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Elevated Level of Enzymes

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The investigation of changes in serum enzymes in diseases is one of the most rapidly expanding fields in clinical biochemistry .Wroblewski and his co werkers in 1956 published their first paper on serum Glutamate-oxaloacetate transaminase (S-GOT) and followed by serum lactate dehydrogenase and brought the possibilities of these enzymes assays in general notice.Thus begun the present efflorance of clinical enzymology and large number of enzymes have been used for diagnosis and prognosis of various disesases.

Sources of Plasma Enzymes: They Can Be Plasma Derived or Cell Derived

Plasma derived enzymes act on substrates in plasma, and their activity is higher in plasma than in cells e.g coagulation enzymes

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Cell derived enzymes have higher activity in cells and overflow into the plasma they are further subdived into:

  1. Secretory: these are mainly derived from digestive glands and function in the extracellular space
  2. Metabolic: these are concerned with intermediary metabolism and function in cells and those enzymes found in the plasma are mainly derived from the soluble and microsomal fractions of the cell.

The cell-derived enzymes enter the plasma in small amounts as a result of continuous normal ageing of the cell or owing to diffusion through undamaged cell membranes. They leave the plasma through inactivation, catabolism in general protein pool and rarely excretion in bile and urine.

Possible mechanism responsible for abnormal level: serum level of a particular enzyme may be increase by diseases that provoke increase in its rate of release or decrease in rate of disposition or excretion.

Increased Serum Level

Increased Release:

  1. Necrosis of cells: due to damage to cells of the tissue. The resultant pattern will depend on normal enzyme content of the tissue/organ and on the extent and type of necrosis.
  2. Increased permeability of cell membrane without necrosis of cells can increase the enzyme level , e.g in early stage of viral hepatitis before jaundice appears. There is ‘ballooning’ degeneration of liver cells, leading to elevated levels of transaminases (S-GPT) And in progressive muscular dystrophy-elevated levels of aldolase, GOT and CPK.
  3. Increased production of the enzyme within cell: such a situation may be seen in treatment of patients with protein anabolic drugs, results in increased synthesis of liver cell transaminases and serum transaminases will increase by overflow.
  4. An increase in tissue source of enzymes due to either increased rate of production in cells or increase in number of cells/and cell mass, as seen in malignancies e.g alkaline phosphatase increase in patients with osteoblastic bone lesions, or acid phosphatase increase in patients with carcinoma prostate.

Impaired Disposition/Excretion:

  • Increased levels of serum ALP and LAP seen in patients with obstructive jaundice
  • Certain increased enzyme levels in cases of renal failure.

Decreased Serum Levels:

  • Decreased formation of the enzyme which may be genetic such as in hypophosphatasia, with decreased ALP level in serum and Wilson’s disease with decreased in serum ceruloplasmin and acquired such as in hepatitis decreased serum level of pseudocholinesterase due to decreased production and decreased serum amylase in patients with chronic hepatic, or pancreatic disease or those who are severely malnourished.
  • Enzyme inhibition such as decreased serum pseudocholinesterase in insecticide poisoning.
  • Lack of cofactors such as decreased serum GOT level in pregnancy and cirrhosis.

Single or serial assay of the serum enzyme activity of a selected enzyme or enzymes may provide information on the nature and extent of a disease process. For the right diagnosis of particular disease, it is always better to estimate few (3 or more ) serum enzyme instead of single enzyme.

Serum Enzymes in Heart Diseases:

Before the introduction of serum GOT assay for the investigation of mycordial infraction the heart had been a “biochemically inaccessible”organ. In cases of suspected of suspected myocardial infaraction when clinical and ECG evidence was equivocal, there was no other means of specifically investigating possible injury to cardiac muscle.

Why Enzyme Diagnosis?

  1. 25-30 per cent of myocardial infarctions are not diagnosed ‘antemortem’ sometimes.
  2. Clinical diagnosis and angiographic studies do not correlate in 25-30 per cent of patients.

ECG findings may not be helpful if:

  1. Prior left bundle branch block is present.
  2. Intramural infarctions may not change ECG pattern.
  3. Diaphragramic infarctions often missed on ECG.

Enzyme Assay That are Carried Out in Myocardial Infarction are

Creatine phosphokinase: it is found in high concentration in skeleton muscle ,myocardium and brain but not in liver and kidney. Its normal value is 4 -60 IU/L.

