Disseminated Intravascular Coagulation (DIC) is a disorder of coagulation that always occurs in the presence of one or more underlying conditions in patients. It is not a disease process that occurs on its own; rather it is the product of an underlying illness that can overwhelm the body. In this disorder the coagulation cascade is thrown so out of balance that thrombosis and hemorrhage can occur at the same time. DIC is defined as the systemic activation of the coagulation system within the blood vessels that leads to depletion of clotting factors, multiple organ damage, and eventually death.
Although the actual mechanism is extremely complex, in general there are four processes that are responsible for the coagulation imbalance that is DIC. To begin to understand these processes it is necessary to remember the coagulation cascade. The instrinisc pathway is activated by procoagulants such as lipids and high molecular weight kininogen within the blood vessels causing clotting factors to activate all the way down the cascade until factor X activates the cleavage of prothrombin to thrombin. In the extrinsic pathway tissue factor activates the pathway and clotting factors are activated until factor X activates thrombin as well. The big picture here is that thrombin is made and thrombin converts fibrinogen into a fibrin clot. In DIC the first process that goes wrong is that thrombin is generated out of control in vast amounts. This constant generation of thrombin depletes the body of clotting factors and platelets. This excess of thrombin in the body also promotes the generation of fibrin clots throughout the vasculature. The second process that goes wrong is that the regulatory proteins that keep thrombin in check are themselves overwhelmed. Antithrombin III, Protein C, and Protein S all normally would work together to limit the action of thrombin. However in DIC these proteins are incapacitated for various reasons. Most notably antithrombin III is constantly consumed during the process of coagulation. It is degraded by the enzyme elastase which is produced by neutrophils that are activated by inflammatory response. Protein C and Protein S are also degraded by cytokines given off in the inflammatory response. Finally production of all three of these proteins is affected once microvascular damage occurs to the liver. The third process that becomes impaired is fibrinolysis. Fibrinolysis is the breakdown of clot formation. This occurs when plasminogen is converted to plasmin which acts upon fibrinogen, fibrin, and fibrin clots. The endothelial cells of blood vessels release chemicals that activate and inhibit plasminogen. In DIC the destruction of vessel walls and the constant consumption of coagulants overwhelm this system causing levels of plasmin to increase out of control (just like thrombin). The result is that plasmin inhibitors are overwhelmed and fibrin/fibrinogen degradation products are produced in great amounts. The fourth process that occurs is inflammatory activation. This is really a circular process as both DIC and the inflammatory state feed off of each other. It is believed that the underlying medical condition sets in motion an inflammatory state which introduces procoagulants (tissue factor, bacteria, lipids, etc.) into the system causing the coagulation cascade to set itself in motion. Many clotting factors, once activated, actually stimulate the release of cytokines from the vascular endothelium to promote inflammation which causes normal events like platelet and neutrophil aggregation. In DIC this adds fuel to the fire. Clots begin to settle into vascular walls and into organs causing more tissue damage and the release of more procoagulants thus propagating the cycle further. At this point the body has no way to bring the system back into balance and without treatment of the underlying condition death will occur.
There are many illnesses that can cause DIC and depending on what type of illness a patient has can determine whether or not DIC is acute or chronic. In acute DIC large amounts of procoagulants are released into the bloodstream within a very short period of time. In this short time the consumption of clotting factors and platelets occurs far more rapidly than the body can replenish them causing mass bleeding. Acute DIC is usually caused by systemic infections due to bacteria but can be caused by viruses, parasites, and even fungi. The idea with acute DIC is that the underlying medical condition is something that damages the body quickly. Other events that can trigger acute DIC include any type of severe trauma, burns, transfusions, obstetric complications, and even snake bites. Some disease states can also provide the right conditions to allow for the development of acute DIC. Acute hepatic failure can trigger a state of acute DIC as can acute myelocytic leukemia. It is important to monitor and treat the underlying condition in order to prevent the possibility of the development of DIC. Chronic DIC is different in that the body is able to compensate for the consumption of coagulation factors and platelets. The body is able to compensate because smaller amounts of procoagulant are being released into the body over a longer period of time. Partners of chronic DIC include diseases such as rheumatoid arthritis, sarcoidosis, ulcerative colitis, and crohn disease. Cancers such as solid tumors, leukemias, and myeloproliferative disorders can also lead to DIC. Even retained products of conception from either miscarriage or an abortion can cause chronic DIC. The key to chronic DIC is that the procoagulant in question leaks into the system slowly over a period of time. In chronic DIC there is little chance for the massive bleeding that is seen with acute DIC, however the chance for tissue and organ damage is just as great.
