Disorders of Carbohydrates Metabolism PDF

23-24 ‫جامعة الفراهيدي – كلية الصيدلة‬ Disorders of Carbohydrates Metabolism Clinical Chemistry for 5th-year Pharmacy Students 1 ‫ رائد ضياء هاشم‬.‫د‬.‫م‬.‫ا‬ Al-Farahidi University...

23-24 ‫جامعة الفراهيدي – كلية الصيدلة‬ Disorders of Carbohydrates Metabolism Clinical Chemistry for 5th-year Pharmacy Students 1 ‫ رائد ضياء هاشم‬.‫د‬.‫م‬.‫ا‬ Al-Farahidi University College of Pharmacy Clinical chemistry for 5th year pharmacy students Disorders of Carbohydrates Metabolism Introduction Carbohydrates, including sugar and starch, are widely distributed in plants and animals. They perform multiple functions, such as being structural components as in RNA and DNA (ribose and deoxyribose sugars) and providing a source of energy (glucose). The main two types of sugars are: A- Monosaccharides: Also called simple sugars, they are soluble in water, common examples: 1. Fructose …………………. 2. Glucose ……………. 3. Galactose B- Disaccharides: Composed of 2 monosaccharides joined together, soluble in water, must be broken down to monosaccharides before they can be absorbed within the digestive system, common examples: 1. sucrose: glucose + fructose 2. lactose: glucose + galactose 3. maltose: glucose + glucose Oligosaccharides consist of 3-9 monosaccharides joined together, only partially digestible in the digestive system, present in some types of plants (onion, soya beans), useful for healthy digestion. Polysaccharides consist of polymers of chains of mono and disaccharides all joined together, tasteless, insoluble in cold water, and the main groups of polysaccharides are: 1- starch (in plants) 2- glycogen (in animals) In summary, carbohydrates can be classified into: 1. monosaccharides: include glucose, fructose and galactose. 2. disaccharides: include sucrose, maltose, and lactose 3. oligosaccharides: contain 3-9 simple sugars (monosaccharide) 4. polysaccharides: these are polymeric carbohydrate molecules composed of long chains of monosaccharide units bound together by glycosidic linkages and on hydrolysis give the constituent monosaccharides or oligosaccharides. Concerning glucose, the sources of blood glucose are: (1) the breakdown of carbohydrates in the diet (grains, starchy vegetables, and legumes) or body stores (glycogen). (2) endogenous synthesis from protein or the glycerol components of triglycerides. When energy intake exceeds expenditure, the excess is converted to fat and glycogen for storage in adipose tissue and liver or muscle, respectively. When energy expenditure exceeds caloric intake, endogenous glucose formation occurs from the breakdown of carbohydrate stores and noncarbohydrate sources (e.g., amino acids, lactate, and glycerol). 1 Al-Farahidi University College of Pharmacy Clinical chemistry for 5th year pharmacy students Insulin, glucagon, and epinephrine maintain the glucose concentration in the blood within a fairly narrow interval under diverse conditions (feeding, fasting, or severe exercise). Diabetes mellitus is the most commonly encountered of carbohydrate metabolism with hundreds of millions of people affected worldwide, 50% of whom are unaware of their illness. On the other extreme, hypoglycemia is much less common, especially in those on no insulin treatment. Biochemical importance of carbohydrates 1. Carbohydrates are important constituents of the cell structure in the form of glycolipid, glycoproteins, heparin, cellulose, starch and glycogen. 2. Carbohydrates serve as an important source and store of energy. 3. Carbohydrates play an important role in the metabolism of amino acids and fatty acids. 4. Lactose promotes the growth of desirable bacteria in the small intestine. It also increases calcium absorption. 5. They protect friction surfaces such as blood vessels, trachea, etc. against mechanical damage. 6. It plays an important role in maintaining osmotic and ionic regulation of the body. 7. It works as an intracellular cementing material. 8. It spares protein. 9. Heparin is a carbohydrate, which works as an anticoagulant in the body. Metabolism of glucose Glucose is the primary energy source for the human body. The first step of carbohydrate digestion occurs in the mouth by the action of salivary amylase on glycogen and starch but its action is strongly inhibited by the acidity of the stomach. The alkaline pancreatic secretion will allow pancreatic amylase to complete the digestion mainly to maltose which will be further hydrolyzed in addition to sucrose and lactose into glucose, galactose and fructose by intestinal disaccharidases to be absorbed. Monosaccharides are actively absorbed with fructose being absorbed more slowly than glucose and galactose. After absorption, the metabolism of glucose proceeds according to the body's requirements. This metabolism results in: (1) Energy production by conversion to carbon dioxide and water (by glycolysis and citric acid cycle). (2) Storage as glycogen in the liver or triglycerides in adipose tissue (glycogenesis). (3) Conversion to ketoacids, amino acids, or protein (by pentose monophosphate pathway). The pentose phosphate pathway, also known as the hexose monophosphate shunt, is an alternative pathway for glucose metabolism that generates the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH), which is used in maintaining the integrity of the red blood cell membrane. 