Behaviour in acute myocardial infraction: After myocordial infraction serum value is found to be increased after 6 hours, reaches a peak level in 24 to 30hours.It is a Sensitive indicator in early stage of myocardial ischaemia, potentially more useful in subendocardial infraction. Magnitude of elevation was found to be greater than the observed with GOT or LDH. No increase in activity noted in heart failure and coronary insufficiency.

Aspartate transaminase or serum glutamateoxaloacetate transaminase (SGOT):

  • Concentration of this enzyme is very high in myocardium
  • Normal value: it varies from 4-17IU/L
  • Behaviour in acute myocardial infraction:In acute myocardial infarction, serum activity rises sharply within the first 12 hour with a peak level at 24 hours.
  • Level of serum enzyme has been well correlated with prognosis.
  • Levels greater than 350IU/L usually fatal(massive infraction).
  • Levels greater than 150IU/L associated with high mortality .
  • Levels greater than 50IU/L associated with low mortality.
  • Elevation has been noted in absence of any ECG change.
  • Highest incidence of abnormal level occurs on second day of infraction.

Extracardiac factors: Elevation seen in other diseases e.g muscle disease and hepatic diseases. But these can be differentiated clinically and simultaneous determination of S-GPT. There is no rise of S-GPT in myocardial infarction.

Lactate Dehydrogenase

Normal serum LDH activity ranges from60-250IU/L .

Behavior in myocardial infraction: In acute myocardial infraction serum activity rises within 12-24 hour, attains peak at 48 hour reaching about 1000 IU/L. Thus, LDH is the last enzyme to rise.The peak rises in S-LDH is roughly proportional to extent of injury to myocardial tissue. S-LDH level greater than 1500IU/L in acute myocardial infarction suggests a grave prognosis. The enzyme is relatively non-specific for myocardial tissue. It is so widespread in body cells that coexistence disease process in other organs may cause elevations. Thus, S-LDH levels are raised in carcinomatosis, pulmonary infarction, renal necrosis, acute leukaemias, granulocytic leukaemia muscle diseases etc.

Alpha Glutamyl Transpeptidase (G-GPT)

Normal value: In male: 10-47IU/L in female: 7-30IU/L

Site: Highest tissue activity of this enzyme is found in kidneys but activity is relatively high in liver, lung, pancrease and prostate. Normal heart contain very litter alpha GT.

Behavior in acute myocardial infraction: Its level increases in serum in acute myocardial infarction. Increase serum activity is found to be late, peak activity between 7 and 11 day and last as long as month.Hence, It is useful test in myocardial infraction at later stages. Its level is also increases in some other diseases like hepatobilliary disorders such as obstructive jaundice, cholangitis and cholecystitis, with primary and secondary neoplasms of liver. Also found elevated in alcoholics and alcoholic cirrhosis. Elevated levels are also seen in opileptic patients with drug therapy with anticonvulsants, probably due to enzyme induction. Since serum alpha-GT are not elevated in any form of bone disorders so it is valuable parameter in differentiating between skeletal(bone) and hepatic dysfunction associated with increased serum ALP.

Histaminase

The enzyme histaminase occurs in different organs in various species. In man, however, normal plasma contains either very small amount of histaminase or none at all but considerable amount is found in human heart muscles

Normal value: 0.1 to 0.76 PU/ml

Behavior in myocardial infraction: Its activity rises within 6 hour of myocardial infraction. It helps in early diagnosis of myocardial infraction even when ECG fail to reveal.

Cholinesterases:

  • It hydrolyze esters of choline to give choline and acid
  • There are two types of this enzyme..
  • True cholinestrases (nerve tissues)
  • Pseudo cholinestrases (heart muscles)
  • Normal value: 2.17-5.17IU/L

Behavior in myocardial infraction: elevation of plasma pseudocholinesterase was observed in 90.5 per cent cases of acute myocardial infarction.Its raised serum activity is found within 12 hour or sometimes within 3 hours.

Serum enzyme activity has been considered as a sensitive index for determination of cellular necrosis in myocardium.

In other diseases like in acute hepatitis its serum enzyme activity is decreased. Its regular low level in chronic hepatitis is often found more valuable. In organophosphorous poisoning cholinesterase is inhibited by organophosphorous compound and serum cholinesterase is therefore useful to detect poisioning.