In order to determine if DIC is present the doctor must use both clinical and laboratory findings. Laboratory testing includes both hematology and coagulation testing. The most important finding early on in patients suspected of having DIC is thrombocytopenia. This can be found by simply running a CBC with differential. When seen under a microscope a peripheral smear will usually include schistocytes, the presence of a left shift in leukocytes, and possibly large young platelets. This would all reflect the presence of clotting in vessels, inflammation, and the high turnover of platelets. The normal values for platelets is age dependent, however the critical value cutoff is around <50,000 platelets/uL and any value under this would certainly be considered thrombocytopenic. The remaining testing is all coagulation. The prothrombin time and activated thromboplastin time will be prolonged since clotting factors are being constantly consumed. Although normal value will differ from lab to lab generally normal ranges for PT are around 9.0-11.0 seconds and for APTT are around 24.0-33.0 seconds. Fibrinogen levels are expected to be decreased since thrombin is busy using it up to make fibrin. However fibrinogen is an acute phase reactant, which will increase in levels in cases of inflammation, so sometimes the levels will remain within normal ranges. A general normal range is 200-475 mg/dL for fibrinogen. The final test that can be run is d-dimer. D-dimer is a degradation product of the cross-linked fibrin polymers that are broken apart during fibrinolysis. D-dimer levels are usually elevated in cases of DIC due to constant formation of fibrin and fibrinolysis. However d-dimer levels are also high after surgery, in cases of trauma, in infections and in cases of inflammation so theses results have to be used in conjunction with other findings. A general normal range for d-dimer is 0.0-3.0 mg/L.
Currently there is no definitive treatment for DIC. The best course of treatment for the patient is to treat the underlying illness in order to rid the body of the procoagulants causing DIC. Through the course of treatment replacement of platelets and clotting factors can be given if needed, however this is only done to stop active bleeding. Although it seems to be common practice there has been no definitive data that giving heparin to reverse the coagulation process is of any benefit to the patient. Heparin will inactivate thrombin but it can only be given to DIC patients in small controlled amounts in order to prevent bleeding. Currently research is being done on giving patients antithrombin III and activated protein C. This research looks promising but the trials are still in their early stages. In the end the best that can be done for the patient is diligent laboratory work and treatment by the clinicans.
References
* Kusuma, B., Schulz, T. (2009). Acute Disseminated Intravascular Coagulation. Hospital Physician, 35-40. Retrieved December 5, 2009 from http://www.turner-white.com/memberfile.php?PubCode=hp_mar09_coagulation.pdf
* Riley, R. (2005). Disseminated Intravascular Coagulation. Retrieved December 5, 2009 from http://www.pathology.vcu.edu/clinical/coag/DIC.pdf
* Becker, J., Wira, C. (2009). Disseminated Intravascular Coagulation. Emedicine from WebMD. Retrieved December 5, 2009 from http://emedicine.medscape.com/article/779097-overview
Sunday, May 30, 2010
Saturday, May 29, 2010
Lactic Acid
Lactic acid is produced and used in the body as a part of carbohydrate metabolism. Under normal circumstances this molecule is very useful to the body and plays an integral role in supplying the body with the energy it needs. However when metabolism is upset due to illness or injury lactic acid can build up in the tissues and the blood. Clinicians can monitor the levels of lactic acid in the body to monitor some disease states and their respective treatments.
