Transcript 2. Acidosis - WordPress.com

DIABETES MELLITUS AND
DIABETIC KETOACIDOSIS (DKA)
DM diagnosis
• Classical symptoms or hyperglycemic crisis with BG ≥200 mg/dl
• FBG ≥126 mg/dl
• 2nd hour BG ≥200 mg/dl in OGTT (1.75 gr/kg, max 75 gr)
• HbA1c >6.5% (method !!)
• FBG 100-125 mg/dl
• Absence of symptoms with hyperglycemia……..OGTT
OGTT
• FBG <100 mg/dl
Normal
• FBG 100-125 mg/dl
IFG
• FBG ≥126 mg/dl
DM
• 2nd hour BG <140 mg/dl
Normal
140-200 mg/dl
IGT
≥200 mg/dl
DM
• Etiopathogenesis of Type 1 DM
• Pathogenesis
• DKA
• Others
Etiopathogenesis of T1DM
• Type I DM is a syndrome characterized by
hyperglycemia and ketosis due to disturbed metabolism
of carbohydrate, fat and protein resulting from insulinopenia
• Type I DM is an autoimmune disorder
triggered by some environmental factors
develops in genetically susceptible individuals
as a result of destruction of pancreatic b-cells
Etiopathogenesis of T1DM
I. Genetic factors:
Group
Normal subjects
Nondiabetic relatives of pts
with IDDM
Parent
Offspring
With affected father
With affected mother
Sibling
Identical twin
HLA-identical sibling
HLA haploidentical
sibling HLA nonidentical
sibling
Risk (%)
(%)
0.4
3
8
3
33
15
5
1
Etiopathogenesis of T1DM
DR3 or DR4
-------> 2-3-fold  risk
Both DR3 and DR4 ------> 7-10-fold  risk (odds ratio 30)
DQ b chain 57. Position Asp (+) ------> protective
Asp (-) -------> 100-fold  risk
DQ a chain 52. Position Arg (+) -------->100-fold  risk
Etiopathogenesis of T1DM
II. Environmental factors:
a) Viral infections:
- Direct cytolytic effect and/or triggering an autoimmune process
- Coxackie B4, Rubella, Mumps, Enteroviruse
b) Dietary factors:
- Cow milk, casein, root vegetables, cereals (in early infancy)
- Breast milk, omega-3, vit D(?)
III. Autoimmunity:
- Insulitis (GAD, ICA,IA2, IAA, ZnT8)
- Diabetes over 10 years
Multiple 70%
Single 15%
Etiopathogenesis of T1DM
Genetic predisposition
Environmental factors initiating Autoimmunity
Infiltration of islet cells by sensitized T-cells (Insulitis)
Secretion of cytokines (IL1, IL-4, TNF) by T-cells
Production of superoxide radicals (NO, O-)
b-cell destruction
Release of b-cell antigens from damaged cells
Activation of antibody production by B lymhocytes against b-cell antigens
Etiopathogenesis of T1DM
Pathogenesis of T1DM
• Insulin
Counterregulatory hormones
(Glucagon, Epinephrin, Cortisol, GH)
• Effects of insulin
1. Glucose entry into cells by activating GLUT-4 in muscle and
adipose tissue
2. Glycogen synthesis in the liver
3. Inhibition of gluconeogenesis and glycogenolysis
4. Triglyceride storage in adipose cells by inhibiting lipase
5. Amino acid uptake and protein synthesis
Symptoms
• Non-emergency:
• Recent onset of enuresis
• Vaginal candidiasis (prepubertal girls)
• Chronic weight loss or failure to gain weight despite of polyphagia
• Recurrent skin infections
• Emergency:
• Polyuria, polydipsia (moderate to severe dehydration)
• Generalized weakness
• Nausea, abdominal pain, vomiting (AGE, acute abdomen!!)