2 Al-Farahidi University College of Pharmacy Clinical chemistry for 5th year pharmacy students Role of different hormones in carbohydrate metabolism The carbohydrate metabolism is regulated & the normal blood sugar level is maintained by a balance between the actions of insulin, glucocorticoids, growth hormones, adrenalin & thyroid hormones. In non-diabetic individuals, insulin is released from pancreas in different patterns: A- Insulin - Around 50% of the total insulin is secreted 1- Insulin increases the utilization of glucose in during the basal periods to prevent excessive energy production & lipogenesis, decreases lipolysis, proteolysis, and glycogenolysis. glucose formation from glycogen as well as non- - The other fraction of insulin is secreted in carbohydrates & indirectly enhances carbohydrate response to meals (postprandial), and it occurs in 2 phases: storage in tissues (glycogenesis). 1- the 1st phase begins within the first 2 2- It increases glucose uptake from the minutes of ingestion and persists for 10-15 extracellular fluid by muscles, adipocytes, minutes. It is associated with a sharp increase mammary glands, lens & many other extrahepatic in insulin release form the stores in the beta tissues. cells of pancreas. 3- It enhances glycolysis in muscles, liver & other 2- the 2nd phase follows the 1st one and continues till normalizing blood glucose level tissues. usually within 60-120 minutes. 4- Insulin also inhibits the production of glucose In patients with type 2 DM, the second phase gluconeogenesis from fats and amino acids, partly is preserved but the 1st one is lost. by inhibiting lipolysis and proteolysis. In patients with type 1 DM, there is a minimal B- Glucagon or no insulin response. Insulin also directly increases the transport of 1- Glucagon is stimulated by a fall in blood sugar amino acids, potassium and phosphate into level; it is antagonistic to insulin & increases blood cells, especially muscle; these processes are sugar and decreases liver glycogen. independent of glucose transport. 2- It increases glycogenolysis in the liver by In the longer term, insulin regulates growth activating glycogen phosphorylase. and development. 3- It decreases hepatic glycogenesis & thus The half-life of insulin in the circulation is between 4 and 5 minutes with total daily reduces the removal of blood glucose by the liver. secretion of about 40 U. 3 Al-Farahidi University College of Pharmacy Clinical chemistry for 5th year pharmacy students C- Adrenaline 1- Adrenaline or epinephrine has glycogenolytic action as it increases blood glucose by enhancing hepatic glycogenolysis. 2-It has gluconeogenic action as it increases hepatic gluconeogenesis. 3- It reduces the utilization of blood glucose by increasing adipose tissue lipolysis. D- Glucocorticoids 1- Adrenal Glucocorticoids tend to raise blood sugar. They help to maintain hepatic glycogen during fasting, glucocorticoids act as antagonists to insulin. 2-It increases gluconeogenesis in the liver by inducing the synthesis of key gluconeogenesis enzymes. 3- They decrease amino acid incorporation into protein by increasing protein catabolism in extrahepatic tissues. E- Growth hormones Growth hormone (GH) is antagonistic to insulin in most of its effects on carbohydrate metabolism. 1- It increases hepatic gluconeogenesis & mobilizes fatty acids from adipocytes for utilization. 2- GH reduces insulin sensitivity & thereby decreases the hypoglycemic effects of insulin. 3- It can also increase muscle & cardiac glycogen levels probably by reducing glycolysis. G F- Thyroid hormones 1- Thyroid hormones raise blood sugar; reduce glucose tolerance & increase glucose utilization. 2- Increase hepatic glycogenolysis. Insulin secretagogues Insulin inhibitors Glucose hypoglycemia, incretin hormones somatostatin (produced in the pancreatic δ-cells), glucagon-like peptide 1 (GLP-1) and glucose- dependent insulinotropic polypeptide (GIP) cholecystokinin, peptide YY drugs (e.g., α-adrenergic agonists, β-adrenergic blockers, diazoxide, phenytoin, phenothiazines Insulin secretion in response to glucose 4 Al-Farahidi University College of Pharmacy Clinical chemistry for 5th year pharmacy students Overview of disorders of carbohydrate metabolism Disorders of carbohydrate metabolism can be classified into two major groups: 1- genetic: usually rare, a major example of inborn errors of metabolism. 