quadrant i e-text f07ma16 disorders of carbohydrate

Code and title of the paper: FO7MA16- Macronutrients

Code and title of the module: FO7MA16- Disorders of Carbohydrate Metabolism

Name of the content writer: Dr.Sushma B.V

Quadrant – I

E-text

F07MA16 – Disorders of Carbohydrate Metabolism

Overview of carbohydrate metabolic disorder

Carbohydrates account for a major portion of the human diet and are metabolized into three

principal monosaccharides: galactose, fructose and glucose. The failure to effectively use this

sugar accounts for the various forms of carbohydrate metabolism disorders. The most common

disorders are acquired. Acquired or secondary derangements in carbohydrate metabolism, such

as diabetic ketoacidosis, hyperosmolar coma, and hypoglycemia, all affect the central nervous

system. As well as various forms and variants of peripheral nerve disease are commonly seen in

diabetes. The other disorders of carbohydrate metabolism are the inborn errors of metabolism (ie,

genetic defects) that affect the catabolism and anabolism of carbohydrates.

Pathophysiology of Inherited Disorders:

Many of the clinical features of the inherited disorders of carbohydrate metabolism are caused by

the following: Lack of glucose for the metabolism of brain, muscle, liver, or kidney (in

circumstances in which ketone bodies cannot be used) inability to break down glucose to

pyruvate inability to oxidize pyruvate fully in the Krebs cycle Some features of the inherited

diseases are due to excessive storage of abnormal substrates or to normal substrates that cells

cannot degrade normally because they lack a specific enzymatic activity. In some diseases,

abnormal metabolites (intermediates of pathways that use carbohydrates) block the normal

function of the pathway or of related pathways. Defects of the enzymes of the pentose shunt

interfere with the normal production of nucleic acids, which are needed by cells as second

messengers and as coenzymes of intermediary metabolism, as well as components of RNA and

DNA. Galactose accumulates in the lens of the eye in galactose kinase deficiency.




Inborn Errors of Carbohydrate Metabolism

Galactosaemia

Glycogen storage diseases

Pyruvate carboxylase deficiency

Fructose-1,6-bisphophatase deficiency

Hereditary fructose intolerance

Glucose-6-phosphate dehydrogenase deficiency

Galactosaemia

Lactose from milk is hydrolysed by intestinal lactase to produce glucose and galactose. There are

three inborn errors of galactose metabolism:

Galactokinase deficiency

Galactose-1-phosphate uridyltransferase (Gal-1-PUT) deficiency

Uridine diphosphate-galactose 4-epimerase deficiency

The Pyrophosphorylase Pathway is an alternative route for production of UDP-galactose

(essential for incorporation of galactose into proteins and lipids). The generation of galactose-1-

phosphate by this pathway explains why galactose-1-phosphate can still be synthesised in

patients with galactosaemia who are on strict dietary galactose restriction

Classical Galactosaemia

This disorder is due to galactose-1-phosphate uridyltransferase deficiency. There is accumulation

of galactose-1-phosphate and galactose and secondary formation of galactitol. It typically

presents by the end of the first week of life with poor feeding, vomiting, lethargy, jaundice,

hepatomegaly, neonatal cataracts and renal tubular disease and is often associated with E. coli

septicaemia. Biochemically there is hyperbilirubinaemia, raised alanine aminotransferase (ALT),

generally elevated plasma and urine amino acids, albuminuria, glycosuria and galactosuria.




A positive urine Clinitest® for reducing substances with a negative Clinistix® test (specific for

glucose) may provide a clue to the diagnosis but is not specific. However in galactosaemia a

negative Clinitest® may occur if there has been insufficient galactose intake due severe vomiting

or reduced milk intake. Furthermore the Clinitest® and Clinistix® may be positive due to the

glycosuria due to the renal tubular dysfunction. Urine sugars can be identified by Thin Layer

Chromatography (TLC).

Milk feeds should be stopped whist awaiting the definitive test results. The definitive test is

quantitative assay of galactose-1-phosphate uridyltransferase (‘Gal-1-PUT’) activity in red cells

or the qualitative Beutler test which is a fluorescent spot test for ‘Gal-1-PUT’.