• Heavy breathing, kussmaul respiration, acetone odeur
• Dowsiness, coma
DIABETIC KETOACIDOSIS (DKA)
Diabetic Ketoacidosis
Diabetic ketoacidosis is an acute complication of diabetes mellitus which
occurs as a result of absolute or relative insulin deficiency together with
excess stress hormones (mainly glucagon)
Beta cell
failure
Insulin
withdrawal
Insulin
Resistance
Fasting
Absolute or
relative
insulin
deficiency
Diabetic
keto
acidosis
Stress
hormone
excess
Stress
Dehydration
DKA
1. Hyperglycemia BG > 200 mg/dl
2. Acidosis
venous pH <7.3
HCO3< 15 mEq/L
3. Ketonemia and or ketonuria
in addition to classical signs and symptoms of diabetes
Degree of acidosis:
Mild DKA:
Venous pH: 7.2-7.3, HCO3: 10-15
Moderate DKA: Venous pH: 7.1-7.2, HCO3: 5-10
Severe DKA:
Venous pH: <7.1,
HCO3: < 5
İnsülin
Stress hormones
Glucagon
Lypolysis
Malonil CoA
Carnitine
CPT-1
Free fatty acids
Glycolysis
Gliserol-3-P
Reesterifikasyon
(Trigliseride
synthesis)
Okzaloasetat
B-Oksidation
Asetil CoA
Transfer of FFA to
mitochondria
Acetoacetate
B-OH butirat
Krebs cycle
Aceton
Pathophysiology of DKA
I. Mechanism of acidosis:
1- Ketoacids:
b-OH butyric acid, acetoacetic acid, aceton
Triglycerides
FFA
3 Free fatty acids + 3 H+
4 ketone bodies + 3 H+
Normally, ratio of b-OH butyric acid /acetoacetic acid is: 3:1
In DKA: this ratio is > 8:1
2- Lactic acid:
Hypovolemia
Poor tissue perfusion
Lactic
acidosis
Low erythrocyte
2,3 diP glycerate level
Poor tissue oxygenation
Pathophysiology of DKA
II. Fluid and electrolyte status:
a- Fluid:
Serum glucose >170 mg/dl (renal threshold)
Glycosuria
Osmotic diuresis (10 ml of water for each gr of glucose)
Ongoing urinary and other fluid losses >intake= Dehydration
b- Sodium:
Total body Na is decreased in DKA due to osmotic diuresis and vomiting.
Approximate loss is 6-12 mEq/kg (Na low / normal)
Pseudohyponatremia
Corrected (real) serum Na:
Na + 1.6 x (glucose-100/100)
Pathophysiology of DKA
II. Fluid and electrolyte status:
a- Potassium
Total body K is also depleted in DKA due to:
- Acidosis (K moves out of the cell and excreted)
- Dehydration (K moves out of muscle cells withH2O
- Intracellular P loss (to maintain electrical neutrality)
- Vomiting
-Approximate loss is 4-6 mEq/kg (K low / normal / high)
Serum K invariably drops down after the initiation of insulin treatment
Precipitating factors in DKA
In known diabetics:
A. Noncompliance with insulin injections
(frequent in adolescents)
B. Increased stress hormones:
-Infections
-Anesthesia, surgery
-Trauma, burns
-Emotional distresses
Incidence of DKA episodes in known diabetics can be decreased by improvement
in diabetic education
Laboratory investigations
A. Emergency bedside tests:
Blood glucose with glucometer
Urine dipstick test for glucose and ketone
B. Routine laboratory tests:
Glucose, acetone, Na, K, Cl, BUN, creatinine, Ca, P, Blood gases (pH, HCO3)
Complete blood count: Hb, Hct, WBC
Chest X-ray, Cultures (Urine, blood, CSF, stool), ECG (for hyperkalemia)
Calculate anion gap:
Na - (Cl+ HCO3)
Calculate plasma osmolality:
Calculate corrected Na:
2 x (Na+K) + (Glucose/18) + (BUN/3)
Na + 1.6 x Glucose-100
100
Treatment
Clinical signs
Pulse
Capillary refill
Mild
N
<2sc
Moderate
Severe
N, weak
Weak or absent
1-3 sc
>3 sc
N, slightly cold
Cold
Skin temp.
