Enzymes in health and diseases final

the ppt describes the role of enzymes in health and diseases

1. Enzymes in health and diseases Presenter : Dr Suma H.V. Moderator : Dr B.G.Malathi

2. Contents Enzymes- Introduction Functional enzymes Non-functional enzymes Enzyme deficiency disorders Summary References

3. Enzymes Biological catalysts that speed up the rate of the biochemical reaction enzymes Substrate products

4. Active site of enzyme The small cleft-like portion of an enzyme where the substrate(s) binds and catalysis occurs is known as the active site or active centre. A diagrammatic representation of an enzyme and its active site

5.  Enzymes in our body help us in the diagnosis of many diseases. Enzyme in the circulatory system are divided into two groups: 1. Plasma functional enzymes 2. Non-plasma functional enzymes

6. PLASMA FUNCTIONAL ENZYME Enzymes that are present in plasma and have specific function Activities of these enzymes are higher in plasma than tissues. The are mostly synthesized in liver and enter the circulation. e.g. lipoprotein lipase, cholinesterase, esterase, ceruloplasmin etc.

7. Impairment of liver function often leads to fall in the activities of plasma function enzyme. e.g. deficiency of ceruloplasmin in Wilson disease.

8. Non Functional Plasma Enzymes Present in plasma in very low concentration in comparison to tissue. Have no known physiological function in blood.

9. Increased levels of non functional plasma enzymes in plasma indicates tissue damage. These enzymes can be used for diagnosis.

10. Source of non functional Plasma enzymes Cell Damage Myocardial infarction and viral hepatitis. Obstruction of Normal pathways: e.g. Obstruction of bile duct increases alkaline phosphatase .

11.   Medical importance of non functional enzymes Diagnosis of diseases -As disease of different organs cause elevation of different plasma enzymes. Prognosis of the disease To follow up the treatment by measuring plasma enzymes before and after.

12. Examples of non-functional enzymes Creatine kinase Lactate dehydrogenase Acid phosphatase Amylase Alkaline phosphatase

13. Cholinesterase( ChE ) Enzymes which hydrolyse esters of choline to give choline and acid. There are two types of cholinesterases . 1.True cholinesterase 2.Pseudo cholinesterase

14. True Cholinesterase ( Found in nerve tissue and RB cells Responsible for the destruction of acetyl choline (neurotransmitter) at neuromuscular junction

15. Pseudo cholinesterase Found in various tissues such as liver, heart muscle and intestine. Circulates in plasma. Normal value of pseudo cholinesterase is 2.17 to 5.17 IU/ml.

16. Organophosphorous insecticides (Parathion) These are organic compounds containing phosphorus, irreversibly inhibit. Their absorption in humans cause poisoning.(neuromuscular damage, muscle weakness, slow breathing) Measurement of ChE level in RBCs is useful to determine the amount of exposure in persons working with these insecticides.

17. Cholinesterase test To cheque the level of acetyl cholinesterase in RBC and pseudo cholinesterase in plasma. AChE and PChE activity can fall to about 80% of normal before any symptoms appear, of poisoning.

18. This decrease in activity indicates excessive absorption of organophosphorus compounds, chronic liver disease, renal disease , malnutrition and some cancers.

19. Lipase It will hydrolyze triglyceride to beta monoglyceride and fatty acid. The enzyme is present in pancreatic secretion. Moderately increased in carcinoma of pancreas, biliary diseases and perforating peptic ulcers.

20. Highly elevated in acute pancreatitis and this persists for 7–14 days.

21. Ceruloplasmin / Ferroxidase Copper binding glycoprotein Reference serum level is 25–50 mg/ dL . Increased in all inflammatory conditions, collagen diseases, malignancies and pregnancy.

22. A value less than 20 mg/ dL is pathognomonic of Wilson’s hepatolenticular degeneration, in which copper toxicity is manifested.

23. Alpha 1 antitrypsin Synthesized in liver Transported to plasma 100-300mg/dl Protects tissues from inflammatory products eg : Neutrophil elastase in lungs

24. Increases 1) Inflammation- an acute phase protein 2) Chronic hepatocellular diseases 3) Biliary tract obstruction 4) Pregnancy

25. Decreases 1) Nephrotic syndrome 2) Emphysema 3) Liver cirrhosis

26. Liver enzymes Enzymes commonly studied for diagnosis of liver diseases are: Alanine aminotransferase (ALT) Aspartate aminotransferase (AST) Alkaline phosphatase (ALP) Gamma glutamyl transferase (GGT)

27. Alanine aminotransferase (ALT) Normal serum level : Male is 13–35 U/L Female is 10–30 U/L Rise in ALT levels may be noticed several days before clinical signs such as jaundice are manifested.

