- The document discusses calcium homeostasis and hormonal regulation, including the roles of calcium, principal organs involved, and normal calcium levels.
- Parathyroid hormone and vitamin D play key roles in hormonal control of calcium metabolism. Parathyroid hormone is secreted by the parathyroid glands and vitamin D is synthesized through exposure to sunlight.
- Hypercalcemia and hypocalcemia are discussed, along with their causes, signs, and symptoms. Primary hyperparathyroidism is an endocrine cause of hypercalcemia. Hypocalcemia can cause neuromuscular and central nervous system issues.
- The document discusses calcium homeostasis and hormonal regulation, including the roles of calcium, principal organs involved, and normal calcium levels.
- Parathyroid hormone and vitamin D play key roles in hormonal control of calcium metabolism. Parathyroid hormone is secreted by the parathyroid glands and vitamin D is synthesized through exposure to sunlight.
- Hypercalcemia and hypocalcemia are discussed, along with their causes, signs, and symptoms. Primary hyperparathyroidism is an endocrine cause of hypercalcemia. Hypocalcemia can cause neuromuscular and central nervous system issues.
- The document discusses calcium homeostasis and hormonal regulation, including the roles of calcium, principal organs involved, and normal calcium levels.
- Parathyroid hormone and vitamin D play key roles in hormonal control of calcium metabolism. Parathyroid hormone is secreted by the parathyroid glands and vitamin D is synthesized through exposure to sunlight.
- Hypercalcemia and hypocalcemia are discussed, along with their causes, signs, and symptoms. Primary hyperparathyroidism is an endocrine cause of hypercalcemia. Hypocalcemia can cause neuromuscular and central nervous system issues.
- The document discusses calcium homeostasis and hormonal regulation, including the roles of calcium, principal organs involved, and normal calcium levels.
- Parathyroid hormone and vitamin D play key roles in hormonal control of calcium metabolism. Parathyroid hormone is secreted by the parathyroid glands and vitamin D is synthesized through exposure to sunlight.
- Hypercalcemia and hypocalcemia are discussed, along with their causes, signs, and symptoms. Primary hyperparathyroidism is an endocrine cause of hypercalcemia. Hypocalcemia can cause neuromuscular and central nervous system issues.
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Clinical Chemistry 3 Lecture 5
CALCIUM HOMEOSTASIS AND HORMONAL REGULATION
Roles of Calcium Signal transduction pathways acts as a second messenger, in neurotransmitter release from neurons Contraction of all muscle cell types Fertilization Enzyme cofactor blood-clotting cascade Proper bone formation
PRINCIPAL ORGANS INVOLVED IN CALCIUM HOMEOSTASIS Small Intestines Bones (Skeletal System) Kidneys Normal Total Calcium: 2.2-2.6 mmol/L (9-10.5 mg/dL) Normal Ionized Calcium: 1.1-1.4 mmol/L (4.5-5.6 mg/dL). CALCIUM HOMEOSTASIS
HORMONAL CONTROL OF CALCIUM METABOLISM Parathyroid Hormone Vitamin D A hormone Structurally similar steroid hormones a metabolic product of the cholesterol synthetic pathway Tissues involved in the synthesis: Skin Liver Kidneys Target Organs: Gut Bone Parathyroids VITAMIN D SYNTHESIS
Parathyroid Hormone secreted from four parathyroid glands in the region of the thyroid gland
Hormonal Control of Calcium Metabolism
HYPERCALCEMIA the state of blood calcium levels above the expected normal range in a healthy population ionized or free calciumbiologically active 50% bound calcium Albumin Citrate Phosphate Signs and Symptoms of Hypercalcemia Central nervous system Altered central nervous system function Lethargy Decreased alertness Depression Confusion Forgetfulness Obtundation Coma GASTRO-INTESTINAL Anorexia Constipation Nausea and vomiting Renal Calcium acts as a diuretic and impairs the kidneys ability to concentrate urine Dehydration hypercalciuria increases the risk of calcium- containing kidney stone Skeletal Patients with most causes of hypercalcemia have increased bone resorption increased bone demineralization, leading to increased fracture risk Cardiovascular Hypercalcemia may cause or exacerbate hypertension ECG: shortened QT interval Endocrine Causes of Hypercalcemia
Primary Hyperparathyroidism parathyroid adenoma/hyperplasia MEN 1 result in tumors of the parathyroids, pituitary, and pancreas loss of a tumor suppressor gene that maps to human chromosome 11 MEN 2 result in tumors of the parathyroids, medullary thyroid hyperplasia or cancer, and pheochromocytoma activating mutation in the ret proto- oncogene, which resides on human chromosome 10 Familial hyperparathyroidism results in primary HPT, without other associated tumors mapped to human chromosome 1.14 Familial hypocalciuric hypercalcemia (FHH) result of a mutation in the calcium- sensing receptor and thus an increased set point for calcium homeostasis mild hypercalcemia and hyperparathyroidism
Parathyroid hormonerelated protein (PTHrP) -substance very similar in structure to PTH -produced by a variety of benign and malignant tumors Breast Lung Kidney Lymphoma -PTHrP shares the N- terminal sequence homology with PTH, it acts similarly and can cause hypercalcemia.