N
Heart rate
N,
BP
N
Ortostatic HT
Hypotension
BUN (mg/dl)
<20
20-30
>30
Fluid deficit (ml/kg)
> 2 years
30
60
90
< 2 years
50
100
150
-If the previous weight of the patient is known, than the percentage of dehydration can be
calculated according to the current weight
-Calculated amount of deficit is usually corrected in 24-36 hours
Total fluid requirement and rate of fluid replacement
Time
Amount
Type
İnitial fluid resuscitation
(1-2 hr)
10-20 ml/kg
SF (% 0.9 NaCl)
Until BG below 300
2500-4000 cc/m2/day
SF
BG 150-300
2500-4000 cc/m2/day
2 SF +1 % 5 dextroz
BG below 150
2500-4000 cc/m2/day
1 SF+ 1 % 10 dextroz
Blood glucose usually corrects earlier than acidosis; DO NOT decrease insulin
Total fluid requirement and rate of fluid replacement
• If serum K level is
(KCl, KPO4)
<2.5 mEq/L
<3
“
3-4 “
5-6 “
60 mEq/L
40 “
30 “
20 “
• Insulin 0.1 U/kg/hr regular insulin
• Insulin infusion can be stopped when HCO3 > 15, pH >7.3
Dose: Prepubertal 0.7 U/kg/day  4
Pubertal
• No HCO3
1.0 U/kg/day  4
• Serum glucose with glucometer: every hour
• Serum Na, K, Cl, pH, HCO3, ketones: every 2 hrs for the first 6 hours, then
every 4-6 hrs
• Vital signs, consciousness, orientation, pupil sizes
Complications of DKA
I. Cerebral edema:
Etiology: Accumulation of idiogenic osmoles
Overhydration
Risk factors: New onset DM
Overhydration (>4000 cc/m2/d)
Negative Na trend and rapid fall in BG
Symptoms: Headache, agitation, dysorientation
Vomiting, bradicardia, hypertansion, apnea
Ophtalmoplegia, pupil asymmetry, papilledema (late)
Absent of light reflex, seizure
Treatment: Elevate head
IV mannitol 1-2 gr/kg/dose or 3%NaCl
Decrease IV fluid and intubate-hyperventilate
II. Hypoglycemia:
Q&A….
Nonketotic Hyperosmolar Coma
- Extreme hyperglycemia (often >1000 mg/dl)
- Extreme hyperosmolality (>320 mOsM) without overt ketoacidosis
- Impaired mental status------------> Coma
usually occurs in elderly patients with T2DM (often not previously diagnosed)
who are unable to keep up with the osmotic diuresis by adequate fluid
intake
severe hyperglycemia is caused by decreased renal glucose excretion due
either to intrinsic underlying renal disease or due to prerenal azotemia
secondary to dehydration
Nonketotic Hyperosmolar Coma
Precipitating factors: steroid , diuretic, phenytoin therapy
infections, cerebrovascular events,
hypertonic peritoneal dialysis, parenteral nutrition
Clinical findings:
Dehydration, hypovolemia and disorientation
Laboratory:
HCO3 may be moderately low (lactic acidosis)
BUN is always elevated
Ketones and FFA are lower due to higher insulin
Treatment:
Intravascular volume expansion
Insulin infusion
Treatment of underlying precipitating factor
Complications:
Thrombosis and embolic events
Adult respiratory distress syndrome
Mortality increases with hyperosmolality
MODY
Early diagnosed diabetes (<25 y)
Autoantibodies negative
No DKA
No or low dose insulin requirement (<0.5 U/kg/d)
Family history (2-3 generation)
Most common: HNF1A (MODY3) and GCK (MODY2)
Oral sulphanylurea responsive (HNF1A and HNF4B)
No treatment in GCK
O&A….