2- acquired: relatively common, the most important examples include diabetes mellitus and its complications (diabetic ketoacidosis, hyperosmolar coma) and hypoglycemia. Diabetes mellitus and related complications Diabetes mellitus (DM) is a group of metabolic disorders of carbohydrate metabolism characterized by hyperglycemia caused by an absolute or relative deficiency of insulin. It is a relatively common medical problem, affecting 1–2% of western populations. It is estimated that around 400 million people currently have diabetes, 80% of whom live in developing countries. In China, it was suggested that up to 11% of the population are diabetic and, more alarming, 50% of the rest of the population are prediabetics. Worldwide diabetes caused at least $612 billion in health expenditures and an estimated 4.9 million deaths in 2014.4 Acute and chronic complications make diabetes the fourth most common cause of death in the developed world. DM results in chronic hyperglycemia, usually accompanied by glycosuria and many other biochemical abnormalities, expressed as a wide range of clinical presentations ranging from asymptomatic patients with relatively mild biochemical abnormalities to patients admitted to hospitals with severe metabolic decompensation of rapid onset that has led to coma. Lack of insulin affects the metabolism of carbohydrates, protein and fat, and can cause significant disturbance of water and electrolyte homeostasis; death may result from acute metabolic decompensation. Long-term complications may develop, including retinopathy, neuropathy and nephropathy. It is a major risk factor for cardiovascular disease. Diabetes may be a secondary consequence of other diseases. For example, in diseases of the pancreas, such as pancreatitis or hemochromatosis, there is a reduction in insulin secretion. In some endocrine disorders, such as acromegaly or Cushing’s syndrome, there is an antagonism of insulin action by abnormal secretion of hormones with opposing activity. Several drugs adversely affect glucose tolerance. Examples of causes of secondary DM or hyperglycemia are listed in the following table: Category of cause Examples Drugs Estrogen-containing oral contraceptives, Corticosteroids, salbutamol, thiazide diuretics Endocrine disorders Acromegaly, Cushing's syndrome, glucagonoma, pheochromocytoma, prolactinoma, thyrotoxicosis Insulin receptor Autoimmune insulin receptor antibodies, congenital lipodystrophy abnormalities Pancreatic disease Chronic pancreatitis, hemochromatosis, pancreatectomy 5 Al-Farahidi University College of Pharmacy Clinical chemistry for 5th year pharmacy students Types of primary DM Most cases of diabetes are not associated with other conditions but are primary. Types of primary DM are: 1- Type 1 diabetes mellitus Biomarkers of β-cell autoimmunity are circulating antibodies, which might be Type 1 diabetes usually presents acutely over days or a few detected in the serum years before the weeks in young non-obese subjects but can occur at any onset of hyperglycemia. These age and represents 5-10% of the total cases of DM. antibodies include: In addition to polyuria, thirst and glycosuria, there is often 1- Islet cell cytoplasmic antibodies marked weight loss and ketoacidosis. Insulin is required for (ICAs) presents in 75 to 85% of patients with type 1 DM. its treatment. Type 1 diabetes is an autoimmune condition 2- Insulin autoantibodies (IAAs) are with genetic and environmental precipitating factors in its present in more than 90% of pathogenesis. It is eventually associated with a complete children who develop type 1 absence of insulin. diabetes before age 5. Islet-cell antibodies that react with the β-cells of the 3- Antibodies to the 65 kDa isoform pancreas have been demonstrated in serum from over 90% of glutamic acid decarboxylase (GAD) present in ≈60% of of patients with newly diagnosed type 1 diabetes but some patients. patients have no evidence of autoimmunity and are 4- Insulinoma-associated antigens classified as type 1 idiopathic. (IA-2A and IA-2βA), detected in The peak incidence occurs in childhood and adolescence. more than 50% of patients. Approximately 75% acquire the disease before the age of 5- Zinc transporter ZnT8 was identified recently as a major 18 but Age at presentation is not a criterion for classification. autoantigen in type 1 diabetes, There is a well-recognized association between type 1 ZnT8 in 60 to 80% of patients. diabetes and other autoimmune endocrinopathies, such as hypothyroidism and Addison’s disease, and also with pernicious anemia. 2- Type 2 diabetes mellitus Usually occurs in older (>40 years) patients who are obese; many patients have clearly had the condition for some time (even years) before diagnosis. It accounts for 90% of cases of diabetes. Type 2 diabetes is rare in younger patients but is increasing with the increased prevalence of obesity in this age group. Among children in Japan, type 2 diabetes is now more common than type 1. Measurable levels of insulin are present, and the metabolic defect appears to lie either in defective insulin secretion or in insulin resistance. In fact, Insulin concentrations may be normal, decreased, or even increased. Weight loss alone is associated with improvement in glycemic control even before starting diet therapy, oral antihyperglycemic drugs or insulin. In general, insulin administration is not required for the prevention of ketosis, as these patients are relatively resistant to its development. However, insulin may be needed to correct the abnormalities of blood glucose. There is a strong genetic element to this disorder as shown from the strong family history in a high percentage of patients. 