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Metabolic Disorder Metabolic Disorder and Disorder of Carbohydrate Metabolism

Caused by an abnormal metabolic process. Congenital
inherited enzyme abnormality

Acquired
disease of an endocrine organ or failure of a metabolically important organ such as the liver.

Inherited metabolic disorders

Inborn errors of metabolism. Caused by a defect in a single gene. Unimportant physical features or skeletal abnormalities. Serious disease and even death.

Metabolic Disorders Associated with Major metabolic pathways

Glycolysis Gluconeogenesis Glycogenolysis Glycogenesis

Hereditary fructose intolerance (HFI)

HFI is an autosomal recessive condition caused by mutations in the ALDOB gene. Deficiency aldolase B. Asymptomatic until they ingest fructose, sucrose, or sorbitol (sugar alcohol found in certain fruits).
avoiding foods containing fructose, sucrose, and sorbitol, patients can live symptom-free lives.

Aldolase B
For fructose metabolism -mostly in the liver, renal cortex, and small intestinal mucosa. Absorbed fructose is phosphorylated by fructokinase: fructose 1phosphate. Aldolase B break F1P into glyceraldehyde and DHAP. After glyceraldehyde is phosphorylated by triose kinase to form G3P. Both products can be used in the glycolytic-gluconeogenic pathway, modified to either glucose or pyruvate. Increased concentrations of DHAP and glyceraldehyde 3-phosphate
drive the gluconeogenic pathway toward glucose, Promote glycogen synthesis.

Symptoms
Vomiting, hypoglycemia, jaundice, hemorrhage, hepatomegaly, hyperuricemia and potentially kidney failure.

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Deficiency of aldolase B
Accumulation of F1P- toxic to cellular tissues Lead to: 1. high levels of F1P traps phosphate in an unusable form
deplete of both phosphate and ATP stores. Lack of phosphate- decrease glycogenolysis in the liver results in hypoglycemia.

2. Inhibits gluconeogenesis. 3. The loss of ATP leads to a multitude of problems including inhibition of protein synthesis and hepatic and renal dysfunction.

Diagnosis
HFI can be effectively managed if properly diagnosed. Diagnosis: genomic DNA screening with allele specific probes or an enzyme assay from a liver biopsy. Once identified, counselling with regard to preventive therapy: dietary exclusion of foods containing fructose, sucrose, or sorbitol.

Treatment
Depends on the stage of the disease, and the severity of the symptoms. Stable patients without acute intoxication are treated by careful dietary planning that avoids fructose and its metabolic precursors. Fructose is replaced in the diet by glucose, maltose or other sugars. Management of patients with HFI often involves dietitians who have a thorough knowledge of what foods are acceptable

Diabetes
A group of metabolic diseases in which a person has high blood sugar. The pancreas does not produce enough insulin Cells do not respond to the insulin that is produced. Symptoms of polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger).

Control of Blood Glucose Level by Insulin

Glucose enters cell through special transporter proteins in cell membranes. Indirectly, under blood insulin's control. Low/absence of insulin prevent glucose from entering those cells (type 1 diabetes). A decrease in the sensitivity of cells to insulin (type 2 diabetes), decreased glucose absorption. In a few cases, there is a defect in the release of insulin from the pancreas. Cause 'cell starvation' and weight loss. Effect: elevated blood glucose levels.

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Diagnosis
Demonstrate any one of the following:
Fasting plasma glucose level 126 mg/dl (7.0 mmol/l ). Plasma glucose 200 mg/dL (11.1 mmol/l ) two hours after a 75 g oral glucose load as in a glucose tolerance test. Symptoms of hyperglycemia and casual plasma glucose 200 mg/dl (11.1 mmol/l ). Glycated hemoglobin (Hb A1C) 6.5%.

A positive result, should be confirmed: by a repeat of any of the above methods on a different day.
two fasting glucose measurements above 126 mg/dl (7.0 mmol/l) is considered diagnostic for diabetes mellitus.

Mechanism of insulin release in normal pancreatic beta cells - Its release is triggered by food, chiefly food containing absorbable glucose

Fasting glucose levels from 110 to 125 mg/dl (6.1 to 6.9 mmol/l): impaired fasting glucose. Plasma glucose at or above 140 mg/dL to 200 mg/dL (7.8 mmol/L-11.1 mmol/L), two hours after a 75 g oral glucose load- impaired glucose tolerance. Prediabetic states, risk factor for progression to full-blown diabetes mellitus, as well as cardiovascular disease.