Beutler Test

Whole blood and a reaction mixture (UDP-glucose, galactose-1-phosphate, NADP) is spotted

onto filter paper at 0 minutes, after 60 minutes incubation & after 120 min incubation. Normal

transferase activity results in the production of NADPH, which is fluorescent under UV light. No

fluorescence indicates galactose-1-phosphate uridyltransferase deficiency. False negative results

2D Urine amino acid TLC Plate showing a generalized aminoaciduria




may occur if the patient has a had a blood transfusion up to 6 weeks before the sample was taken.

False positive results may occur if the patient has glucose-6-phosphate dehydrogenase deficiency

as the endogenous activity of this enzyme is used to generate NADPH. This can be confirmed

with the quantitation of galactose-1-phosphate in erythrocytes or DNA analysis

Treatment and Management : If galactose is excluded from diet then life-threatening illness

usually resolves quickly. Long-term complications e.g. low IQ, growth delay, ovarian

dysfunction, still occur despite early diagnosis and treatment possibly due to endogenous

galactose production. Partial enzyme deficiencies occur and several variant alleles exist e.g.

Duarte; usually benign (identified on newborn screening in some European countries & USA)

Galactokinase Deficiency

This is a rare disorder where there is an inability to phosphorylate galactose and galactose and

galactitol are excreted in urine Neonatal (but not congenital) cataracts occur-often bilateral due

to the accumulation of galactitol in the lens. There is a positive urine reducing substances due to

galactose in urine usually with a negative Clinistix®.

Diagnosis is by measurement of galactokinase activity in red cells. Treatment is with a galactose-

free diet. The cataracts are reversible if milk excluded in first few weeks of life

UDP-galactose 4- epimerase deficiency

Mild form of UDP-galactose 4- epimerase deficiency occurs due to reduced protein stability and

more pronounced in cells with long lifespan e.g. erythrocytes. The growth and development

appears to be normal in an individual affected.

Severe form of UDP-galactose 4- epimerase deficiency is very rare. This is a similar presentation

to classical galactosaemia. There will be accumulation of UDP-galactose & galactose-1-

phosphate in this condition. The deficiency is identified using Beutler test confirmed by

increased normal and red cell galactose-1-phosphate. The definitive test is assay of UDP-

galactose-4- epimerase activity in erythrocytes.




Glycogen Storage Diseases

Glucose is stored in the form of glycogen, mainly in liver and muscle. Glycogen is made up of

straight chains of glucose residues with α-1,4 linkages, branched at intervals with α-1,6 linkages.

Glycogen metabolism is highly regulated by several amplifying reaction cascades. Adrenaline

and glucagon stimulate glycogen breakdown. Glycogen synthesis is increased by insulin.

In glycogen storage diseases, liver (hepatomegaly, hypoglycaemia) and muscle (exercise

intolerance, weakness) are the most affected tissues

GSD I

GSD I accounts for approximately 25% of GSD cases. Glucose-6-phosphatase deficiency (GSD

Ia) is a defect in the release of glucose from glucose-6-phosphate and affects both glycogenolysis

and gluconeogenesis.

It presents with hepatomegaly, short stature and truncal obesity. Biochemically there is

hypoglycaemia, lactic acidaemia, hyperuricaemia and hyperlipidaemia

Histological analysis shows excess of fat and glycogen in hepatocytes GSD Ib is a defect in a

transporter protein and has the above features plus neutropaenia, recurrent bacterial infections

and inflammatory bowel disease

The diagnosis is nowadays confirmed by DNA analysis in the majority of patients. It is also

possible to measure the activity of glucose-6-phosphatase and the transporter protein function in

a fresh liver biopsy with comparison of fresh and frozen results to distinguish type Ia from Ib

Pyruvate Carboxylase Deficiency

This presents with lactic acidosis, neurological dysfunction (seizures, hypotonia, coma). It is a

defect in the first step of gluconeogenesis which is the production of oxaloacetate from pyruvate.

In addition to the effect on gluconeogenesis, lack of oxaloacetate affects the function of the

Krebs cycle and the synthesis of aspartate (required for urea cycle function).