3- Gestational diabetes Gestational diabetes is a term describing carbohydrate intolerance of variable severity that is either first recognized or has its onset during pregnancy. It can, therefore, include patients 6 Al-Farahidi University College of Pharmacy Clinical chemistry for 5th year pharmacy students with previously unrecognized type 1 or type 2 diabetes. In the United States, gestational diabetes mellitus (GDM) occurs in 6% to 8% of pregnancies. In these patients and in established diabetic patients who become pregnant, poor blood glucose control is associated with a higher incidence of intrauterine death and fetal malformation and urgent treatment is needed. The best strategy for screening and diagnosing gestational diabetes remains controversial. In early pregnancy, an important aim of screening is to identify previously undiagnosed type 2 diabetes, and women with risk factors such as a high body mass index, a family history of diabetes, or previous gestational diabetes should have HbA1c or fasting blood glucose measured. If results diagnostic of diabetes are obtained they should be regarded as having pre-existing diabetes. Women with intermediate results should be assessed for the need for home glucose monitoring. All women with risk factors should undergo an oral glucose tolerance test at 24–28 weeks. When GTT is used, the criteria for the diagnosis of gestational diabetes differ from the criteria applied for non-pregnant subjects, these criteria are: 1- a fasting plasma glucose of 92 mg/dl or more. 2- a one-hour value of 180 mg/dl or more. 3- a two-hour value of 153 mg/dl or more. It is important to mention that random or fasting glucose measurement is not recommended for screening because of poor specificity. Women with GDM are at significantly increased risk for the subsequent development of type 2 diabetes mellitus, which occurs in 6 to 62%. At 6 to 12 weeks postpartum, all patients who had GDM should be evaluated for diabetes using nonpregnant OGTT criteria. If diabetes is not present, patients should be reevaluated for diabetes at least every 3 years. 4- Neonatal diabetes Neonatal diabetes is diabetes diagnosed within the first 6 months of life and maybe transient or permanent. Up to 60% of patients with permanent neonatal diabetes have a mutation in one of the potassium channel genes, which results in failure of insulin production. 5- Maturity onset diabetes of the young (MODY) This autosomal dominant disorder is rare and characterized by: - presentation occurs in adolescents or young adults before the age of 25 years. - represent around 1% of all cases of DM. - frequently misdiagnosed as type 1 or type 2 DM. - many subtypes of MODY are present, with different severity, and sometimes require no treatment. - the more severe subtype is usually responsive to sulphonylureas. - insulin therapy may be required later in life. 6- Latent autoimmune diabetes in adults (LADA) Latent autoimmune diabetes in adults (LADA) is a disorder in which, despite the presence of islet antibodies at diagnosis of diabetes, the progression of autoimmune β-cell failure is slow. 7 Al-Farahidi University College of Pharmacy Clinical chemistry for 5th year pharmacy students LADA patients are therefore not insulin-requiring, at least during the first 6 months after diagnosis of diabetes. LADA is characterized by the following: - LADA is the most prevalent form of adult-onset autoimmune diabetes and probably the most prevalent form of autoimmune diabetes in general. - LADA shares genetic features with both type 1 and type 2 diabetes. - Phenotypically, LADA patients are often misdiagnosed as having type 2 diabetes. - LADA patients generally have worse HbA1c levels than type 2 diabetes patients. - Clinically, LADA patients tend to have a lower mean age at diabetes onset, lower body mass index and more frequent need for insulin treatment than patients with type 2 diabetes. Diagnosis The diagnosis of DM is based on the measurement of A1C level, fasting or random blood glucose level, or oral glucose tolerance testing. Urine glucose measurements are inadequate for diagnosing diabetes. They potentially yield false-positive results in subjects with a low renal threshold for glucose, and in a patient, with diabetes, they may yield false-negative results if the patient is fasting. The reference range of plasma glucose is: - FBS: 70 – 100 mg/dl - 2-hour postprandial plasma sugar: < 140 mg/dl (including GTT) According to the WHO criteria, DM is diagnosed when one or more of the following features are present: 1- a random venous plasma [glucose] of 200 mg/dl or more. 2- a fasting plasma [glucose] of 126 mg/dl or more. A single result is sufficient in the presence of typical hyperglycemic symptoms of thirst and polyuria. In their absence, a venous plasma [glucose] in the diabetic range should be detected on at least two separate occasions on different days. 3- HbA1c of more than 6.5%. 4- plasma sugar 200 mg/dl or more on 2 hours of GTT (or postprandial). According to previous criteria, a third group will appear other than diabetic or non-diabetic groups, this group is known as impaired fasting glucose when FBS lies between 100-125 mg/dl, or impaired glucose tolerance when 2 hours' postprandial plasma sugar lies between 140-200. This group has a higher risk of developing DM. Monitoring the treatment of diabetic patients There is now excellent evidence that in both type 1 and type 2 diabetes, the incidence of long-term complications such as retinopathy can be reduced by achieving tight control. This level of control requires meticulous monitoring of glycemic control. Monitoring treatment of DM can be done by: 1- Home blood glucose monitoring In a patient already diagnosed with DM, a FBS of less than 140 mg/dl and a 2-hour' postprandial blood sugar of less than 160 mg/dl is considered acceptable and the DM is considered controlled. 