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 METABOLIC DISORDERS
Segun Mojiminiyi

Mixed bag of disorders of metabolism

I Call This the Salad Topic…
 We’ll talk about….

• Metabolic Syndrome
• Hyperuricemia and associated disorders
• Hypoglycemia

• Glycogen storage diseases

Obesity and Diabetes
Metabolic syndrome
Big Problem in Kuwait…..
 Why we get fat from eating too
many sweets!???

Remember Intermediary
Metabolism???

The Interconversion of Fuels

 Normal Insulin Function
Insulin
s e Insulin Insulin
c o e
u
Gl cos
Glu n s
o e
e

a
l i u c

eR
l in su Gl ucos
s u In
TG Gl

os
In lin

uc
s u

Gl
Glucose In
Glucose n u l in
u li ns
I
Glucose Inslin cose
s u Glu ose
In l u c
Insulin G
Insulin Insulin
 Normal Insulin Action
Net Result:
• Increase in glucose uptake by
muscle, liver, and fat
• Decrease glucose output by the
liver
• Increase TG storage, decreased
TG breakdown
Effects of steadily high insulin levels on feeding. Constantly high
insulin causes blood glucose to be stored as fats and glycogen. Because
it becomes difficult to mobilize the stored nutrients, hunger returns soon
after each meal.
 Insulin ResistanceIns
I
InnssIIu
nsuulin
Ins Iunnlilsinn
u lin
Inns
Ins ulisnulliIin
ulin Inn suulliin
e
c os
Glu ose Inssulinn
u c
G l
i nn e
ulin
l os

a
l inin suuli in c

eR
l u
s u l Iinn s ul in G o se
Innsliusnul IlniInns sul TG lu c

os
I unlinsu In G
nnsIuInulinlin

uc
s
I

Gl
Glucose I ns su l i n
I n inn suulinin
I l
u li Iinn s ul in
s
Glucos e Innsliusnul IlniInns sul
Glucose I unlinsu In e
s Iunlin
I n sIu lin lucos e
n s
I n su G os
Insulin I n c
Insulin I Glu
Insulin Insulin
Insulin
Insulin Insulin
Insulin Insulin
Insulin
Insulin
Insulin
Insulin Insulin
Insulin Insulin
Insulin Insulin
 Insulin Resistance
Net Result:
• Increased insulin production to
force glucose uptake
• Decreased inhibition of glucose
rate of appearance from the
liver
• Decreased inhibition of TG
breakdown FFA in blood.
Consequences of
Prolonged
Hyperinsulinemia
 Consequences of Prolonged
Hyperinsulinemia….

• Prolonged high levels of insulin:

– glucose continues to enter cells, but stored
in liver and fat cells and less glucose for
immediate fuel
– hunger returns quickly and eating increases
resulting in weight gain
Consequences of Prolonged
Hyperinsulinemia
TG
Cholesterol
LDL
HDL
Insulin (hyperinsulinemia)
Post-prandial glucose
 We started to notice
some patients with……
 17

Metabolic Syndrome
Synonyms

• Insulin resistance syndrome

• (Metabolic) Syndrome X
• Dysmetabolic syndrome
• Multiple metabolic syndrome
 18

Metabolic Syndrome (continued)

Causes

• Acquired causes
– Overweight and obesity
– Physical inactivity
– High carbohydrate diets (>60% of energy
intake) in some persons
• Genetic causes
The metabolic syndrome is identified by
the presence of three or more of these
components:
• Central obesity as measured by waist circumference:
Men — Greater than 40 inches (102 cm)
Women — Greater than 35 inches (88 cm)
• Fasting blood triglycerides greater than or equal to 1.7
mmol/L
• Blood HDL cholesterol:
Men — Less than 1.03 mmol/L
Women — Less than 1.2 mmol/L
• Blood pressure greater than or equal to 130/85 mmHg
• Fasting glucose greater than or equal to 6.1 mmol/L
 The Metabolic Syndrome:
Significance
Body Size
 BMI
 Central Adiposity

Insulin Resistance
+
Hyperinsulinemia

Glucose Uric Acid Novel Risk

Dyslipidemia Hemodynamic
Metabolism Metabolism Factors

±  Uric acid  TG  SNS activity  CRP

 Urinary  PP lipemia  Na retention  PAI-1
Glucose
uric  HDL-C
intolerance Hypertension 
acid clearance Fibrinogen
Small, dense LDL

CORONARY HEART DISEASE

How about the Link to

Diabetes?
 BMI and Risk of Type 2 Diabetes
100 *
80
Age-
adjusted 60
RR
*


40 *


*

20 *

* *
*
 *
  
0 
<22 22– 23– 24– 25– 27– 29– 31– 33– > 35
22.9 23.9 24.9 26.9 28.9 30.9 32.9 34.9
BMI (kg/m2)
P<0.05
BMI=body mass index; RR=relative risk.
Colditz et al. Ann Intern Med 1995;122:481.
Uric Acid Metabolism and
Gout
Closely Related to the
Metabolic Syndrome…..
 URIC ACID AND GOUT