28. ALT Moderate increase (50–100 U/L) of ALT Chronic liver diseases such as cirrhosis, hepatitis C Non-alcoholic steatohepatitis (NASH). Marked increase values (300–1000 U/L) -Acute hepatitis , either toxic or viral in origin.

29. Aspartate aminotransferase (AST) Normal serum level 8 to 20 U/L. Marker of liver injury Moderate to drastic increase - parenchymal liver diseases like hepatitis and malignancies of liver.

30. AST was used as a marker of myocardial ischemia in olden days. The level is significantly elevated in myocardial infarction. As AST is raised in various other conditions, the troponins have replaced AST as a diagnostic marker in ischemic heart disease

31. Alkaline phosphatase (ALP) Produced by osteoblasts of bone, epithelial cells of liver Associated with calcification process. 20-140 IU/L Moderate (2–3 times) increase in ALP level is seen in hepatic diseases such as infective hepatitis, alcoholic hepatitis or hepatocellular carcinoma

32. Very high levels of ALP (10–12 times of upper limit) Extrahepatic obstruction (obstructive jaundice) caused by gallstones or by pressure on bile duct by carcinoma of head of pancreas. Intrahepatic cholestasis may be due to virus (infective hepatitis) or by drugs (chlorpromazine).

33. Drastically high levels of ALP (10–25 times of upper limit) Paget’s disease ( osteitis deformans ) Rickets Osteomalacia Osteoblastoma Metastatic carcinoma of bone.

34. Isoenzymes of alkaline phosphatase Alpha-1 ALP - Synthesized by epithelial cells of biliary canaliculi . - It is about 10% of total activity - Increased in obstructive jaundice.

35. Isoenzymes of alkaline phosphatase Alpha-2 heat labile ALP - It is produced by hepatic cells.

36. Alpha-2 heat stable ALP - It is of placental origin. - Not destroyed at 65°C but is inhibited by phenylalanine . Regan isoenzyme or carcino placental isoenzyme .

37. Isoenzymes of alkaline phosphatase Pre-beta ALP - It is of bone origin - This is heat labile - Elevated levels are seen in bone diseases .

38. Gamma Glutamyl Transferase (GGT) It is used for the synthesis of glutathione. It is seen in liver, kidney, pancreas, intestinal cells, and prostate gland. Serum value is 10–30 U/L.

39. It is moderately increased in infective hepatitis and prostate cancers. GGT is clinically important because of its sensitivity to detect alcohol abuse .

40. Acid Phosphatase Acid phosphatase (ACP) hydrolyses phosphoric acid ester Reference serum value 2.5–12 U/L. Secreted by prostate cells, RBC, platelets and WBC.

41. The prostate isoenzyme is inactivated by tartaric acid . ACP increased in Prostate cancer Bone metastasis of prostate cancer. In these conditions, the tartrate labile isoenzyme is elevated. This assay is very helpful in follow-up of treatment of prostate cancers. So, ACP is an important tumor marker .

42. Since blood cells contain excess quantity of ACP, care must be taken to prevent hemolysis while taking blood from the patient.

43. Amylase This enzyme splits starch to maltose. Activated by calcium and chloride ions. Produced by pancreas and salivary glands. Reference serum value 50–120 IU/L.

44. Moderate increase in serum levels Chronic pancreatitis Mumps ( parotitis ) Obstruction of pancreatic duct.

45. Markedly increased levels Acute pancreatitis which is a life-threatening condition. Values peaks between 5–12 hours after the onset of disease and returns to normal levels within 2–4 days after the acute phase has subsided.

46. Reference value of amylase in urine is less than 375 U/L. It is increased in acute pancreatitis. It is increased on the 1 st day and remains to be elevated for 7–10 days.

47. Enolase It is a glycolytic enzyme. Neuron-specific enolase (NSE) is an isoenzyme seen in neural tissues and Apudomas .