8 Al-Farahidi University College of Pharmacy Clinical chemistry for 5th year pharmacy students 2- HbA1c This test is also used to monitor treatment for someone with DM. It helps to evaluate how well the patient's glucose levels have been controlled by treatment over the last 2-3 months. For monitoring purposes, an HbA1c of less than 7% indicates good glucose control and a lower risk of diabetic complications for the majority of diabetics. Advantages and disadvantages of assays for glucose and HbA1c Glucose HbA1c Patient preparation prior to collection Stringent requirements if None. of blood measured for diagnostic purposes. Processing of blood Stringent requirements for Avoid conditions for more than rapid processing, separation 12hr at temperatures >23C. and storage of plasma or Otherwise, keep at 4C (stability serum minimally at 4°C. minimally 1 week). Measurement Widely available Not readily available worldwide Standardization Standardized to reference Standardized to reference method procedures. method procedures. Routine calibration Adequate. Adequate. Interferences: Illness Severe illness may increase Severe illness may shorten glucose concentration. red-cell life and artifactually reduce HbA1c values. Hemoglobinopathies Little problem unless the May interfere with patient is ill. measurement in some assays. Hemoglobinopathy traits No problems. Most assays are not affected. Affordability Affordable in most low and Unaffordable in most low and middle-income country middle-income country settings. settings. Some of the factors that influence hba1c and its measurement 1. Erythropoiesis 4. Erythrocyte destruction Increased HbA1c: iron, vitamin B12 deficiency, Increased HbA1c: increased erythrocyte life span: decreased erythropoiesis. Splenectomy. Decreased HbA1c: administration of Decreased A1c: decreased erythrocyte life span: erythropoietin, iron, vitamin B12, hemoglobinopathies, splenomegaly, rheumatoid arthritis or reticulocytosis, chronic liver disease. drugs such as antiretrovirals, ribavirin and dapsone. 2. Altered Hemoglobin 5. Assays Genetic or chemical alterations in hemoglobin: Increased HbA1c: hyperbilirubinemia, carbamylated hemoglobinopathies, HbF, and hemoglobin, alcoholism, large doses of aspirin, chronic methemoglobin, may increase or decrease opiate use. HbA1c. 3. Glycation Variable HbA1c: hemoglobinopathies. Increased HbA1c: alcoholism, chronic renal failure, decreased intra-erythrocyte pH. Decreased HbA1c: hypertriglyceridemia Decreased HbA1c: aspirin, vitamin C and E, certain hemoglobinopathies, increased intra- erythrocyte pH. Variable HbA1c: genetic determinants. 9 Al-Farahidi University College of Pharmacy Clinical chemistry for 5th year pharmacy students 3- Microalbumin Urinary ‘microalbumin’ is a term that refers to urinary albumin loss that is greater than normal, but which remains below the threshold of detection by the urinalysis dipstick tests widely used for detecting the presence of urinary protein. The presence of microalbuminuria has been shown to signal an eventual progression to diabetic nephropathy. 4- Fructosamine The measurement of plasma fructosamine concentrations may be used to assess glucose control over a shorter time course than that of HbA1c (about 2–4 weeks), but the assay has methodological limitations. Fructosamine reflects glucose bound to plasma proteins, predominantly albumin, which has a plasma half-life of about 20 days but is problematic in patients with hypoalbuminemia, for example, due to severe proteinuria. This assay may sometimes be useful in pregnancy and also if hemoglobin variants, for example, HbS or HbC, exist that may interfere with certain HbA1c assays. Metabolic complications of diabetes mellitus Patients with diabetes can develop severe metabolic derangements potentially leading to coma and even death. Acute metabolic complications of DM can be classified as follows: 1- hyperglycemia, with or without ketoacidosis 2- lactic acidosis, with or without hyperglycemia 3- hypoglycemia, due to insulin excess 1- Diabetic ketoacidosis (DKA) Diabetic ketoacidosis may be the presenting feature in a patient not previously recognized as having diabetes. In a patient with known diabetes, it may be precipitated by omitting insulin doses, or by the insulin dose becoming inadequate because of an increase in hormones with opposing action. This complication occurs in patients with type I DM. The major metabolic abnormalities result from hyperglycemia, ketoacidosis, or both which will result in various clinical and laboratory signs. Ketoacidosis results from the accumulation of ketone bodies that are produced from beta-oxidation of fatty acids due to insulin deficiency. Clinical features Symptoms Polyuria, thirst Weight loss Nausea, vomiting Blurred vision Abdominal pain