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• Ketoacidosis and HHS
  Anand CV
  Published on: 11 August 2004
• Pathophysiology of diabetic ketoacidosis
  Viktor Rosival
  Published on: 23 July 2004

• Published on: 11 August 2004

  Ketoacidosis and HHS

  • Anand CV, Professor of Biochemistry
  • Other Contributors:
    • Usha Anand

  Dear Editor

  We read with interest the educative review by Drs English and Williams,[1] and would like to congratulate the authors for their effort.

  The authors have raised a question- namely why ketoacidosis does not occur in HHS. Accumulation of ketone bodies in the blood in DKA stems from a greatly accelerated hepatic production rate, such that the capacity of non-hepatic tissues to use them, is exceeded....

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  Dear Editor

  We read with interest the educative review by Drs English and Williams,[1] and would like to congratulate the authors for their effort.

  The authors have raised a question- namely why ketoacidosis does not occur in HHS. Accumulation of ketone bodies in the blood in DKA stems from a greatly accelerated hepatic production rate, such that the capacity of non-hepatic tissues to use them, is exceeded. A part of the answer may be that the non-hepatic tissues can utilize acetoacetic acid and 3-hydroxybutyric acid at an appreciable rate.That is why ketoacidosis may not manifest in HHS. Formation of acetone by spontaneous decarboxylation of acetoacetic acid may represent a compensatory mechanism to combat the acidosis. That is because the strong acid viz, acetoacetic acid is spontaneously converted into the metabolically inert acetone, which is predominantly excreted by the kidney. The odour of nail varnish remover in breath emphasizes the fact that the lungs efficiently can get rid of acetone. The reaction is :

  CH₃-CO-CH₂-COOH (Acetoacetic acid) → CH₃-CO-CH₃ (Acetone) + CO₂ (Carbon dioxide). Why did the liver make the ketone bodies in the first place? In biochemical terms, in the liver, there is a depletion of oxaloacetate (OAA), the catalyst of the citrate cycle. OAA is a key gluconeogenic substrate in the liver (and the kidney) and, glucagon -stimulated gluconeogenic mechanisms are enhanced in diabetes mellitus.

  Also, for the operation of the urea cycle in the liver, aspartate has to be regenerated by transamination of OAA. Hence, due to lack of OAA, the citrate cycle remains impaired in insulin deficiency. However, in non-hepatic tissues, there does not seem to be any such depletion of OAA. In hypercatabolic states prevailing in the poorly controlled diabetic, protein catabolism is inevitable. This would provide free amino acids in increasing quantities for transamination reactions.

  The non-hepatic tissues can utilize enormous quantities of acetoacetate. This requires succinyl CoA. The reaction is catalyzed by aceto acetate: succinyl CoA, CoA transferase.

  Acetoacetate + succinyl CoA → Acetoacetyl CoA + succinate

  The following "anaplerotic" reactions are known to take place in the non-hepatic tissues, as otherwise, the availability of the citrate cycle intermediates would become a limiting factor.

  1. Conversion of pyruvate to malate by the "malic enzyme".

  Pyruvate + HCO₃- + NAD(P)H + H⁺ → malate + NAD(P)⁺.

  Malate can be converted into succinyl CoA through the citrate cycle.

  2. Conversion of glutamate to keto glutarate by glutamate dehydrogenase. Glutamate + NAD⁺ → alpha-keto glutarate + NH4 + NADH + H⁺

  The alpha-ketoglutarate is converted into succinyl CoA by alpha-ketoglutarate dehydrogenase complex as shown.

  2a. alpha-ketoglutarate + NAD⁺ + CoASH → Succinyl CoA + CO₂ + NADPH + H⁺

  3. Conversion of propionyl CoA (formed from valine and isoleucine) to succinyl CoA.

  Propionyl CoA + HCO₃- + ATP → D-Methyl malonyl CoA ® L-Methyl malonyl CoA → Succinyl CoA.

  The non-hepatic tissues are able to utilize the acetoacetate because of the availability of succinyl CoA and that should be one of the reasons for not finding ketoacidosis in HHS. Atleast a part of the citrate cycle viz, from alpha-ketoglutarate onwards should be operational for utilization of any of the aforementioned metabolites.