In the acute neonatal form the lactic acidosis is severe, there is moderately raised plasma

ammonia, citrulline (& alanine, lysine, proline) and ketones. Fasting results in hypoglycaemia

with a worsening lactic acidosis. The diagnosis can be confirmed by assay of pyruvate

carboxylase activity in cultured skin fibroblasts. Patients rarely survive >3 months in the severe

form

Fructose-1,6-Bisphosphatase Deficiency

The defect leads to impaired gluconeogenesis and accumulation of precursors of

gluconeogenesis: lactate, pyruvate, alanine, ketones. The only glucose source is dietary or via

glycogenolysis. The latter may be a problem in neonates as they usually have low glycogen

stores. Acute episodes may be precipitated by fasting or infection. Diagnosis is by assay of

Fructose-1,6-bisphosphatase activity in leucocytes or liver homogenate. However there are some

reports of normal leucocyte activity in individuals with deficient liver activity.

Treatment involves correction of the acidosis and hypoglycaemia and the avoidance of fasting.

Once diagnosed, growth and development are usually normal

Hereditary Fructose Intolerance

Fructose is a monosaccharide found in fruit, honey and many vegetables. The disaccharide

sucrose, composed of glucose and fructose, is found in many foods. Sorbitol (also from fruit and

vegetables) can be converted into fructose by the liver. Hereditary Fructose Intolerance (HFI), a

defect in fructose metabolism (deficiency of aldolase B), only presents after ingestion of foods

containing fructose, sucrose or sorbitol. When an infant with HFI is weaned, they suffer from

nausea, vomiting, gastrointestinal discomfort and lethargy. They are at risk of liver and kidney

failure and death, if fructose is not withdrawn.

Affected individuals may reach adulthood undiagnosed due to development of an aversion to

fructose- containing foods. Around 50% of adults with HFI have no dental caries, so

occasionally the diagnosis has been made by dentists. Biochemical features include

hypoglycaemia (accumulated fructose-1-phosphate inhibits glucose production),

hypophosphataemia, elevated plasma lactate, positive urine reducing substances, hyperuricaemia

and a generalised aminoaciduria.




Diagnostic clues include a rapid improvement on withdrawal of fructose from the diet and a

compatible nutritional history. Definitive diagnosis is by mutation analysis (there is one

relatively common mutation in northern Europeans: A149P) or measurement of enzyme activity

in a liver biopsy. An intravenous fructose tolerance test can be done but this needs to be done in

a specialist centre and is not recommended in young children. In affected patients there is a

decrease in plasma glucose and phosphate

Glucose-6-phosphate dehydrogenase deficiency

This is an X-linked defect in the first, irreversible step of the pentose phosphate pathway. A

decrease in NADPH production makes red bloods cell membranes vulnerable to oxidative stress,

leading to haemolysis. The most common manifestations are early neonatal unconjugated

jaundice and acute haemolytic anaemia. However most individuals with the deficiency are

clinically asymptomatic. The haemolytic crises are usually in response to an exogenous trigger

such as certain drugs (e.g. antimalarials), food (broad beans) or an infection. Female

heterozygotes may have symptoms but the severity varies due to non-random X chromosome

inactivation)

The highest frequency is in those of Mediterranean, Asian or African origin. The diagnosis is by

measurement of the enzyme activity in erythrocytes either by a qualitative test similar to the

Beutler test or by quantitation. However the test is not reliable in detecting female heterozygotes

and if required molecular testing is the preferred method

Major index which describes metabolism of carbohydrates, is a sugar level in blood. In

healthy peoples it is 4, 4-6, 6 mmol/l. This value is summary result of complicated interaction of

many exogenous and endogenous influences. The first it reflects a balance between amount of

glucose which entrance in blood and by amount of glucose which is utilized by cells. The

second, glucose level in blood reflects an effect of simultaneous regulatory influence on

carbohydrates metabolism of the nervous system and endocrine glands – front pituitary gland

(somatotropic, thyreotropic, adrenocorticotropic hormones), adrenal cortex (adrenalin

,noradrenalin)layer, pancreas (insulin, glucagone, somatostatin), thyroid (thyroxin,




triiodthyronine). Among enumerated hormones only insulin lowers glucose concentration in

blood the rest of hormones increase it.

