Lecture 26 - Metabolic Disorders

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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

Glucose Glucose

Insulin Insulin Insulin

a eR

uc

os

TG

e s o e c u Gl ucos Gl

Gl

Glucose

e s o e c u Gl cos Glu n i l in su l u In s In lin u s In

Insulin Insulin Insulin

in l n u li ns u I Inslin cose u Glu ose s c In u l G

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 e os c Glu ose c u l G

nsuulin InnssIIu lin Ins Iunnlilsinn u Inns Ins ulisnulliIin ulin Inn suulliin Inssulinn ulin e os

Gl

uc

os

eR

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nn i l c inin suuli in u l l G se u l Iinn s ul in o s c lu Innsliusnul IlniInns sul G TG I unlinsu In s nnsIuInulinlin I Glucose I ns su n i l I n inn suulinin I l u li Iinn s ul in s e Glucos Innsliusnul IlniInns sul I unlinsu In e Glucose Iunlin s n s I n sIu lin lucos e I n su G os I n c Insulin I Glu Insulin 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……

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Metabolic Syndrome Synonyms • Insulin resistance syndrome • (Metabolic) Syndrome X • Dysmetabolic syndrome • Multiple metabolic syndrome

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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 Metabolism ±

Glucose intolerance

Uric Acid Metabolism Uric acid  Urinary uric acid clearance 

Dyslipidemia TG  PP lipemia  HDL-C 

Small,

Hemodynamic SNS activity  Na retention Hypertension 

dense LDL

CORONARY HEART DISEASE

Novel Risk Factors CRP  PAI-1  Fibrinogen 

How about the Link to Diabetes?

BMI and Risk of Type 2 Diabetes 100

*

80 Ageadjusted 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 2

1

1

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.

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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 Cpeptide.

Fasting Hypoglycaemia Classification insulin A. Excess glucose utilisation : Insulin injection high

c-peptide

Oral hypoglycaemics

high

high

Insulinomas

high

high

low

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 - Post-gastrectomy

hours of eating)

- 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 Liver cirrhosis, failure

Andersen disease

Muscle phosphorylase Glycogen storage disease type V Muscle pain on exercise Rhabdomyolysis

McArdle disease elevated CK

Hepatic phosphorylase Glycogen storage disease type VI

hers disease

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