Glucose Measurement
A glucose meter (or glucometer). A small drop of blood (pricking the skin with a lancet) - placed on a disposable test strip that the meter reads and uses to calculate the blood glucose level. The meter then displays the level in mg/dl or mmol/l.

Principles of Glucose Measurement

Oxidation of glucose to gluconolactone catalyzed by glucose oxidase (GOx)/glucose dehydrogenase (GDH). Most glucometers use an electrochemical method. Test strips contain a capillary that sucks up the blood sample. The glucose in the blood reacts with an enzyme electrode containing glucose oxidase (or dehydrogenase). The enzyme is reoxidized with an excess of a mediator reagant (eg;ferricyanide ion, a ferrocene derivative or osmium bipyridyl complex). The mediator further reoxidised to generates an electrical current. The total charge passing through the electrode is proportional to the amount of glucose in the blood that has reacted with the enzyme.

Glucose Tolerance Test

Glucose is given and blood samples taken afterward to determine how quickly it is cleared from the blood. Preparation The patient not to restrict carbohydrate intake in the days or weeks before the test. The test should not be done during an illness, as results may not reflect the patient's glucose metabolism when healthy. The patient is instructed to fast (water is allowed) for 812 hours prior to the tests.

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Glucose Tolerance Test

Procedure A zero time (baseline) blood sample is drawn. Then, the patient is given a measured dose (below) of glucose solution to drink within a 5 minute time frame.
The WHO recommendation: 75g oral dose in all adults, adjusted for weight only in children

Management and Medication

Keeping blood sugar levels as close to normal without causing hypoglycemia.
diet, exercise, and use of appropriate medications (insulin in the case of type 1 diabetes, oral medications, as well as possibly insulin, in type 2 diabetes).

Blood is drawn at intervals for measurement of glucose (and sometimes insulin) levels. The intervals and number of samples vary according to the purpose of the test/physician request. For simple diabetes screening: 0 and 2 hour samples

Metformin is generally recommended as a first line treatment for type 2 diabetes. Type 1 diabetes is typically treated with insulin therapy.

Malignant hyperthermia (MH)/ malignant hyperpyrexia

A rare life-threatening condition. Triggered by exposure to certain drugs used for
general anesthesia (volatile anesthetic: halothane, sevoflurane, desflurane, isoflurane, enflurane) neuromuscular blocking agent, succinylcholine. others

Genetics
Autosomal dominant. The defect is typically located on the long arm of chromosome 19 involving the ryanodine receptor. Chromosome 7q and chromosome 17. Affect uptake of intracellular Ca2+, usage of ATP, muscle excitability.

Drastic and uncontrolled increase in skeletal muscle oxidative metabolism. Which overwhelms the body's capacity to supply oxygen, remove carbon dioxide, and regulate body temperature, eventually leading to circulatory collapse and death if not treated quickly.

Disease mechanism
Mutation of the ryanodine receptor, located on the sarcoplasmic reticulum (SR) (organelle of skeletal muscle cells that stores calcium). Triggering agent causes channels of mutant protein to open, greatly increased Ca2+ release. The process of sequestering this excess Ca2+ consumes large amounts of ATP). Excessive heat is generated (hyperthermia). The muscle cell is damaged by the depletion of ATP and possibly the high temperatures. Cellular constituents "leak" into the circulation
potassium, myoglobin, creatine, phosphate and creatine kinase.

Disease Mechanism
Mutation affecting L-type voltage-gated calcium channel. 5 times more sensitive to activation by caffeine (and presumably halothane). These channels interact with and activate RYR1, result in a drastic increase of intracellular Ca2+, thereby, muscle excitability.

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Diagnosis
Diagnosed on clinical grounds, but various investigations are generally performed. Blood tests
raised creatine kinase, potassium, phosphate (leading to decreased calcium), myoglobin (result of damage to muscle cells). Metabolic acidosis and respiratory acidosis (raised acidity of the blood) may both occur.

Treatment
i.v. administration of dantrolene , the only known antidote.
Dantrolene is a muscle relaxant that appears to work directly on the ryanodine receptor to prevent the release of calcium.

Discontinuation of triggering agents. Supportive therapy directed at correcting hyperthermia, acidosis, and organ dysfunction.

Severe rhabdomyolysis (damage to skeletal muscle) lead to acute renal failure (accumulation of CK) - kidney function.

Pyruvate kinase deficiency

A variety of mutations that lead to lowered production, activity, or stability of pyruvate kinase. Used by red blood cells. Deficiency cause break down of RBC (hemolytic anemia). Both autosomal dominant and autosomal recessive inheritance (more common).