Signs Dehydration Hypotension (postural or supine) Cold extremities Tachycardia Air hunger (Kussmaul breathing) Smell of acetone Confusion, coma (10%) 10 Al-Farahidi University College of Pharmacy Clinical chemistry for 5th year pharmacy students Laboratory findings usually present in DKA include: The rate of production of H ions that 1- high blood glucose, around 250-600 mg/dl. accompanies ketone bodies formation 2- ketones in both plasma and urine. exceeds the ability of all buffer 3- serum Na: normal or low. systems leading to accumulation of H ions and development of metabolic 4- serum K: high at presentation then severely decreased acidosis. with treatment. Hyperkalemia occurs secondary to 5- urea: high because of dehydration. acidosis and lack of insulin, although 6- acid-base status: metabolic acidosis (pH low, HCO3 low, there is a total body deficit due to pCO2 low) increased urinary potassium loss in the presence of an osmotic diuresis. With the correction of the initial Treatment causes of hyperkalemia, a profound When treating patients with DKA, the following points must life-threatening hypokalemia might be considered and closely monitored: ensue. Correction of fluid loss with intravenous fluids: If the potassium level is greater than 6 Correction of fluid loss makes the clinical picture clearer and mEq/L, avoid potassium infusion. If the potassium level is 4.5-6 mEq/L, 10 may be sufficient to correct acidosis. The presence of even mEq/h of potassium chloride is mild signs of dehydration indicates that at least 3 L of fluid administered. If the potassium level is has already been lost. 3-4.5 mEq/L, 20 mEq/h of potassium Correction of hyperglycemia with insulin infusion, chloride is administered. followed by subcutaneous insulin. In severe hypokalemia, insulin should Correction of electrolyte disturbances, particularly be delayed till correction serum potassium to avoid serious cardiac potassium loss. dysrhythmia. Correction of acid-base balance The rate of glucose lowering should be Treatment of concurrent infection, if present: around 100mg/hour. It is essential to maintain extreme concern for any Only short acting insulin is allowed to concomitant process, such as infection, cerebrovascular be used in treatment of DKA. 10% dextrose should be used when accident, myocardial infarction, sepsis, or deep venous glucose level reaches 250 mg/dl to thrombosis. permit further insulin infusion. The initial dose of insulin is 0.1 U/KG/h. This dose to be continued till 2- Hyperosmolar Hyperglycemic State glucose level reaches 180 mg/dl, then Hyperosmolar hyperglycemic state (HHS) is one of two half the dose is used till ketoacidosis fully treated. serious metabolic derangements that occur in patients with Cerebral edema may develop with diabetes mellitus DM and can be a life-threatening rapid correction of hyperglycemia. emergency. It is less common than the other acute complication of diabetes, diabetic ketoacidosis (DKA). HHS was previously termed hyperosmolar hyperglycemic nonketotic coma (HHNC); however, the terminology was changed because coma is found in fewer than 20% of patients with HHS. HHS usually presents in older patients with type 2 DM and carries higher mortality than DKA, estimated at approximately 10-20%. Infection is the most common precipitating factor of HHS. 11 Al-Farahidi University College of Pharmacy Clinical chemistry for 5th year pharmacy students Laboratory findings usually present in HHS include: 1- high blood glucose, usually > 600 mg/dl. 2- ketones are absent or very minimal in both plasma and urine. 3- serum Na: usually high due to hemoconcentration secondary to severe water loss. Cerebral cellular dehydration, which 4- serum K: usually normal. contributes to the coma, may also 5- urea: higher than that of DKA. cause hyperventilation, and a 6- acid-base status: pH is normal or slightly decreased respiratory alkalosis, although sometimes plasma lactic acid may rise, (> 7.30) evoking a metabolic acidosis and thus 7- serum osmolality of 320 mOsm/kg or greater. a mixed acid–base disturbance may 8- HCO3 > 18 mmol/l occur. insulin activity is sufficient to suppress Treatment lipolysis but insufficient to suppress The main goals in the treatment of hyperosmolar hepatic gluconeogenesis or to facilitate glucose transport into cells. hyperglycemic state (HHS) are as follows: There may also be an increased risk of To vigorously rehydrate the patient while thrombosis. maintaining electrolyte homeostasis To correct hyperglycemia To treat underlying diseases To monitor and assist the cardiovascular, pulmonary, renal, and central nervous system (CNS) function. Rapid and aggressive intravascular volume replacement is always indicated as the first line of therapy for patients with HHS. Isotonic sodium chloride solution is the fluid of choice for initial treatment because sodium and water must be replaced in these severely dehydrated patients. Although many patients with HHS respond to fluids alone, IV insulin in dosages similar to those used in diabetic ketoacidosis (DKA) can facilitate the correction of hyperglycemia. Insulin used without concomitant vigorous fluid replacement increases the risk of shock. Adjust insulin or oral hypoglycemic therapy based on the patient’s insulin requirement once the serum glucose level has been relatively stabilized. 