harrison text book of internal medicine

1. Acute complications of
diabetes mellitus
DKA,HHS and Hypoglycemia

2. • DKA and HHS are acute, severe disorders directly related to diabetes.
• DKA was formerly considered a hallmark of type 1 DM, but also
occurs in individuals with type 2 DM who can sometimes
subsequently be treated with oral glucose-lowering agents
• HHS is primarily seen in individuals with type 2 DM

3. Diabetic ketoacidosis

4. Pathophysiology
• DKA results from relative or absolute insulin deficiency combined
with counterregulatory hormone excess
• The decreased ratio of insulin to glucagon promotes gluconeogenesis,
glycogenolysis, and ketone body formation in the liver, as well as
increases in substrate delivery from fat and muscle (free fatty acids,
amino acids) to the liver

5. • Reduced insulin levels, in combination with elevations in
catecholamines and growth hormone, increase lipolysis and the
release of free fatty acids
• Normally, these free fatty acids are converted to very low-density
lipoprotein (VLDL) in the liver
• However, in DKA, hyperglucagonemia alters hepatic metabolism to
favor ketone body formation, through activation of the enzyme
carnitine palmitoyltransferase I.

6. • At physiologic pH, ketone bodies exist as ketoacids, which are
neutralized by bicarbonate
• As bicarbonate stores are depleted, metabolic acidosis ensues.
Increased lactic acid production also contributes to the acidosis.

7. Labs

8. • Serum or plasma assays for β-hydroxybutyrate are preferred because
they more accurately reflect the true ketone body level.
• Despite a total-body potassium deficit, the serum potassium at
presentation may be mildly elevated, secondary to the acidosis and
volume depletion
• Total-body stores of sodium, chloride, phosphorus, and magnesium are
also reduced in DKA but are not accurately reflected by their levels in
the serum because of hypovolemia and hyperglycemia

9. • Elevated blood urea nitrogen (BUN) and serum creatinine levels reflect
intravascular volume depletion.
• Leukocytosis, hypertriglyceridemia, and hyperlipoproteinemia are
commonly found
• Hyperamylasemia may suggest a diagnosis of pancreatitis, especially
when accompanied by abdominal pain. However, in DKA the amylase
is usually of salivary origin and thus is not diagnostic of pancreatitis.

10. Treatment

12. HYPERGLYCEMIC HYPEROSMOLAR STATE
Clinical Features :
• The prototypical patient with HHS is an elderly individual with type 2
DM, with a several-week history of polyuria, weight loss, and
diminished oral intake that culminates in mental confusion, lethargy,
or coma.
• The physical examination reflects profound dehydration and
hyperosmolality and reveals hypotension, tachycardia, and altered
mental status

13. • Notably absent are symptoms of nausea, vomiting, and abdominal pain
and the Kussmaul respirations characteristic of DKA
• HHS is often precipitated by a serious, concurrent illness such as
myocardial infarction or stroke. Sepsis, pneumonia, and other serious
infections are frequent precipitants and should be sought

14. Pathophysiology ;
• Relative insulin deficiency and inadequate fluid intake are the underlying
causes of HHS.
• Insulin deficiency increases hepatic glucose production (through
glycogenolysis and gluconeogenesis) and impairs glucose utilization in
skeletal muscle (see above discussion of DKA).
• Hyperglycemia induces an osmotic diuresis that leads to intravascular
volume depletion, which is exacerbated by inadequate fluid replacement
• The absence of ketosis in HHS is not understood. Presumably, the insulin
deficiency is only relative and less severe than in DKA.

15. • Labs: refer earlier table.
• Treatment: similar to dka.
• Underlying or precipitating problems should be aggressively sought and treated
• In HHS, fluid losses and dehydration are usually more pronounced than in DKA
due to the longer duration of the illness.
• The patient with HHS is usually older, more likely to have mental status changes,
and more likely to have a life-threatening precipitating event with accompanying
comorbidities.
• Even with proper treatment, HHS has a substantially higher mortality rate than
DKA (up to 15% in some clinical series).

16. Hypoglycemia
• Hypoglycemia may be documented by Whipple’s triad:
• (1) symptoms consistent with hypoglycemia,
• (2) a low plasma glucose concentration measured with a precise
method, and
• (3) relief of symptoms after the plasma glucose level is raised.
• The lower limit of the fasting plasma glucose concentration is
normally ~70 mg/dL

17. Causes for hypoglycemia

19. Physiologic response to decreasing glucose levels

21. Management of acute hypoglycemia
• If conscious : oral glucose(initial dose is 15–20 g of glucose)
• If unconscious: IV administration of glucose (25 g) should be followed
by a glucose infusion guided by serial plasma glucose measurements.
• If IV therapy is not practical, SC or IM glucagon (1.0 mg in adults) can
be used, particularly in patients with T1DM.

22. Impact of hypoglycemia in management of DM
• Recurrent morbidity in most people with type 1 diabetes (T1DM) and in
many with advanced type 2 diabetes (T2DM), and it is sometimes fatal.
• It precludes maintenance of euglycemia over a lifetime of diabetes and
thus full realization of the well-established microvascular benefits of
glycemic control.
• It causes a vicious cycle of recurrent hypoglycemia by producing
hypoglycemia-associated autonomic failure—i.E., The clinical syndromes of
defective glucose counterregulation and of hypoglycemia unawareness.

23. Hypoglycemia-Associated Autonomic Failure (HAAF)-
defective glucose counterregulation and hypoglycemia unawareness
• Defective glucose counterregulation compromises physiologic
defense (particularly decrements in insulin and increments in
glucagon and epinephrine),
• and hypoglycemia unawareness compromises behavioral defense
(ingestion of carbohydrate).
• This impaired responses create a vicious cycle of recurrent iatrogenic
hypoglycemia by reducing the sympathoadrenal response to a given
level of subsequent hypoglycemia

25. • Management
• Hypoglycemia unawareness and, to some extent, the reduced epinephrine
component of defective glucose counterregulation are reversible by as little
as 2–3 weeks of scrupulous avoidance of hypoglycemia in most affected
patients.
• Other management strategies: pancreatic transplantation
• Continuous glucose monitors with continuous subcutaneous infusion
• Portable wearable “artificial pancreas” incorporating continuous glucose
sensor modulation of either insulin alone or bi-hormonal delivery of both
insulin and glucagon has been established
• Stem cell-derived β-cells also offer promise of novel therapeutic
interventions to reduce hypoglycemia.