, Taylor, and Pyke (unpublished observa- tions) have used this method to determine fasting KETOSIS plasma ketone levels in untreated diabetics, estab- lished diabetics, and in apparently healthy non- Ketosis is of crucial importance in the management diabetics. The results are given in Tables I and II. of diabetic patients. The presence of significant There was no correlation of the plasma ketone amounts of ketone bodies in the urine is usually an values with age or sex. indication of the need for insulin and is the best single chemical guide to the type of treatment a TABLE I patient needs. However, some patients show an copyright. appreciable ketonuria at diagnosis which neverthe- MEAN FASTING PLASMA KETONE LEVELS Aceto- $-OH- Ratio less subsides on simple treatment and does not acetate butyrate Total BHB: AA reappear. If the patient's clinical condition warrants (lAM) (AM) it, therefore, it is often justifiable to delay the use of Normal controls (23) 21 42 63 ± 7 2-7 ± 04 insulin since such treatment, once started, tends to Obese(>O% (8) 15 33 48 ± 8 2-2 0-2 be continued, and the fact that insulin is not essential overweight) Aketonuric (21) 82 269 351 + 55 3-8 0-8 may never be appreciated. diabetics About 40% of diabetics attending clinics in (new cases) http://jcp.bmj.com/ Britain need insulin, judging from our experience at King's College Hospital. This may be a slight TABLE II overestimate of the average figure, as there is a high MEAN FASTING PLASMA KETONE LEVELS IN DIABETICS proportion of young patients in our clinic. Cer- Aceto- 6-OH - tainly only a minority of diabetics need insulin to Degree of Number acetate butyrate Total prevent serious ketosis; the rest are at little risk of Ketonuria of Cases (,uM) (OAM) (JM) going into precoma or coma, even in the presence of None 21 82 269 351 on September 26, 2021 by guest. Protected infection. Mild 5 297 1,042 1,339 Considerable 2 780 3,011 3,791 The assessment of ketosis, so important in clinical In coma 1 2,127 7,509 9,636 management, has hitherto depended largely on urine tests. Modern enzyme tests are highly sensitive and specific. The simpler chemical tests, such as The values agree closely with those reported by Acetest tablets1 or Ketostix strips" are sensitive to Bergmeyer and Bernt (1965), who also used an about 5 to 10 mg/100 ml of aceto-acetic acid; they enzymatic method, but are substantially lower than are much less sensitive to acetone, but this is in any the values reported by Werk and Knowles (1961) case a minor component. and Johnson, Sargent, and Passmore (1958) using Measurement of ketones in plasma has until chemical methods. The ratio of ,-hydroxybutyrate recently not been very satisfactory, though an adap- to aceto-acetate in normals (2.7:1) was similar to tation of Rothera's test has been known for many that reported by Williamson et al (1962). In the years and more recently Acetest tablets have been obese subjects the mean was slightly but not sig- nificantly lower than in normal subjects. 'Ames Company, Division of Miles Laboratories, Stoke Poges, Bucks. In the diabetics without ketonuria the mean 57 J Clin Pathol: first published as 10.1136/jcp.s1-2.1.57 on 1 January 1969. Downloaded from 58 D. A. Pyke plasma value was over five times that of normal sugar level, high ketone values are also found but subjects. There appeared to be no correlation be- as the blood sugar declines after insulin injection, so tween the degree of ketonaemia and the blood does the ketone level. glucose levels. The ratio of ,B-hydroxybutyrate to Frequent blood ketone measurement has also aceto-acetate was not significantly different from amplified the old observation that hypoglycaemia that found in normal subjects, but it was significantly leads to ketonuria by showing that plasma ketones higher than in the obese subjects. also are increased. A fall of blood glucose to less In the diabetics with ketonuria blood ketone than about 50 mg/100 ml regularly leads to an in- levels were much higher (Table II); in those with crease in ketonaemia, sometimes with ketonuria. mild ketonuria the mean total value was 20 times The mechanism of increased hepatic ketogenesis in normal and in the two patients with considerable response to hypoglycaemia is unknown. Hypo- ketonuria it was 60 times the normal value. In the glycaemia