Pathophysiology
Erythrocytes manufacture ATP through glycolysis. pyruvate kinase: phosphoenolpyruvate to pyruvate. Deficiency : RBCs with decreased energyhemolysis

Pathophysiology
Mechanism: not well understood Lack of ATP impairs the Na+/K+-ATPase and other ATPdependent processes
cellular loss of K+ and water and an intracellular accumulation of Na+.

Tests for Diagnosis

Physical exam: enlarged spleen. Tests: Bilirubin in the blood. A complete blood count (CBC). Genetic testing for mutation in the pyruvate kinase gene. Large red blood cells (macrocytosis)
enlargement of red blood cells with near-constant hemoglobin concentration mean corpuscular volume (MCV) greater than 100 femtolitres

Cellular swelling
rigidity of the RBC splenic hemolysis from an inability to distort through splenic sinusoids.

Buildup of 2,3-bisphosphoglycerate (2,3 BPG)

affect tissue oxygenation. decreased oxygen affinity for the hemoglobin and earlier oxygen unloading than under normal conditions.

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Tests for Diagnosis

Levels of haptoglobin (Hp) in the blood
Hp (protein) binds free hemoglobin (Hb) released from erythrocytes. Level decrease in hemolysis: suicide protein

Treatment
People with severe anemia
blood transfusions.

Osmotic fragility
the degree of hemolysis when red blood cells are placed in a hypotonic solution.

Splenectomy
reduce the destruction of red blood cells. Does not help in all cases.
Newborns with dangerous levels of jaundice: exchange transfusion may be recommended

Pyruvate kinase activity Stool urobilinogen

product of bilirubin reduction (intestines: bacterial action). Increased bilirubin in hemolysis- increased urobilinogen in the gut.

Glycogen storage disease (glycogenosis and dextrinosis)

Defects of glycogen synthesis or breakdown within muscles, liver, and other cell types. Cause:
any inborn error of metabolism (genetically defective enzymes) involved in these processes.

GSD
glucose is converted into glycogen for storage by enzymes action. Other enzymes convert the glycogen back to glucose (in need of E- exercise). GSD
These enzymes are defective, deficient, or absent. Buildup of abnormal amounts and types of glycogen (liver/muscle tissues).

GSD
Glycogen storage: the liver/muscle tissue. Usually affect the liver functions, muscles, or both. GSD that mainly affect the liver are
types I, III, IV, and VI.

Mainly affect muscles

types V and VII. Type II affects nearly all organs

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TYPE
Number GSD type I GSD type II GSD type III GSD type IV GSD type V GSD type VI GSD type VII GSD type IX GSD type XI GSD type XII GSD type XIII GSD type 0 Enzyme deficiency glucose-6-phosphatase acid alpha-glucosidase glycogen debranching enzyme glycogen branching enzyme muscle glycogen phosphorylase liver glycogen phosphorylase muscle phosphofructokinase phosphorylase kinase, PHKA2 glucose transporter, GLUT2 Aldolase A -enolase glycogen synthase Eponym von Gierke's disease Pompe's disease Cori's disease or Forbes' disease Andersen disease McArdle disease Hers' disease Tarui's disease Fanconi-Bickel syndrome Red cell aldolase deficiency -

Symptoms
Depend on type. common:
Low blood sugar Enlarged liver Slow growth Muscle cramps

Test and Diagnosis

Diagnosed in infancy or childhood as a result of symptoms. enzyme activity assay and analysis for glycogen content
Type I, III, VI, and IX: can be assessed by performing a liver biopsy. of GSD III and GSD IX: Muscle biopsy can also test for subtypes.

DNA testing (genetic testing)

common mutation testing (for mutations that are more common in certain populations) and/or gene sequencing.

Histologic features of biopsy staining: help to determine subtypes

Micrograph of glycogen storage disease with histologic features consistent with Cori disease. Liver biopsy. H&E stain

Treatment
Depend on the type and symptoms. General treatment guidelines affecting the liver:
The goal of treatment is to maintain normal blood glucose levels. A nasogastric infusion of glucose in infants and children under age two. Dietary changes,
In children over age two, frequent small carbohydrate feedings are given throughout the day. Elimination of foods that are high in fructose or lactose (type I only)

Treatment
GSD affecting the muscles. Based on child's specific symptoms. The goal: avoid muscle fatigue and/or cramps induced by exercise. This is done by:
limiting strenuous exercise. Improving exercise tolerance by oral intake of glucose/ injection of glucagon Eating a high protein diet

Type IV is sometimes treated with liver transplantation.