Uric Acid is End product of Purine metabolism

5-6 mmol/day of uric acid is produced on normal

diet
Revise Uric Acid Metabolism
 Factors affecting Plasma
urate :
Physiological Factors:
Sex : Males have a higher serum urate level
Diet
High purine foods --all meats and sea food,
beans, peas, lentils, cauliflower, asparagus,
mushrooms, spinach……..
Alcohol
Increased production (ATP turnover)
Decreased excretion (lactic/keto acidosis)
Race
Urate is low in indigenous Pacific races
Urate is high in people of African origin
 Factors affecting Plasma
urate :
Pathological Factors:
Increased Production:
Inherited disorders - HGPRT deficiency, glycogen

storage diseases

Diseases associated with over production

(breakdown of cells):
Myeloproliferative disorders, other malignancies

Tissue hypoxia

Drugs
Cytotoxic drugs (cell breakdown)
 Factors affecting Plasma
urate : Role of the Kidneys
Factors causing reduced renal clearance of urate
hypovolaemia
Diuretics, salicylate
Lactate, ketones,
CRF

Increased renal clearance of urate (What will this cause?):

Drugs - probenecid
high doses of vitamin C
Fanconi/ Fanconi like syndromes
 Excess Uric Acid Causes Gout
• Leads to deposits of uric acid in the joints
– Causes acute arthritic joint inflammation
Acute Gouty Attacks with Tophi
 Advanced Gout
Clinically Apparent Tophi
1 2

1 3

1. Photos courtesy of Brian Mandell, MD, PhD, Cleveland Clinic.

2. Photo courtesy of N. Lawrence Edwards, MD, University of Florida.
3. ACR Clinical Slide Collection on the Rheumatic Diseases, 1998.
Tophus
 Other Disease Associations
of HYPERURICAEMIA
• Uric acid nephropathy and renal failure
» Hyperuricaemia secondary to renal insufficiency
» Renal insufficiency secondary to hyperuricaemia
• Renal Uric acid stones
– Causes :
» Increased production of uric acid
» Increased renal clearance
» Low solubility of uric acid
» Acidic urine
» Concentrated urine –hot weather
• Metabolic syndrome
» hypertension, hyperglycaemia, dyslipidaemia and obesity
Lesch-Nyhan Syndrome
 Lesch-Nyhan syndrome

Lesch-Nhyan syndrome, an X-linked disorder that

results from a mutation in the gene for
hypoxanthine-guanine phosphoribosyltransferase,
is characterized by severe neurological defects.
• mental retardation
• self-mutilation
• Aggressive behaviour
• cerebral palsy
• elevated uric acid (gout)
 INVESTIGATION OF Gout
and HYPERURICAEMIA
1. Family history of Gout
2. Clinical history and examination
eg – Obesity, renal disease
3. Laboratory tests:
- Urine uric acid excretion to identify over
producers and under excretors.
- RFT -renal disease
- LFT – alcoholic liver disease;
- Serum and Urine Proteins –myeloma
- Acid-Base Status - anion gap –acidosis
- Glucose –Diabetes
- Lipids –dyslipidaemia
- Haematology - Full blood count – look for
haematological malignancy
 HYPOURICAEMIA
Causes :
Decreased urate production :
Xanthine oxidase deficiency
Allopurinol therapy

X
Xanthine
Oxidase

Allopurinol
Increased urate excretion :
Renal tubular disease eg Fanconi syndrome
Uricosuric agents eg Probenecid
Hypoglycemia
 Hypoglycemia –
Definition Serum Glucose
< 2.5 mmol/l

Fasting Hypoglycemia or
Reactive Hypoglycemia
 Two Main Types of Fasting
Hypoglycemia:
1. Excessive Glucose utilisation
2. Decreased Glucose Production

You Can Distinguish Between the 2

Types by Measuring Insulin and C-
peptide.
 Fasting Hypoglycaemia
Classification insulin c-peptide
A. Excess glucose utilisation :
Insulin injection high low

Oral hypoglycaemics high high

Insulinomas high high

B. Diminished glucose production:

Liver disease low low

Glycogen storage diseases low low

Adrenocortical insufficiency low low

Pituitary insufficiency low low

 Reactive Hypoglycaemia

Reactive to food:(hypoglycaemia within 4 hours of eating)

- Post-gastrectomy

- Eating rapidly absorbable carbohydrate

How to investigate hypoglycaemia
Laboratory Test
1. Plasma glucose : during symptoms of
hypoglycaemia ...OR
Prolonged fast - fasting for 24 - 72 hours

2. Insulin and C peptide during

hypoglycaemic episode
3. Urine toxicology screen….what are we
looking for?
4. Other tests to diagnose specific
diseases such as......?
Rare Cause of Hypoglycemia

If you are lucky – you’ll see a case during

your professional life!!
I am teaching you because misdiagnosis
could be fatal
 Glycogen Storage Diseases

Type 0
Type I - von Gierke's Disease
Type Ib
Type Ic
Type II - Pompe Disease
Type IIb
Type III - Cori Disease
Type IV - Andersen Disease
Type V - McArdle Disease
Type VI - Hers Disease
Type VII - Tarui Disease
Type VIII
Type IX
Type X
 GLYCOGEN STORAGE
DISEASE I
VON GIERKE DISEASE

Defect: GLUCOSE-6-PHOSPHATASE DEFICIENCY

Organs affected: The liver and kidney are involved
Biochemical Features:
hypoglycemia
Hyperlipidaemia
Hyperuricaemia
Lactic acidosis
ketonemia
 Other Glycogen Storage Diseases
Acid maltase
Glycogen storage disease type II Pompe disease
A lysosomal defect severe myopathy,
cardiomyopathy
No hypoglycemia, liver involvement

Debrancher
Glycogen storage disease type III Cori or Forbes disease

Brancher
Glycogen storage disease type IV Andersen disease
Liver cirrhosis, failure

Muscle phosphorylase
Glycogen storage disease type V McArdle disease
Muscle pain on exercise elevated CK
Rhabdomyolysis

Hepatic phosphorylase
Glycogen storage disease type VI hers disease

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