Milk-alkali Syndrome (Burnetts Syndrome) results from the ingestion of large amounts of calcium together with an absorbable alkali patients being treated for peptic ulcers using carbonate or bicarbonate salts with milk or cream can lead to: Hypercalcemia Metabolic alkalosis Renal impairment HYPOCALCEMIA the state of blood calcium levels below the expected normal range in a healthy population
Signs and Symptoms of Hypocalcemia Neuromuscular Chvosteks sign Numbness and tingling in the face, hands, and feet may be seen Trousseaus sign Central nervous system Irritability Seizures Personality changes Impaired intellectual functioning Cardiovascular Cardiac contractile dysfunction METABOLIC BONE DISEASES Rickets and Osteomalacia Rickets refers to the disease state in growing bone (in children). Osteomalacia refers to the abnormal mineralization of bone in adults, or after closure of the ephiphysial plates. Osteoporosis the most prevalent metabolic bone disease in adults.
Clinical Chemistry 3 Lecture 4 THE THYROID GLAND
The Thyroid Gland Produces 2 hormones: Thyroid Hormones (T3 & T4) produced by thyrocytes critical in regulating body metabolism, neurologic development, and numerous other body functions Calcitonin produced by parafollicular cells C involved in calcium homeostasis
Thyroid Anatomy and Development Location: Lower Anterior Neck Shape: butterfly, consisting of 2 lobes and an isthmus Weight: 16-30 grams in adults Embryology: outpouching of the foregut at the base of the tongue Thyroid Hormone Synthesis
Metabolism of Thyroxine
Three Forms Of Iodothyronine 5-deiodinase Type 1 iodothyronine 5-deiodinase the most abundant form found mostly in the liver and kidney responsible for the largest contribution to the circulating T3 pool Type 2 iodothyronine 5-deiodinase found in the brain and pituitary gland maintain constant levels of T3 in the central nervous system Type 3 iodothyronine 5-deiodinase found in fetal tissues prevent the rise of serum T3 they maintain high levels of rT3 during intrauterine life Protein Binding of Thyroid Hormone Thyroxin-binding Globulin (TBG) Thyroxin-binding Prealbumin Albumin
Control of Thyroid Function
TESTS FOR THYROID EVALUATION TSH most useful test for assessing thyroid function is the TSH T3 & T4 usually measured by: radioimmunoassay (RIA) chemiluminometric assay similar immunometric technique Thyroglobulin measured by double- antibody RIA enzyme-linked immunoassay (ELISA) immunoradiometric assay (IRMA) immunochemilu- minescent assay (ICMA) methods INTERPRETATION OF THYROID TESTS
#PREVALENCE OF THYROID AUTOANTIBODIES
Hypothyroidism Decreased free T4 with normal to elevated TSH
Thyrotoxicosis constellation of findings that result when peripheral tissues are presented with, and respond to, an excess of thyroid hormone. Causes: excessive thyroid hormone ingestion leakage of stored thyroid hormone from storage in the thyroid follicles excessive thyroid gland production of thyroid hormone SIGNS AND SYMPTOMS OF THYROTOXICOSIS Signs Tachycardia Tremor Warm, moist, flushed, smooth skin Lid lag, widened palpebral fissures Ophthalmopathy (Graves disease) Goiter Brisk deep tendon reflexes Muscle wasting and weakness Dermopathy/pretibial myexedema (Graves disease) Osteopenia, osteoporosis Symptoms Nervousness, irritability, anxiety Tremor Palpitations Fatigue, weakness, decreased exercise tolerance Weight loss Heat intolerance Hyperdefecation Menstrual changes (oligomenorrhea) Prominence of eyes
Graves Disease the most common cause of thyrotoxicosis an autoimmune disease in which antibodies are produced that activate the TSH receptor DISORDERS ASSOCIATED WITH THYROTOXICOSIS
Clinical Chemistry 3 Lecture 6 LIVER FUNCTION Gross Anatomy Of The Liver Blood Supply of the Liver Excretory System Of The Liver Microscopic Anatomy BIOCHEMICAL FUNCTIONS Four Major Functions: Excretion/secretion Synthesis Detoxification Storage EXCRETORY AND SECRETORY Transforms unconjugated to conjugated bilirubin Ligandin responsible for transporting unconjugated bilirubin to the endoplasmic reticulum, where it may be rapidly conjugated METABOLISM OF BILIRUBIN
