Pathogenesis of DKA and HHS

Insulin is a powerful anabolic hormone which helps nutrients to enter the cells, where these nutrients
can be used either as fuel or as building blocks for cell growth and expansion. The complementary
action of insulin is to antagonise the breakdown of fuel stores. Thus, the release of free fatty acids from
adipose tissue depots (lipolysis) is normally restrained by the action of insulin. When a person is fasting
for a long time, insulin levels will fall and lipolysis will occur; uncontrolled diabetes has often been
compared to a state of accelerated fasting.
The resulting flux of free fatty-acids is then either metabolized by 'energy-hungry' tissues, e.g.
muscle, or used by the liver to make glucose (gluconeogenesis) which in its turn will be used as fuel
for certain tissues, most notably the brain.

In diabetic ketoacidosis, the insulin level is

inappropriately low in relation to the presence
of fuel substrates, leading to inappropriately
high rates of lipolysis (see figure 1).

The excess of free fatty acids is oxidized to

ketoacids (acetoacetate and beta-
hydroxybutyrate), which are the hallmark of
DKA. Since lipolysis is easily inhibited at low
levels of insulin, ketoacidosis only develops in
the presence of severe insulin deficiency, and is
therefore characteristic of type 1 diabetes. Partial insulin deficiency may be sufficient to inhibit
ketogenesis but insufficient to inhibit hepatic gluconeogenesis, which has a higher threshold for
suppression by insulin. This situation is more characteristic of type 2 diabetes.

It should be appreciated that many people experience uncontrolled diabetes without progressing to a
life-threatening metabolic emergency. This progression may be due to prolonged insulin deficiency,
as in undiagnosed diabetes, sometime aggravated by the attempt to quench thirst with glucose-
containing drinks. Alternatively, the transition to a metabolic emergency may be driven by stress due
to intercurrent infection or sepsis - which in itself may cause (lactic) acidosis. The release of stress
hormones such as cortisol and catecholamines and several vicious cycles (see figure 1) will further
aggravate the metabolic dysregulation and acidosis.

Thus, for example, acidosis promotes vomiting, leading to progressive dehydration. Progressive
dehydration leads to renal insufficiency, thus impairing renal compensation for the metabolic acidosis.
This negative spiral inevitably resulted in death before the advent of treatment with insulin and fluids.

Symptoms of DKA and HHS

As can be deduced from the pathophysiology, hyperglycaemia associated with DKA can be deceptively
mild in treated diabetes, sometimes as low as 12-14 mmol/l, whereas in HHS it is invariably high
(figure 2). Hyperglycaemia will lead to polyuria, dehydration, weight loss, polydipsia and thirst.
Electrolyte disturbances result from loss of water usually in excess of salt loss; hypovolaemia and
severe intravascular dehydration will be accompanied by tachycardia and may give rise to
thromboembolic complications (such as stroke or myocardial infarction), whereas cellular dehydration
may ultimately cause the hyperosmolar coma
The acidosis will also lead to the classical 'Kussmaul' breathing pattern, in which the patients attempts
respiratory compensation for the metabolic acidosis by hyperventilation, taking deep sighing breaths.
Many electrolytes are lost to the body by polyuria and vomiting, resulting in whole-body deficiency.
Salt depletion is severe but responds well to fluid replacement. Potassium deficiency is a feature of
ketoacidosis due to the exchange of intracellular potassium and the intravascular hydrogen ion.
Potassium is then lost in the urine, resulting in depletion of whole body potassium - although it is
important to appreciate that plasma levels may be raised or normal at the time of presentation.
Hypokalaemia is common in the treatment phase as potassium re-enters cells under the influence of
insulin and can result in cardiac dysrythmia. Timely potassium replacement is therefore a key element
of management. Phosphate deficiency is also a common problem, and may give rise to muscle
weakness.
Ketones have a paralytic effect on smooth muscle cells, which may lead to gastric retention (with a
gastric splash on physical examination) and profuse vomiting as well as a distended bladder. Acidosis
may rarely cause abdominal pain and simulate a surgical acute abdomen. The typical smell of acetone
can be detected in the patient's breath, although some people are unable to detect this smell.

Clinical differences between DKA and HHS

Diabetic ketoacidosis is the characteristic metabolic emergency of type 1 diabetes. Those affected
therefore tend to be young, with either undiagnosed or insulin-treated diabetes. They manifest the
features of acidosis, namely Kussmaul respiration and vomiting, and have the characteristic odour of
acetone on their breath. The mental state ranges from fully alert to drowsy.
The hyperosmolar state is more commonly seen in the middle aged or elderly, and is more often
associated with intercurrent illness or sepsis. Features of acidosis are lacking, but drowsiness or coma
are more frequent due to the extreme dehydration, and renal dysfunction is more marked.

Classical findings in Diabetic Ketoacidosis versus the Hyperglycaemic Hyperosmolar State

Symptoms DKA HHS

Glucose (mmol/l) >= 14 >33

pH =<7.30 .7.30

HCO3- (mEq/l) <18 >15

Ketones (urine stick) ++ +/-

Osmol (mOsmol/kg) Variable >320

Anion Gap >10 <12

Mental Status Alert to coma Drowsy to coma

Water Deficit (l/kg) 0.1 0.1-0.2