48. NSE is a tumor marker for Carcinoid tumor Neuroblastoma Pheochromocytoma Medullary carcinoma of thyroid,

49. Lactate dehydrogenase Present in heart, brain, liver and skeletal muscle Lactate to pyruvate Normal serum LDH level is 100-200 U/L Any increase in the LDH level suggests tissue damage

50. Creatine Kinase (CK) -Brain, heart and skeletal muscle. -Normal serum levels of CK - 15 - 100 U/L in males - 10 - 80 U/L in females. -CK-BB -CK-MM -CK-MB -Brain type can indicate a stroke or a brain tumour

51. -After a heart attack, CK shows up more rapidly in the blood than LDH. In myocardial infarction, CK levels (CK – MB isoenzyme ) start to rise within 3 – 6 hours of infarction.

52. Monitoring the presence of both enzymes extends the possibility of diagnosis, which is useful, since a very mild heart attack might be difficult to diagnose. An elevated level of the isozyme from heart in blood is a definite indication of damage to the heart tissue

53. Enzyme deficiency disorders Inherited disorders with loss/ decreased enzyme activity Increased amount of substrate in serum Prenatal diagnosis in amniotic fluid Examples Galactosemia Glucose-6-phosphatase dehydrogenase deficiency Phenylketonuria Albinism, alkaptonuria etc

54. Glucose-6-phosphate Dehydrogenase Important enzyme in hexose-monophosphate shunt pathway of glucose. Deficiency – inborn error of metabolism X – linked recessive It is mainly used for production of NADPH.

55. Drug-induced hemolytic anemia : In the GPD deficient individuals, RBC lifespan may be reduced, without disease manifestations. But when they take certain drugs ( aspirin , mepacrine , primaquine , sulpha ), there will be sudden damage to RBCs. Fava beans (star beans, corner beans) may also induce hemolytic anemia which is called favism .

56. Carrier State has Biological Advantage The gene for GPD is located in X-chromosome . In heterozygous condition, the GPD level in RBC is half the normal value. GPD deficiency seems to protect the person from falciparum malaria . The malarial parasites require NADPH for optimal growth.

57. Met- hemoglobinemia : NADPH Met-hemoglobin hemoglobin

58. Galactosemia

59. Galactose-1-phosphate uridylyltransferase  Classic  galactosemia Inborn error of galactose metabolism Autosomal recessive Symptoms - Jaundice Vomiting Poor weight gain Irritability Seizures

60.  Phenylalanine hydroxylase Phenylketonuria Genetic disorder inherited. It is due to mutations in the PAH gene This results in the buildup of dietary phenylalanine to potentially toxic levels.

61. Homogentisate 1,2 - dioxygenase

62. Albinism

63. Albinism Genetic condition – X linked recessive Defeciency of tyrosinase Lacks melanin pigment Affects eye, skin, hair

64. Enzymes as Therapeutic Agents Streptokinase (from Streptococcus) or Urokinase (from urine) can lyse intravascular clots and are therefore used in myocardial infarction. Pepsin and trypsin are given to patients with defective digestion. Asparaginase is used as an anticancer drug. Streptodornase with streptokinase used to facilitate drainage in septic surgical conditions

65. Enzyme in Diseases I. Hepatic diseases Alanine aminotransferase (ALT): Marked increase in parenchymal liverdiseases Aspartate aminotransferase (AST): Elevated in parenchymal liver disease Alkaline phosphatase (ALP): Marked increase in obstructive liver disease Gamma glutamyl transferase (GGT): Increase in obstructive and alcoholic liver

66. II. Myocardial infarction Creatine kinase (CK-MB): CK-MB isoenzyme is specific III. Bone diseases Alkaline phosphatase (ALP) Marked elevation in rickets and Paget’s disease

67. IV. Muscle diseases Creatine kinase (CK-MM): Marked increase in muscle diseases. Aspartate aminotransferase (AST): Increase in muscle disease; not specific Aldolase (ALD): Earliest enzyme to rise, but not specific

68. V. Prostate cancer Acid phosphatase (ACP): Marker for prostate cancer. Metastatic bone disease especially from a primary form prostate. Inhibited by L tartrate . VI. Pancreatic disease Amylase: Marker for acute pancreatitis and inflammation of salivary glands Lipase: Marker of pancreatitis, more specific than amylase

69. References Harper’s textbook of biochemistry Textbook of biochemistry . Rafi M D Tietz fundamentals of clinical chemistry

70. Thank you