SYNTHETIC Responsible for synthesizing: Carbohydrates use the glucose for its own cellular energy requirements circulate the glucose for use at the peripheral tissues store glucose as glycogen (principal storage form of glucose) within the liver itself or within other tissues Lipids approximately 70% of the daily production of cholesterol (roughly 1.52.0 g) Proteins Almost all proteins are synthesized by the liver except for the immunoglobulins and adult hemoglobin DETOXIFICATION AND DRUG METABOLISM serves as a gatekeeper between substances absorbed by the gastrointestinal tract and those released into systemic circulation LIVER FUNCTION ALTERATIONS DURING DISEASE JAUNDICE Upper normal limit of total bilirubin 1.0-1.5 mg/dL Jaundice is noticeable at 3.0 mg/dL ICTERUS used in the clinical laboratory to refer to a serum or plasma sample with a yellow discoloration due to an elevated bilirubin level CLASSIFICATION OF JAUNDICE
GILBERT DISEASE reduced activity of the enzyme glucuronyltransferase, which conjugates bilirubin and a few other lipophilic molecules CRIGLER-NAJJAR SYNDROME TYPE 1 Mode of Inheritance: Autosomal Recessive characterised by: serum bilirubin usually above 345 mol/L (310755 mg/dL) no UGT1A1 (UDP glucuronosyltransferase 1 family, polypeptide A1) expression no response to treatment with phenobarbital* CRIGLER-NAJJAR SYNDROME TYPE 2 Type II differs from type I in several aspects: Bilirubin levels are generally below 345 mol/L (100430 mg/dL) and some cases are only detected later in life. Because of lower serum bilirubin, kernicterus is rare in type II. Bile is pigmented, instead of pale in type I or dark as normal, and monoconjugates constitute the largest fraction of bile conjugates. UGT1A1 is present at reduced but detectable levels (typically <10% of normal), because of single base pair mutations. Therefore, treatment with phenobarbital is effective, generally with a decrease of at least 25% in serum bilirubin. In fact, this can be used, along with these other factors, to differentiate type I and II. The inheritance pattern of Crigler Najjar syndrome type II has been difficult to determine but is generally considered to be autosomal recessive. [
DUBIN-JOHNSON SYNDROME An autosomal recessive disorder Increase of conjugated bilirubin in the serum without elevation of liver enzymes (ALT, AST) Defect in the ability of hepatocytes to secrete conjugated bilirubin into the bile Diagnosis A hallmark of DJS is the unusual ratio between the byproducts of heme biosynthesis. Unaffected subjects have a coproporphyrin III to coproporphyrin I ratio of approximately 34:1. In patients with DJS, this ratio is inverted with coproporphyrin I being 34x higher than coproporphyrin III. ROTOR SYNDROME
CIRRHOSIS clinical condition in which scar tissue replaces normal, healthy liver tissue scar tissue replaces the normal liver tissue blocking the flow of blood through the organ and prevents the liver from functioning properly Causes: Chronic Alcoholism Chronic Hepatitis B, C, D autoimmune hepatitis inherited disorders (e.g., 1-antitrypsin deficiency, Wilson disease, hemachromatosis, and galactosemia) nonalcoholic steatohepatitis blocked bile ducts Drugs Toxins infections REYE SYNDROME a term used to describe a group of disorders caused by infectious, metabolic, toxic, or drug- induced disease found almost exclusively in children Associted with: viral syndrome Varicella Gastroenteritis upper respiratory tract infection such as influenza aspirin during a viral syndrome ASSESSMENT OF LIVER FUNCTION/LIVER FUNCTION TESTS Review: BILIRUBIN Ehrlichs (Diazo) Reaction diazotized Sulfanilic Acid + Urine colored product (RED)= urobilinogen Van den Bergh Reaction determines the amount of conjugated bilirubin in the blood the reaction produces azobilirubin Principle: diazotised sulfanilic acid + serum + stabilizer = produce purple colored azobilirubin Malloy and Evelyn Reaction Principle: diazotised sulfanilic acid + serum + 50% methanol (accelerator)= RED PURPLE Jendrassik and Grof Principle: diazotised sulfanilic acid + serum + caffeine- benzoate-acetate (accelerator)= PURPLE REFERENCE RANGES FOR BILIRUBIN IN ADULTS AND INFANTS