The glucose concentration in blood describes carbohydrates metabolism both of healthy man and

sick. Illnesses base of which is disorder of carbohydrates metabolism can flow with rise of

glucose concentration in blood and with lowering of it. Rise of glucose concentration is termed

as hyperglycemia and lowering of glucose concentration is termed as hypoglicemia. For

example, hyperglicemia is very typical for diabetes mellitus, hypoglycemia for glycogenosis.

Diabetes mellitus

Diabetes mellitus, or simply diabetes, is a group of metabolic diseases in which a person has high

blood sugar, either because the pancreas does not produce enough insulin, or because cells do not

respond to the insulin that is produced. This high blood sugar produces the classical symptoms of

polyuria (frequent urination), polydipsia (increased thirst) and polyphagia (increased hunger).

There are three main types of diabetes mellitus (DM).

Type 1 DM results from the body's failure to produce insulin, and currently requires the person

to inject insulin or wear an insulin pump. This form was previously referred to as "insulin-

dependent diabetes mellitus" (IDDM) or "juvenile diabetes".

Type 2 DM results from insulin resistance, a condition in which cells fail to use insulin properly,

sometimes combined with an absolute insulin deficiency. This form was previously referred to as

non insulin-dependent diabetes mellitus (NIDDM) or "adult-onset diabetes".

The third main form, gestational diabetes, occurs when pregnant women without a previous

diagnosis of diabetes develop a high blood glucose level. It may precede development of type 2

DM.

Other forms of diabetes mellitus include congenital diabetes, which is due to genetic defects of

insulin secretion, cystic fibrosis-related diabetes, steroid diabetes induced by high doses of

glucocorticoids, and several forms of monogenic diabetes.




Untreated, diabetes can cause many complications. Acute complications include diabetic

ketoacidosis and nonketotic hyperosmolar coma. Serious long-term complications include

cardiovascular disease, chronic renal failure, and diabetic retinopathy (retinal damage). Adequate

treatment of diabetes is thus important, as well as blood pressure control and lifestyle factors

such as stopping smoking and maintaining a healthy body weight.

All forms of diabetes have been treatable since insulin became available in 1921, and type 2

diabetes may be controlled with medications. Insulin and some oral medications can cause

hypoglycemia (low blood sugars), which can be dangerous if severe. Both types 1 and 2 are

chronic conditions that cannot be cured. Pancreas transplants have been tried with limited

success in type 1 DM; gastric bypass surgery has been successful in many with morbid obesity

and type 2 DM. Gestational diabetes usually resolves after delivery.

Classification of diabetes mellitus up to now remains clinical. Main types – insulin-dependent

diabetes mellitus and insulin-independent diabetes mellitus. These two diabetes types affect

the majority of patient. There are counts six millions of patient with insulin-dependent diabetes

mellitus in the world. This is mainly illness of white race. It occur more frequent in highly

developed countries (Finland, Italy, Sweden, Denmark, Canada, Norway, USA, England). There

are about 100 millions of patient with insulin-dependent diabetes mellitus. They consist 85 % of

all diabetics. They belong to mainly native population of USA (american indians), Fiji, South

Africa, India, Polynesia.

Insulin-dependent diabetes mellitus

Insulin-dependent diabetes mellitus arises as result of absolute insulin insufficiency. It is

described by insulinopenia and by inclination to ketoacidosis. This diabetes occur more

frequently in children and young peoples (till 30 years). Insulin is needed for sustentation of

patient life. Attached to it’s absence ketoacidic coma develops. Insulin-dependent diabetes

mellitus has genetic base. Inclination to diabetes of this type is conditioned by some genes of

major histocompatibility complex (MHC).




DIAGNOSIS:

Fasting plasma glucose level ≥ 7.0 mmol/l (126 mg/dl)

Plasma glucose ≥ 11.1 mmol/l (200 mg/dL) two hours after a 75 g oral glucose load as

in a glucose tolerance test

Symptoms of hyperglycemia and casual plasma glucose ≥ 11.1 mmol/l (200 mg/dl)

Glycated hemoglobin (Hb A1C) ≥ 6.5%.