causes an increase in the secretion of one patient who was in diabetic coma the value was growth hormone and of catecholamines, both of over 150 times normal. which are ketogenic, but the effect of hypoglycaemia This general correlation between the ketone levels in producing ketonuria is not abolished by hypo- in blood and urine did not apply in every case; for physectomy or adrenalectomy. However, sympathec- instance, two patients without ketonuria had blood tomy does impair ketogenesis in pancreatectomized levels as high as those with ketonuria. dogs (Houssay, Rietti, Ashkar, Del Castillo, Galli, These results confirm that urine tests for aceto- Roldan, and Urgoiti, 1967), and /3-adrenergic acetate provide a rough guide to the degree of blockade with propranol is known to inhibit the ketonaemia. They also show that there is hyper- lipolytic effect of hypoglycaemia, so it is possible ketonaemia in nearly all newly diagnosed diabetics, that the effect of hypoglycaemia is mediated by the for only one of the 21 cases had a normal blood sympathetic nervous system. Alternatively the effect ketone value. This degree of hyperketonaemia does may be due simply to decreased peripheral glucose not, however, signify a tendency to clinical ketosis uptake as a direct result of the low blood sugar. as we ordinarily understand that term, since none Since starvation, vomiting, and hypoglycaemia of the 21 patients needed insulin treatment in a two- can each lead to increased ketonaemia and ketonuria,copyright. year follow-up period. the significance of the latter must be assessed criti- Recently a simpler and quicker micro-method for cally when used in the control of diabetes. measuring plasma aceto-acetate on the AutoAna- These two studies show then that there are con- lyzer has been described by Salway and his colleagues siderable variations in ketonaemia in diabetes. In (personal communication). After dialysis the plasma our study of newly diagnosed cases raised levels aceto-acetate reacts with 2:5-dichlorobenzene dia- were very common, though in cases of established zonium chloride to produce a yellow product which diabetes reported by Watkins and FitzGerald (per- http://jcp.bmj.com/ is measured photometrically. By this method the sonal communication) they were found in only a normal fasting aceto-acetate level is less than 100 minority. However the level of ketonaemia in both ,uM (Watkins and FitzGerald, personal communi- series was well below that found in patients suffer- cation). In a large number of diabetics 80% of the ing from clinical ill-effects of ketosis, ie, in precoma values were in the normal range, about 14% were or coma. between 100 and 200 tzM, and 6% were raised to over 200 As might be expected, patients with DIABETIC COMA ,tM. on September 26, 2021 by guest. Protected uncontrolled diabetes had high blood ketone values, Diabetic precoma and coma have a characteristic but so did other patients whose diabetes appeared age and sex incidence. They occur especially in to be well controlled and who did not show keto- juvenile-onset diabetics, though the patients are not nuria. A few patients with very high blood sugar necessarily young when they are admitted in coma. values nevertheless had low ketone levels. Thus this In a series of 100 consecutive admissions half the study too showed poor correlation between blood patients were aged over 40 and about one fifth were sugar and blood ketone levels. over 60. Age has great relevance to the prognosis, This simple technique of plasma ketone measure- which is considerably worse in patients over 60 ment has enabled serial observations to be made years than in those below this age. Most studies on patients throughout the 24 hours. In a well show that admission for severe ketosis is commoner controlled patient on oral antidiabetic therapy the in females than in males at all ages, especially in plasma aceto-acetate may remain in the normal adolescence when emotional crises are an important range, but in a patient on insulin with considerable contributory cause. swings of blood sugar level the ketone level also Diabetic coma remains a common and important swings; in the early morning with a rising blood hazard. Among 3,438 patients attending the Diabetic J Clin Pathol: first published as 10.1136/jcp.s1-2.1.57 on 1 January 1969.