Case studies

CASE STUDY 1:
A 20 year old male, a known insulin-dependent diabetic, was brought to hospital in a coma. Analysis of a blood sample gave the following results:
Analyte
Patient
Reference(*)
glucose
41mM
3.0 - 5.5mM
acetoacetate
2.6mM
<0.20mM
-hydroxybutyrate
12.0mM
<0.25mM
HCO3-
7mM
23-33mM
urea
10.1mM
3.0 - 8.0mM
* The reference values refer to the concentrations in a “normal” patient.
Why is [glucose] high?
The patient described in this case study is a known case of Insulin-dependant diabetes mellitus (Type 1 Diabetes Mellitus). Type 1 DM is a metabolic disorder resulting from the autoimmune destruction of the pancreatic beta cells located in the Islets of Langerhans which results in a progressive disability to secrete insulin (Votey & Peters, 2007). Type 1 DM can present at any age the most common presentation being in childhood, as in this case, but one-fourth of cases are diagnosed in adults. (Levitsky & Misra, 2008).
The destruction of pancreatic islet cells in patients with Type 1 DM leads to an absolute or relative deficiency of insulin, which is a key enzyme involved in the metabolism of glucose, resulting in hyperglycemia and abnormal carbohydrate, fat and protein metabolism. The patient in this case is currently suffering from Diabetic Ketoacidosis (DKA). In this condition, the hyperglycemia is multifactorial, resulting not only from the underutilization of glucose, occurring due to insulin deficiency, but also from overproduction (Charfen & Fernandez-Frackelton, 2005, pp. 610-611). DKA is a state where insulin deficiency is compounded by an increase in the counter-regulatory stress hormones such as glucagon and cortisol. These hormones result in the overproduction of glucose via the processes of glycogenolysis (conversion of glycogen into glucose) and gluconeogenesis (de novo production of glucose in the liver) (Charfen & Fernandez-Frackelton, 2005, p. 611; Wallace & Matthews, 1997, p. 773). Thus, it is the combination of glucose underutilization and overproduction that leads to hyperglycemia in diabetic patients presenting with DKA.
What are acetoacetate and β-hydroxybutyrate, and how are they produced in the body?
Acetoacetate, β-hydroxybutyrate and Acetone are products of fatty acid metabolism which are termed as ‘Ketone Bodies’ or simply ketones (Wallace & Matthews, 1997, p. 773). These substances are weak organic acids and when they accumulate in the human body, they can lead to metabolic acidosis (Charfen & Fernandez-Frackelton, 2005, p. 611). In DKA, the insulin deficiency and increased levels of stress hormones result in an increase in the process of lipolysis, i.e. the production of acetyl CoA from fatty acids (Wallace & Matthews, 1997, p. 773). In addition to increased lipolysis, there is inhibition of lipogenesis which prevents the acetyl CoA from being utilized via the TCA cycle. Instead, acetyl CoA is oxidised into acetoacetate and β-hydroxybutyrate via the HMG-CoA pathway which occurs exclusively in the hepatic mitochondria, resulting in ketonemia (i.e. the presence of ketones in the blood) (Charfen & Fernandez-Frackelton, 2005, pp. 611-612; Newsholme, Leech, & Board, 2010, pp. 138-139).
Explain the concentrations of the acetoacetate and β-hydroxybutyrate.
In this patient, the levels of acetoacetate and β-hydroxybutyrate are very high as compared to the normal ranges. As discussed above, in patients with DKA, the deficiency of insulin along with the excess of counter-regulatory hormones, results in lipolysis. Moreover, there is inhibition of lipogenesis. Both these factors result in increased concentrations of acetoacetate and β-hydroxybutyrate via the mechanisms discussed above.
Why is the β-hydroxybutyrate greater than the acetoacetate?
As depicted in the lab findings of this patient, the concentration of β-hydroxybutyrate greater than the acetoacetate. Acetoacetate and β-hydroxybutyrate are both products of metabolism of fatty acids produced via the HMG-CoA pathway in the hepatic mitochondria (Newsholme, Leech, & Board, 2010, p. 138). During this process, the first metabolite produced is acetoacetate which is later reduced to β-hydroxybutyrate by hydroxybutyrate dehydrogenase. Normally, about five times more β-hydroxybutyrate is produced during this process as compared to acetoacetate (Newsholme, Leech, & Board, 2010, p. 139). The ratio of β-hydroxybutyrate to acetoacetate is dependent on the number of available NADH molecules which can be reduced. The greater the number of NADH molecules available, the higher the amount of β-hydroxybutyrate produced would be. Free fatty acid metabolism and acidosis results in a more reduced redox state in the cell. This favours the formation of greater quantities of β-hydroxybutyrate from acetoacetate via the utilization of NADH (Tataranni & Bogardus, 2003, p. 578). In addition, due to the existing deficiency of insulin, the utilization of ketones via oxidation is also impaired and thus the reconversion of β-hydroxybutyrate to acetoacetate does not occur (Tataranni & Bogardus, 2003, p. 578). Thus, the cumulative effect is a much higher concentration of β-hydroxybutyrate as compared to acetoacetate.
Attempt to explain the increased [urea].
The urea levels are increased in the above patient due to the profound dehydration that accompanies DKA. The marked hyperglycaemia occurring during DKA results in an increased extracellular osmotic potential which draws water out of cells resulting in dehydration (Charfen & Fernandez-Frackelton, 2005, p. 615). Moreover, once the renal threshold for glucose is exceeded, there is spill-over of glucose into the urine resulting in glucosuria. This leads to osmotic diuresis leading to an overall loss of water and electrolytes from the body (Charfen & Fernandez-Frackelton, 2005, p. 611). Once dehydration ensues, there is a reduction in renal perfusion leading to a decrease in GFR which manifests as an increase in the urea levels.
Another reason for the increase in urea levels is the utilization of proteins as an alternative energy source since glucose cannot be utilised. When proteins are used as metabolites by the counter-regulatory hormones, nitrogen is produced as a by product. The accumulation of nitrogen eventually leads to an elevation of urea in the blood (Brenner, 2005, p. 54).
Attempt to explain the decreased [HCO3-].
In DKA, there is presence of ketones in the blood, which leads towards acidosis. The ketones, including acetoacetate and β-hydroxybutyrate, ionize producing hydrogen ions which lower the pH and cause acidosis. In order to neutralise the effect of these hydrogen ions, the serum bicarbonate binds to them, thus acting as a buffer. This results in low serum levels of bicarbonates in patients with DKA.
If the concentration of free fatty acids in the plasma were measured, would they be less than or more than normal? Explain.
In patients with DKA, the levels of free fatty acids in...