Pathogenesis of insulin-dependent diabetes mellitus:

Persons with Diabetes mellitus form a low resistibility of β-cells which is lightly collapse and is

very difficult to restore. High readiness to destruction combines in them by limited capacity for

regeneration. The system of HLA genes are inherited from generation to generation, therefore

inclination of β-cells to destruction also is inherited from generation to generation. However

general amount of β-cells is attached to birth identically in patients and healthy.

Typical affection of Langergans islets attached to insulin-depending diabetes is

infiltration of them by lymphocytes and selective destruction of β-cells. Clinical illness picture

develops when 80-95% of β-cells are already destroyed. In such patients mass of pancreas is less,

than in healthy people. Amount and volume of Langergans islets also is less. Thus insulin-

depending diabetes is result of equilibrium violation between destruction of β-cells and their

regeneration. Both process – increase of destruction and limitation of regeneration – are

genetically conditioned. Depending upon affection mechanism of β-cells there are two forms of

insulin-dependent diabetes mellitus – autoimmune and virus-inductive.

Autoimmune insulin-dependent diabetes arises in persons with genome DR3. It is associated

with other autoimmune endocrinopathies, for example, with illnesses of thyroid gland

(autoimmune thyreoiditis, diffuse toxic goiter), adrenal gland (Addison’s disease). This diabetes

type develops in any age more frequent in women. Autoimmune is diabetes described by

presence in blood of patient autoantibodies against of Langergans islets.




Virus-induced insulin-dependent diabetes mellitus binded with genome DR4 and different

from autoimmune on mechanisms of development. In this case there are no autoantibodies

against islets of pancreas. It certainly can appear in blood but rapidly (pending of year)

disappear. They do not perform essential role in pathogenesis of illness. Development of this

diabetes type frequently preceed from viral infectious epidemic parotitis, german measles,

measles, viral hepatitis. Virus-induced diabetes arises early before 30 years of life. It is

identically widespread and among males, both among women.

Insulin-independent diabetes mellitus

This diabetes type principle differs from the first. Patients, as a rule don’t need to exogenic

insulin. Metabolic disorders attached to this diabetes are minimal. Diet therapy and per oral

glucose decreasing medicines are sufficiently for their compensation. Only in stress (trauma

action, sharp infection) conditions patient use insulin. Illness can course for years without

hyperglycemia. Sometimes it is disclosed in age more 40 years.

There are three factors group, which play a decisive role in forming of this diabetes type. Here

are the genetic factors, functional disturbance of β-cells and insulin resistance.

Genetic factors determine hereditary liability to disease. Specific genetic marker (special

diabetogenic gene) is not found. It is known only, that inclination to insulin-independent diabetes

is not coupled with major complex of histocompatibility.

Function of β-cells of patient with insulin-independent diabetes is violated. Amount of them is

diminished. Attached to loading by glucose they do not multiply insulin secretion in necessary

amount. Diabetologist connects these violations with amyloidosis of Langergans islets.

Insulin-resistance arises or on genetic base or as result of influence of external factors (risk

factors). Biological insulin action is mediated over receptors. They are localized on cells-targets

membranes (myocytes, lypocytes). Interaction of insulin and receptor is followed with changes




of physical state of cells-targets membrane. As result of this transport system is activated, which

carries glucose over cellular membrane. Transmembrane moving of glucose is provided by

proteins-transmitters.

Clinical features of diabetes: hyperglycemia, glucosuria and polyuria.

Hyperglycemia is connected, foremost with lowering of glucose utilization by muscular and

fatty tissues. Lowering of glucose utilization has membranogenic nature. In case of insulinopenia

and in case of insulin-resistance nteraction of insulin and receptor is damaged. Therefore protein-

transporters of glucose are not included in membranes of cells-targets. This limits glucose

penetration in cells. It is use on power needs (in myocytes) diminishes. Lypogenesis is slowed-

glucose deposit in fats form (in lypocytes). Glycogenesis slows- synthesis of glycogene (in

hepatocytes and myocytes). On other hand, attached to diabetes a supplementary amount of

glucose is secreted in blood. In liver and muscles of diabetics glycogenolysis is a very active.

Definite endowment in hyperglycemia belongs to gluconeogenesis. Here with glucose will is

derivated in liver from amino acids (mainly from alanine).