  Another important mechanism which the authors have overlooked is, in chronic metabolic acidosis, the kidneys excrete ammonium 2 rather than NaH₂PO₄. After three days of the onset of acidosis, enormous amount of ammonium is excreted by the kidneys. Excretion of NaH₂PO₄ would drain the body of Na⁺ in no time and also would require the pH of the urine to be low. In acidosis, it is well known that activation of the enzyme glutaminase and glutamate dehydrogenase occurs- both of which form ammonium. The main advantage of excretion of protons as ammonium is that, it can be excreted without any decrease in urinary pH ( pK of NH₄ is 9.3). Excretion of ammonium spares the body of Na⁺ and K⁺. At the onset of acidosis, the excretion of H₂PO₄ requires Na⁺, but as the body's Na⁺ stores become depleted, K⁺ excretion rises. If NH₄ were not available, even moderate acidosis could quickly become fatal 3.

  References

  1.English P, Williams G. Hyperglyaemic crises and lacti acidosis in diabetes mellitus. Postgrad Med J 2004; 80:253-261.

  2.The citric acid cycle. In: Nelson DL and Cox MM. Lehninger Principles of Biochemistry. 3rd ed, Worth, New York, 3rd ed, 2000, pp 567-592.

  3. Baggott J. Gas transport and pH regulation. In Textbook of Biochemistry with Clinical Correlations. Devlin TM, ed. Wiley-Liss, New York, 4th ed, 1997, pp 1026-1054.

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  Conflict of Interest:
  None declared.

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• Published on: 23 July 2004

  Pathophysiology of diabetic ketoacidosis

  • Viktor Rosival, Physician

  Dear Editor

  In their recent review English and Williams state "The primary mechanism for the development of ketoacidosis (DKA) and hyperglycaemic hyperosmolar state (HHS) is ... insulin deficiency per se ... together with a concomitant elevation of the counter-regulatory hormones" but "why ketoacidosis does not occur in HHS is unknown".[1]

  However, the pure existence of HHS is strong evidence against the sta...

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  Dear Editor

  In their recent review English and Williams state "The primary mechanism for the development of ketoacidosis (DKA) and hyperglycaemic hyperosmolar state (HHS) is ... insulin deficiency per se ... together with a concomitant elevation of the counter-regulatory hormones" but "why ketoacidosis does not occur in HHS is unknown".[1]

  However, the pure existence of HHS is strong evidence against the statement that "The primary mechanism for the development of DKA is insulin deficiency per se". There are several other observation to support this evidence:

  1. Schade and Eaton measured insulin concentration in the blood of 106 patients with DKA: they found sufficient amounts of insulin.[2]

  2. DKA occurs also in diabetic patients with normal values of blood glucose.[3]

  3. "Hepatic mitochondria oxidise free fatty acids to the ketone bodies acetoacetate and 3-hydroxybutyrate".[1] According to Niwa there are increased amounts of 36 organic acids in DKA.[4] Acetoacetic and 3-hydroxybutyric acids usually show the highest increase. However, some patients have increased amounts of the remaining 34 organic acids, resulting in life threatening acidosis with pH of 6.85 and negative acetoacetate and 3-hydroxybutyrate.[5] The influence of insulin on these 34 acids has not been reported.

  It seems that re-evaluation of the role of insulin in the pathogenesis of DKA is necessary.

  References

  (1) English P, Williams G. Hyperglycaemic crises and lactic acidosis in diabetes mellitus. Postgrad Med J 2004;80:253-61.

  (2) Schade DS, Eaton RP. Prevention of diabetic ketoacidosis. J Am Med Ass 1979;242:2455-8.

  (3) Jenkins D, Close CF, Krentz AJ, Nattrass M, Wright AD. Euglycaemic diabetic ketoacidosis: does it exist? Acta Diabetol 1993;30: 251-3.

  (4) Niwa T. Mass spectrometry in diabetes mellitus. Clin Chim Acta 1995;241-242:190-220.

  (6) Vernon DD, Postellon DC. Nonketotic hyperosmolal diabetic coma in a child: management with low-dose insulin infusion and intracranial pressure monitoring. Pediatrics 1986;77:770-2.

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  Conflict of Interest:
  None declared.

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