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Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency

X-linked recessive hereditary disease.

Metabolic Disorders Associated with Special Pathways

Pentose phosphate pathway Sugar Interconventions, nucleotide-linked sugar formation Biosynthesis of complex polysaccharides Glycoproteins proteoglycans

Abnormally low levels of glucose-6-phosphate dehydrogenase. Exhibit nonimmune hemolytic anemia in response to a number of causes
most commonly infection or exposure to certain medications or chemicals.

Closely linked to favism, a disorder characterized by a hemolytic reaction to consumption of broad beans, with a name derived from the Italian name of the broad bean (fava).

Signs and symptoms

Most individuals are asymptomatic. Hemolysis can manifest in a number of ways:
Prolonged neonatal jaundice, possibly leading to kernicterus (bilirubin-induced brain dysfunction serious complication). Hemolytic crises in response to:
Illness (especially infections) Certain drugs (eg: certain anti-malaria drugs, analgesics) Certain foods, most notably broad beans. Certain chemicals Diabetic ketoacidosis

Very severe crises can cause acute renal failure.

Pathophysiology
G6PD is an enzyme in the pentose phosphate pathway. Converts glucose-6-phosphate into 6-phosphoglucono--lactone. Maintaining the level of NADPH. NADPH maintains reduced glutathione supply. Used to mop up free radicals (protect from oxidative damage).

Tests and Diagnosis

The diagnosis is generally suspected based on symptoms:
when patients develop anemia, jaundice and symptoms of hemolysis after challenges from any of the above causes, especially when there is a positive family history.

The G6PD/NADPH pathway is the only source of reduced glutathione in RBC. RBCs are oxygen carriers
risk of damage from oxidizing free radicals Protected by G6PD/NADPH/glutathione.

Direct test: "Beutler fluorescent spot test.

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The Beutler fluorescent spot test

Visually identifies NADPH produced by G6PD under UV light. When the blood spot does not fluoresce-positive. false negative: in patients who are actively hemolysing. It can therefore only be done 23 weeks after a hemolytic episode.

Tests and Dignosis

Other tests: Complete blood count and reticulocyte count (immature RBC); in active G6PD, Heinz bodies can be seen in red blood cells on a blood film. Liver enzymes (to exclude other causes of jaundice) Lactate dehydrogenase (elevated in hemolysis and a marker of hemolytic severity) Haptoglobin (decreased in hemolysis) A "direct antiglobulin test" (Coombs' test)-test for autoantibodies this should be negative, as hemolysis in G6PD is not immunemediated.

Heinz bodies (also referred to as "HeinzEhrlich bodies") are inclusions within RBC composed of denatured hemoglobin.

Possible Treatment
The most important measure is prevention. In the acute phase of hemolysis, blood transfusions. Dialysis in acute renal failure. Splenectomy, as this is an important site of red cell destruction. Folic acid should be used in any disorder featuring a high red cell turnover.

Essential fructosuria
Autosomal recessive. Mutations in the KHK gene- deficiency of the hepatic fructokinase (ketohexokinase). The first enzyme involved in the degradation of fructose to fructose-1-phosphate. Incomplete metabolism of fructose (liver) -excretion in urine (depends largely on dietary intake). Clinically benign condition.
No clinical symptoms

Galactosemia
Rare genetic metabolic disorder (autosomal recessive). Lactose - lactase - glucose and galactose. Galactosemia
Lack of enzymes needed for further metabolism of galactose. Accumulate-toxic to various tissues

fructose is either excreted unchanged in the urine or metabolized to fructose-1-phosphate by alternate pathways. No treatment is indicated.

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Galactose is converted into glucose by the action of three enzymes:

Pathophysiology
Galactose is reduce to galactitol. Catalyze by aldose reductase is the enzyme responsible for the primary stage of this pathway. Galactitol accumulates in body tissues and is excreted in the urine. Contributes to many of the negative effects of galactosemia. Clinical significance:
Hepatomegaly (an enlarged liver), cirrhosis, renal failure, cataracts, brain damage, and ovarian failure.

Type

Gene

Locus 9p13 17q24

Enzyme galactose-1-phosphate uridyl transferase galactokinase

Name classic galactosemia galactokinase deficiency galactose epimerase deficiency, UDPGalactose-4-epimerase deficiency

Type 1 GALT Type 2 GALK1

Type 3 GALE

1p36-p35

UDP galactose epimerase

Galactosemia test
Routine newborn screening (NBS). a blood test (heel of the infant) or urine test
checks for three enzymes that are needed to change galactose.

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