Lactic acid is produced and used by the body. All cells can break glucose down into pyruvate via glycolysis; the first step of carbohydrate metabolism. This occurs in the cytoplasm of all cells. Pyruvate is broken down further to produced ATP. This is done in two ways. It can either diffuse into the mitochondria of a cell in order to enter into the Citric Acid cycle (Krebs cycle) or it can be broken down into lactate by lactate dehydrogenase. The Citric Acid cycle produces more ATP and less waste in comparison to the amount of ATP produced when lactate is made. However not all cells have mitochondria (i.e. erythrocytes) nor is there always enough oxygen present in cells to run the Citric Acid cycle. The main producers of lactate are skeletal muscle, erythrocytes, the brain, and the gut. The lactate produced by these cells will diffuse out into the blood stream and be picked up by another group of cells who will convert lactate back to glucose. Lactate metabolizers include the cells of the liver, the heart, and the kidneys.
When the body does not have an adequate supply of oxygen for glucose metabolism pyruvate is converted to lactate in the cells. The ATP created is then hydrolyzed to release the energy needed from its phosphate bond. The byproducts of this reaction are hydrogen ions, ADP, and a Pi ion. Under the normal conditions of the Citric Acid cycle these products would be recycled in the presence of oxygen, however in a hypoxic environment the constant hydrolysis of ATP leads to the accumulation of hydrogen ions causing a state of acidosis. It is important to note that it is the accumulation of these hydrogen ions and not the accumulation of lactate that causes acidosis. As lactate molecules leave a cell they give up a hydroxyl anion (OH-) and pick up a hydrogen ion to form lactic acid. The spare hydroxyl anion picks up another hydrogen ion to form water. This is one way that the excess hydrogen ions are buffered out. Lactate also acts as a buffer in that it can absorb extra hydrogen ions in the reverse reaction back into pyruvate via the enzyme lactate dehydrogenase. This occurs naturally as needed. In a healthy person these buffering capabilities are enough to keep the body balanced and avert a possible acidosis state; however under the conditions of illness and tissue hypoxia lactate production can spiral out of control and add to the problem.
Lactate levels are drawn by clinicians in order to evaluate and monitor conditions where there is a chance that tissue hypoxia or acidosis is occurring. Such conditions include sepsis, shock, heart attack, coma, seizures, uncontrolled diabetes, liver failure, and renal failure. Because lactate is normally being made in the body the normal range in plasma is around 0.4-2.0 mmol/L. A patient is generally considered to have hyperlactatemia once lactate levels rise between 4-5 mmol/L. Hyperlactatemia is a state of increased lactate levels with adequate tissue oxygenation and adequate acid-base balance. This can occur in liver failure and sepsis patients before tissue hypoperfusion sets in. The National Surviving Sepsis Campaign recommends that all patients at risk for sepsis have a baseline lactate level drawn upon admission and all patients with a lactate level >4 mmol/L are entered into special early goal-directed therapy. Hyperlactatemia is different from lactic acidosis. Lactic acidosis is the term given when lactate levels are increased and there is a disruption in the acid-base balance creating a state of acidosis. There are two levels of lactic acidosis. Type A is lactic acidosis with poor tissue perfusion and Type B is lactic acidosis with normal tissue perfusion. Type A cases are usually due to events that cut off oxygen supply such as shock, heart attacks, and strokes. Type B cases are usually due to illnesses such as diabetes, liver failure, drugs, toxins, and inborn errors of metabolism. Lactate can also be measured in cerebrospinal fluid. Lactate levels in CSF will be increased in the event of strokes, intracranial hemorrhage, epilepsy, and most importantly bacterial meningitis. Lactate levels in CSF are usually ordered in order to distinguish between bacterial and viral meningitis. Normal levels for lactate CSF are around 0.6-2.2 mmol/L.
Lactate levels are not a diagnostic marker of disease; rather they are another tool provided by the laboratory that clinicians can use to monitor disease states. When used in conjunction with other testing, lactate levels can tell a clinician whether or not a patient is metabolizing glucose correctly. It can also show that the body is metabolizing lactate correctly. A lactate level in conjunction with other testing can show whether or not the body is getting enough oxygen. More importantly this test can be used as a marker for monitoring patient treatment. It is currently the gold standard test to start and monitor treatment for sepsis patients. It is both an interesting metabolite and an insightful test.