DETERMINATION OF UROBILINOGEN (SEMIQUANTITATIVE) Principle Urobilinogen (Urine) + p-dimethyl aminobenzaldehyde (Ehrlichs reagent) = red color Reference Range (Urine) 0.11.0 Ehrlich units every 2 hours 0.54.0 Ehrlich units per day (0.86.8 mmol/day) Reference Range (Fecal) 75275 Ehrlich units per 100 g of fresh feces 75400 Ehrlich units per 24-hour specimen LIVER ENZYMES Most Clinically Useful: Aminotranferases alanine amino transferase [ALT] SGPT aspartate aminotransferase [AST]) SGOT Phosphatases alkaline phosphatase [ALP] 5- neucleotidase) Gamma -glutamyltransferase (GGT) Lactate dehydrogenase AMINOTRANFERASES ALT a more liver-specific marker than AST the serum activity of both transaminases rises rapidly in almost all diseases of the liver and may remain elevated for up to 26 weeks Markedly increased in: viral hepatitis drug- and toxin-induced liver necrosis Hepatic ischemia Normal or only mildly elevated in: cases of obstructive liver damage PHOSPHATASES Alkaline Phosphatase zinc metalloenzymes widely distributed in all tissues marker of extrahepatic biliary obstruction stone in the common bile duct intrahepatic cholestasis drug cholestasis primary biliary cirrhosis moderate increase: hepatocellular disorders such as hepatitis and cirrhosis 5-Nucleotidase responsible for catalyzing the hydrolysis of neucleoside-5-phosphate ester serum levels become significantly elevated in hepatobiliary disease more liver specific compared to ALP PHOSPHATASES membrane-localized enzyme found in high concentrations in the kidney, liver, pancreas, intestine, and prostate but not in bone plays a role in differentiating the cause of elevated levels of ALP highest levels of GGT are seen in biliary obstruction hepatic microsomal enzyme ingestion of alcohol or certain drugs elevates GGT Barbiturates Tricyclic Antidepressants Anticonvulsants a sensitive test for cholestasis caused by chronic alcohol or drug ingestion useful if jaundice is absent for the confirmation of hepatic neoplasms an enzyme with a very wide distribution throughout the body released into circulation when cells of the body are damaged or destroyed serves as a general, nonspecific marker of cellular injury Tests Measuring Hepatic Synthetic Ability SERUM PROTEINS Useful in quantitating the severity of hepatic dysfunction Not sensitive to minimal liver damage SERUM ALBUMIN correlates well with the severity of functional impairment chronic rather than in acute liver disease (decreased) SERUM -GLOBULINS decrease with chronic liver disease low or absent -globulin suggests - antitrypsin deficiency as the cause of the chronic liver disease SERUM -GLOBULIN transiently increased in acute liver disease elevated in chronic liver disease IgG and IgM levels chronic active hepatitis IgM Primary Biliary Cirrhosis IgA Alcoholic Cirrhosis PROTHROMBIN Decreased Prothrombin Time is prolonged Indicates severe diffuse liver disease and a poor prognosis Tests Measuring Nitrogen Metabolism PLASMA AMMONIA a reflection of the livers ability to convert ammonia to urea so that it can be excreted through the kidneys increase in the bloodstream and may ultimately cause hepatic coma HEPATITIS
Serology Of Hepatitis B Infection With Recovery
Serology Of Chronic Hepatitis With Formation Of Antibody To HBeAg
TYPICAL INTERPRETATION OF SEROLOGIC TEST RESULTS FOR HBV INFECTION
SEROLOGICAL PROFILES OF CHRONIC HEPATITIS B VIRUS INFECTION
CLINICAL FEATURES OF HEPATITIS D VIRUS (HDV) COINFECTION AND SUPERINFECTION IN HEPATITIS B VIRUS (HBV) CARRIERS