3- Hypoglycemia Hypoglycemia is defined as plasma glucose of less than 45 mg/dl. Symptoms are often related more to the rate of fall of blood glucose than to the absolute value observed. Hypoglycemia may be caused by many conditions other than excess insulin, but these conditions are unrelated to DM. Treatment with either insulin or insulin secretion stimulant drugs may lead to hypoglycemia. Urgent treatment is mandatory as prolonged hypoglycemia can lead to brain damage. 12 Al-Farahidi University College of Pharmacy Clinical chemistry for 5th year pharmacy students 4- Lactic acidosis In basic terms, lactic acid is the normal endpoint of the anaerobic breakdown of glucose in the tissues. The lactate exits the cells and is transported to the liver, where it is oxidized back to glucose. In the setting of decreased tissue oxygenation, lactic acid is produced as the anaerobic cycle is utilized for energy production. With a persistent oxygen deficiency and overwhelming of the body's buffering abilities, lactic acidosis ensues. Lactic acidosis is a life-threatening condition characterized by the accumulation of lactic acid in the body with low pH, it is a known cause of metabolic acidosis caused by many medical disorders. Diabetes mellitus itself and many drugs used for its treatment (metformin) are the causes of lactic acidosis that require urgent intervention because lactic acidosis could be fatal. To make a diagnosis, the plasma level of lactic acid with blood gas analysis are essential in addition to the clinical features of the patient. Inborn Errors of Carbohydrates Metabolism 1- Galactosemia Hereditary galactosemia is among the most common carbohydrate metabolism disorders and can be a life-threatening illness during the newborn period. The incidence varies widely and reaches 1:16,000 in certain countries compared to 1:7,000 in others. It is usually diagnosed during routine neonatal screening. Galactose-1-phosphate uridyltransferase (GALT) deficiency is the most common enzyme deficiency that causes hypergalactosemia as it is responsible for converting ingested galactose to glucose. Galactose will be converted into galactitol which is a toxic substance leading to: ❖ Hepatomegaly ❖ Cirrhosis ❖ renal failure ❖ feeding intolerance ❖ vomiting ❖ hypoglycemia ❖ seizure ❖ lethargy ❖ intellectual impairment ❖ cataracts. If untreated, the mortality rate is extremely high while removing lactose largely eliminates the toxicity associated with the newborn disease, but long-term complications routinely occur. Treatment includes cessation of breastfeeding or the standard formula and using a specialized formula. 13 Al-Farahidi University College of Pharmacy Clinical chemistry for 5th year pharmacy students 2- Glycogen storage diseases Glycogen storage disease is a generic name encompassing at least 10 rare inherited disorders of glycogen storage in tissue. Because the liver and skeletal muscle have the highest rates of glycogen metabolism, these are the structures most affected. The liver forms are marked by hepatomegaly (caused by increased liver glycogen stores) and hypoglycemia (caused by an inability to convert glycogen to glucose). The muscle forms, in contrast, have mild symptoms that usually appear in young adulthood during strenuous exercise owing to the inability to provide energy for muscle contraction. 3- Fructose-1,6-bisphophatase deficiency Patients with this deficiency have episodes of apnea, hyperventilation and hypoglycemia, ketosis, and lactic acidosis caused by severe impairment of gluconeogenesis. The condition is diagnosed by demonstrating the enzyme defect in liver biopsy specimens. 4- Hereditary fructose intolerance A deficiency of fructose-1-phosphate aldolase produces this rare disorder with hypoglycemia and liver failure. Fructose ingestion inhibits glycogenolysis and gluconeogenesis, producing hypoglycemia. Early detection is important because this condition responds to a diet devoid of sucrose and fructose. 5- Glucose-6-phosphate dehydrogenase deficiency This is an X-linked defect in the first, irreversible step of the pentose phosphate pathway. It represents the most common enzyme defect encountered in clinical practice affecting around 400 million people worldwide. 14 Al-Farahidi University College of Pharmacy Clinical chemistry for 5th year pharmacy students A decrease in NADPH production makes red blood cell membranes vulnerable to oxidative stress, leading to hemolysis. NADPH serves as a substrate for glutathione reductase. The reduced glutathione has the ability to convert hydrogen peroxide into water and prevent damage to cellular structures, particularly the cell wall of red blood cells (RBCs) since they have limited capacity for repair once they mature. The most common manifestations are early neonatal unconjugated jaundice and acute hemolytic anemia. The patient presents with anemia, jaundice, dark colour urine and splenomegaly. However, most individuals with the deficiency are clinically asymptomatic. The hemolytic 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. The highest frequency is in those of