Glucosuria: In healthy man practically has not glucose in urine. It is excreated in amount not

more 1 g. Attached to sugar diabetes amount of exreted glucose increases repeatedly. It is

explainet by next way. If glucose concentration in blood and primary urine does not exceed 9

mmol/l, epithelium of canaliculi reabsorbed it. This maximum concentration is called nephritic

threshold. If a glucose concentration exceeds a nephritic threshold (9 mmol/l), part of glucose

goes in secondary urine (glucosuria).

Polyuria: Glucose is osmotic active substance. Increasing of it’s concentration in primary urine

raises osmotic pressure. Water is exuded from organism together with glucose (osmotic diuresis).

Patient excretes 3-4 l of urine per day, sometimes till 10 l.

The very frequent diabetes complications are following: ketoacidosis, macroangiopathy,

microangiopathy, neuropathy.




Ketoacidosis: In healthy peoples synthesis of ketone bodies in liver is strictly controled. Main

regulatory mechanism is access limitation of fat acids in mytochondries of hepatocytes. Over

head permissible concentration limit of ketone bodies in blood is approximately 0,1 mmol/l. In

case of exceeding this level regulatory mechanisms are stated. Foremost ketone bodies put

specific receptors back up on membrane β-cells of Langergan’s islets. Insulin excretion in blood

increases. Insulin stimulates resynthesis of fat acids. First stage of resynthesis is derivation if

malonil-КоА. Surplus amount of malonil-КоА oppresses penetration of fat acids in

mytochondries. Synthesis of ketone bodies slows.

Microangipathy develop in shallow vessels – arterials, venues, capillaries. Two process form

their pathogenic base – thicking of basal membrane and reproduction endothelium. Direct cause

of microangiopathy is hyperglycemia and synthesis of glycoproteids in basal membrane. There

are two main clinical forms microangipathy : diabetic retinopathy and diabetic nephropathy.

Neuropathy manifest by violation of nerves function sensible, motor, vegetative. Essence of

these decreases is demyelinisation of nervous fibres, decrease of axoplasmatic flow.

To Summarize

Carbohydrate disorders may result from deficiencies of enzymes that split sugars to their

smallest parts in the small intestine or from a deficiency of a compound that carries glucose and

galactose from the small intestine into the blood. Symptoms of carbohydrate disorders may be

similar, whatever the cause, and include watery diarrhea, gas, and bloating. Abdominal cramping

may occur and if diarrhea persists, dehydration and acidosis may be severe. There can be organ

involvement, such as the liver, where certain enzyme activity and metabolic pathways are

centered. Treatment is mainly can be nutrition management which involves substrate restriction

such as lactose/galactose restriction in someone with galactosemia. In addition to disorders

involved in the breakdown of carbohydrates, there are several different inherited enzyme defects

that interfere with the breakdown of glycogen (a storage form of carbohydrate in the body) and




raise the glycogen content of the organ in which the enzyme is located. Because stored glycogen

is a between-meal and nighttime source of blood sugar, when enzymes that breakdown glycogen

do not function, blood glucose concentrations often drop to dangerously low levels. Clinical

features include seizures, delayed mental and motor development, hypotonia, and impaired

language skills and behavior. Consequently when this enzyme is deficient, the body must use fat

as a fuel source. The ketogenic diet is commonly used as nutrition management. Nutrition

management includes maintaining normoglycemia by providing a continuous glucose supply. It

may also be necessary to restrict carbohydrates in the pathway such as lactose and fructose,as

well as limiting fat intake. There can also be enzyme defects in the glucose transport protein

(GLUT1) found in erythrocytes, fibroblasts, and the blood-brain barrier. GLUT1 functions

effectively in glucose uptake in the absence of insulin. The ketogenic diet is a rigid,

mathematically calculated, doctor-supervised therapy. It is high in fat and low in carbohydrate

with adequate protein, providing 3-5 times as much fat as carbohydrate and protein combined.

This combination changes the way energy is used in the body. Fat is converted in the liver into

fatty acids and ketone bodies. This elevated level of ketone bodies in the blood (ketosis) leads to

a reduction in the occurrence of seizures.

quadrant i e-text f07ma16 disorders of carbohydrate

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