Diagnostic Applications of Enzyme in Liver Diseases

First diseases against which serum enzymes were applied. Test were successful because of large size of organ, wide variety and abundance of enzyme.

The following when elevated in serum are useful for the diagnosis of liver disfunction.

Alanine Transaminase(ALT)

Function:it is found in plasma and in various body tissues but is most common in liver..

Aspartate Transaminases(AST)

It is found in liver heart skeletal muscles kidney brain and RBC.

Two isoenzymes are present:

GOT1/CAST the cystolic isoenzyme derives mainly from red blood cells and heart GOT2/MAST the mitochondrial isoenzyme present predominantly in liver.

Normal level of ALT ranges from 7-56 unit/litre and 10-40 units/litre for AST. Mild elevations are generally considered to be 2-3 times higher than normal rage. In some conditions,these enzymes can be severally elevated in the 1000s range. Elevated level of liver enzyme generally signify damage or injury. The most common disease causing abnormally elevated ALT or AST are acute viral liver infectious (e.g Hep A and Hep B), Chronic viral Hepatitis (Hep B and Hep C ), Cirrhosis of the liver, Liver damage from alcohols abuse or alcoholic fatty liver, Hemochromatosis, Diminished blood flow to liver, hepatocellular carcinoma, metastatic cancer of the liver, Auto attack immune hepatitis, fatty liver or steatohepatitis. Certain medications overdose can also causes abnormal AST or ALT level such as acetaminophen (Tylenol liver damage)

The enzyme that markedly increase in intra hepatic and extra hepatic cholestasis are alkaline phosphatase and 5-nucleotidase

Serum R-Glutmile Transpeptidase:

It is present in cell membrane of many tissues but most notable in liver and has significant in medicine as a diagnostic maker. Its elevated level is used in diagnosis of alcoholic liver diseases also it is useful in detecting obstructive jaundice,chonangitis and cholecystitis with primary and secondary neoplasm of liver. Also found elevated in alcoholics and also in alcoholic cirrhosis.GT is the most common sensitive indicator in alcoholics.

Lactate dehydrogenase : it is found in liver heart pancrease and kidney.

It is released during tissue damage. It is a maker of diseases.Normal value of LDH ranges from 140-280 units/litre. It helps in diagnosis of myocardial infraction, infective hepatitis, leukemia, muscular diastrophy, lung diseases.They also help determine how well chemotherapy is working during treatment for lymphoma and its increased activity is an indicator of liver diseases.In acute viral hepatitis LDH predominate.After damage to either of the tissues that is myocardium or liver total serum LDH is increased and it may be useful to know the origin of this enzyme increase.

Serum Enzymes in Cancer

Chief enzymes assays useful in cancer are :

Acid phosphatase :

There are two types depending upon activity in different PH

A type of acid phosphatase (PH=6.0) found in erythrocytes.

A type of acid phosphatase (PH=5) found in kidney plasma liver pancrease, prostate epithelium

Normal value: normal serum contains small amount of acid phosphatase 0.6-3.1K.A units/100ml

Precautions: It is extremely labile enzyme.Enzyme assays should be done on fresh samples immediately and also avoid haemolysis.

Clinical diagnostics: Main relation in diagnosis of metastatic prostate carcinoma. Enzyme is formed from mature prostatic epithelial cells. Its level also rise is Gaucher’s disease, paget’s disease, hyperparathyroidism, osteolytic metastasis from breast and other carcinomas. Marked rise with thrombocytosis, myeloproliferative disorders chronic granulocytic leukaemia etc.

Beta Glucuronidase

Though it not routinely done it is useful in certain cancers. Beta glucuronidase catalyzes glucurunotransferase reactions as well as hydrolysis of beta-D-glcuopyaranosides by mean of which its activity is usually estimated. It is widespread in human tissues but most abundant in liver, spleen, endometrium, breast and adrenals.

Normal value: for males range from 210-550m-IU and for females 90-400m-IU

Diagnosis

Serum and urinary beta glucuronidase activity is increased markly in cancer of urinary bladder. Very high activity is reported in carcinoma of head of pancrease and in 50 per cent of cases of breast and cervix cancer without liver metastasis. Its activity also increases in last trimester of pregnancy. Assay of beta-glucourinoidase activity of vaginal fluid has been suggested as useful in diagnosis of malignancies of female genital tract.