Mediterranean, Asian or African origin. The diagnosis is by measurement of the enzyme activity in erythrocytes. Hypoglycemia Hypoglycemia is defined as a blood glucose level below the target value although there is no consensus about this value. Different values have been applied to define hypoglycemia such as: < 50 mg/dl, < 60 mg/dl and even < 70 mg/dl. Generally speaking, symptoms do not develop till the level of blood glucose is less than 55 mg/dl although many factors influence the appearance of symptoms and their severity. Hypoglycemia reflects an abnormality in glucose homeostasis which might be caused by various conditions but the most common cause of hypoglycemia is an iatrogenic cause, specifically in patients with diabetes mellitus, commonly in those on insulin therapy as patients with type 1 diabetes are 3 times more likely to develop hypoglycemia compared to patients with type 2. The classical diagnosis of hypoglycemia depends on confirming the presence of Whipple's triad: ❖ the presence of the typical symptoms of hypoglycemia ❖ confirming low blood glucose level ❖ immediate recovery after administration of glucose Causes of hypoglycemia in non-diabetic individuals include critical illness, alcohol, cortisol deficiency, malnourishment and insulinoma. 15 Al-Farahidi University College of Pharmacy Clinical chemistry for 5th year pharmacy students Clinical features Neuroglycopenic (Result from direct CNS deprivation of glucose) ▪ Confusion ▪ Fatigue ▪ Seizure ▪ Coma ▪ Death Neurogenic (Result from sympathetic stimulation in response to hypoglycemia) ▪ Adrenergic ✓ tremor, palpitations, anxiety ▪ Cholinergic ✓ (hunger, diaphoresis, paresthesias) Surprisingly, patients with diabetes mellitus might develop signs and symptoms of hypoglycemia at higher levels of blood glucose. This phenomenon is called pseudohypoglycemia and is thought to be due to an altered set point at which neuroglycopenic and neurogenic used to occur as a result of chronic hyperglycemia. At the same time, diabetic patients with a history of recurrent hypoglycemia might experience asymptomatic hypoglycemia despite the significant low blood glucose level. This condition is called hypoglycemia-associated autonomic failure (HAAF) and its pathophysiology is not well understood although defective adrenomedullary adrenaline response to hypoglycemia is a characteristic finding. Significant impairment of cardiovascular function is expected in patients with recurrent hypoglycemia due to the associated increase in blood pressure, stroke volume and myocardial contractility. Approach consideration The direct cause of hypoglycemia needs to be diagnosed after resuscitating the patient as a serious underlying condition might be overlooked. In most cases, the history is highly suggestive of the underlying cause, especially in diabetic patients. When the cause is not clear, a systematic workup is essential which includes: 1- blood glucose 2- serum insulin 3- serum C-peptide 4- serum cortisol 5- serum ACTH 6- renal function 7- liver function 16 Al-Farahidi University College of Pharmacy Clinical chemistry for 5th year pharmacy students Many factors have been suggested to be associated with severe hypoglycemia such as: ❖ Age (both extremes of age) ❖ Strict glycemic control ❖ Increasing the duration of diabetes ❖ Sleep ❖ History of previous severe hypoglycemia ❖ Associated renal impairment Hypoglycemia-induced cardiac arrhythmia has been implicated to be the direct cause of sudden death during sleep that might be encountered in young patients with type 1 diabetes "dead in bed syndrome". Furthermore, within 5 years of the onset of type 1 diabetes mellitus, the secretion of the counter-regulatory hormones will be impaired significantly making the recovery of hypoglycemia more difficult. Management The severity of hypoglycemia and the patient's level of consciousness are the main factors that determine the mode of treatment. For mild cases where the level of consciousness is intact: ▪ Oral fast-acting carbohydrate (10–15 g) is taken as a glucose drink or tablet. ▪ This should be followed by a snack containing complex carbohydrates. For severe cases: ▪ Intravenous 75–100 mL 20% dextrose over 15 mins (= 15 g; give 0.2 g/kg in children) Or ▪ Intravenous 150–200 mL 10% dextrose over 15 mins Or ▪ Intramuscular glucagon (1 mg; 0.5 mg in children) – may be less effective in patients on sulphonylurea or under the influence of alcohol. Full recovery may not occur immediately and reversal of cognitive impairment may not be complete until 60 minutes after normoglycemia is restored. When hypoglycemia has occurred in a patient treated with long- or intermediate-acting insulin or a long-acting sulphonylurea, such as glibenclamide, the possibility of recurrence should be anticipated; to prevent this, infusion of 10% dextrose, titrated to the patient’s blood glucose, or provision of additional carbohydrate may be necessary. Failure to regain consciousness after the restoration of blood glucose level is a clue to the development of cerebral oedema which is associated with a high mortality rate. For those on insulin therapy, the next dose should not be omitted but reduced by 10-20% and medical advice should be sought. 17