Enolase: it is a glycolytic enzyme.

Diagnostics application:Higher concentration of enolase in cerebrospinal fluid more strongly related to low grade astrocytoma.The same study show that fastest rate of tumour growth occur in patients with high level of CSF enolase.

5-nucleotidase :

Its normal level is 2-17U/L

Clinical significance:The concentration of 5nucleutidase protein in the blood is often used as a liver function test in individuals that show signs of liver problems. The combined assays of serum 5 nucleutidase and alkaline phosphatase are extremely helpful in diagnosis of obstructive hepatobiliary disorders, Cholestasis, distruction of liver cells, hepatitis liver ischemia,liver tumor.

Serum Enzymes in Muscle Diseases

Skeletal muscle disorders include the diseases of muscle fibres or of muscle nerves.In these disorders LD, ALD and ALT level are raised. In muscular diastrophy LDH-5 is increased.

Serum CPK: Assays of aldolase has been replaced by serum CPK which is more sensitive and more specific. . In case of neurogenic diseases that is Neurogenic muscular atrophy and hereditary diseases, CPK is raised. Raised value are seen in most cases of muscular dystrophy and dermatomyositis of usually 1000IU/L. It is highly elevated in crush injuries fractures and acute cerebro muscular accidents. Highest values are found in deuchenne type of muscular dystrophies.The increased is most marked in acute phase, in early childhood, the actual value depends upon both: severity of the disease and on mass of diseased muscle. The rise occur before the clinical manifestation and serum enzyme level used to detect”carriers”. Raised value are also found in hypothyroidism owing to secondary muscle diseases.

AST: It is important to keep in mind that the source of AST in blood test may reflect pathology in organ other than liver. Infact when the AST is higher than ALT, a muscle source of these enzyme should be considered. For example, muscle inflammation due to dermatomyositis may cause AST greater than ALT.

Serum Aldolase

Aldolase was until recent years the enzyme of choice in investigation of diseases of muscles being more sensitive than GOT. It is found in high concentration in muscle, brain and neoplastic tissue. Its normal value is 2-6 m-IU. Its level in increase in dermatocytositis, deuchenne type of muscular dystrophy.

Enzymes in cerebrospinal fluid:

  • Lactate dehydrogenase is increased in CSF in meningitis.
  • Enzyme in diagnosis of bone diseases

Serum Alkaline Phosphatase

ALP remains the only useful enzyme assay for investigation. It is most valuable index of osteoblastic activity. Increase in serum ALP activity seen in rickets, osteomalacia, hyperparathyroidism and particularly in Paget’s Disease (Pelvis, skull, spine and legs). In primary and secondary malignancies of bone, the level depends on the severity and degree of new born formation. In hypophosphatasia, where there is defective calcification, low tissue and serum ALP activity is observed.

Serum enzyme in tract diseases:The enzyme of GI origin which is regularly assayed is serum amylase. The other enzyme is serum lipase but it is not routinely done in most of laboratories.

Serum Amylase

When pancreas is damage, amylase is released into the blood. Its normal range is 80-180 somogy units/100ml. The peak value is observed within 8-12 hours after the onset of disease.

Clinical diagnosis: serum amylase assay is the investigation of choice in the diagnosis of acute pancreatitis. Its activity is seen greater than 1000units.In other diseases as amylase is secreted in the parotid glands, raised serum values not exceeding 1000 units, are usually found in mumps and other form of Parotitis and also when there is salivary duct stone. This may be of value occasionally in differential diagnosis of Meningoelcephalitis and in facial swellings of other causes. A raised serum amylase though not exceeding 500 units is often found in other acute abdominal catastrophes like Perforated peptic ulcer and Intestinal obstruction. After administration of opiates raised value may be seen.

Serum Lipase

It is more specific in pancreatic disorder and remains raised for longer periods. Its normal value is 9-20m IU. Increase in serum lipase is a reflection of pancreatic disorders. In acute pancreatitis serum lipase activity increases promptly at the time of onset of symptoms, values as high as 2800U/L having been reported.Elevated serum lipase level also reported in perforated duodenal and peptic ulcer and in intestinal obstruction Moderate increase in serum lipase were found in about 1/3 patient with cirrhosis. In normal cases duodenal juice amylase is increased and serum level is unaltered. In chronic pancreatitis duodenal juice value is unaltered but serum level increases.

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