References
· Gunnerson, K., Sat, S. (2009). Lactic Acidosis. Emedicine from WebMD. Retrieved on December 20, 2009 from http://emedicine.medscape.com/article/167027-overview
· Lactate. (2009). Lactate: The Test. Lab Tests Online. Retrieved on December 20, 2009 from http://www.labtestsonline.org/understanding/analytes/lactate/test.html
· Serum Lactate Measured. (2009). Implement the Sepsis Resuscitation Bundle: Serum Lactate Measured. Institute for Healthcare Improvement. Retrieved on December 20, 2009 from http://www.ihi.org/IHI/Topics/CriticalCare/Sepsis/Changes/IndividualChanges/SerumLactateMeasured.htm
· Kraviz, L. (2004). Lactate: Not Guilty as Charged. Retrieved on December 20, 2009 from http://www.unm.edu/~lkravitz/Article%20folder/lactate.html
· Burtis, C. A., Ashwood, E. R., Bruns, D. E., Tietz Textbook of Clinical Chemistry & Molecular Diagnostics. St. Louis, Missouri: Elsevier (2006). p. 877-878.
Lactic acid is produced and used by the body. All cells can break glucose down into pyruvate via glycolysis; the first step of carbohydrate metabolism. This occurs in the cytoplasm of all cells. Pyruvate is broken down further to produced ATP. This is done in two ways. It can either diffuse into the mitochondria of a cell in order to enter into the Citric Acid cycle (Krebs cycle) or it can be broken down into lactate by lactate dehydrogenase. The Citric Acid cycle produces more ATP and less waste in comparison to the amount of ATP produced when lactate is made. However not all cells have mitochondria (i.e. erythrocytes) nor is there always enough oxygen present in cells to run the Citric Acid cycle. The main producers of lactate are skeletal muscle, erythrocytes, the brain, and the gut. The lactate produced by these cells will diffuse out into the blood stream and be picked up by another group of cells who will convert lactate back to glucose. Lactate metabolizers include the cells of the liver, the heart, and the kidneys.
When the body does not have an adequate supply of oxygen for glucose metabolism pyruvate is converted to lactate in the cells. The ATP created is then hydrolyzed to release the energy needed from its phosphate bond. The byproducts of this reaction are hydrogen ions, ADP, and a Pi ion. Under the normal conditions of the Citric Acid cycle these products would be recycled in the presence of oxygen, however in a hypoxic environment the constant hydrolysis of ATP leads to the accumulation of hydrogen ions causing a state of acidosis. It is important to note that it is the accumulation of these hydrogen ions and not the accumulation of lactate that causes acidosis. As lactate molecules leave a cell they give up a hydroxyl anion (OH-) and pick up a hydrogen ion to form lactic acid. The spare hydroxyl anion picks up another hydrogen ion to form water. This is one way that the excess hydrogen ions are buffered out. Lactate also acts as a buffer in that it can absorb extra hydrogen ions in the reverse reaction back into pyruvate via the enzyme lactate dehydrogenase. This occurs naturally as needed. In a healthy person these buffering capabilities are enough to keep the body balanced and avert a possible acidosis state; however under the conditions of illness and tissue hypoxia lactate production can spiral out of control and add to the problem.
Lactate levels are drawn by clinicians in order to evaluate and monitor conditions where there is a chance that tissue hypoxia or acidosis is occurring. Such conditions include sepsis, shock, heart attack, coma, seizures, uncontrolled diabetes, liver failure, and renal failure. Because lactate is normally being made in the body the normal range in plasma is around 0.4-2.0 mmol/L. A patient is generally considered to have hyperlactatemia once lactate levels rise between 4-5 mmol/L. Hyperlactatemia is a state of increased lactate levels with adequate tissue oxygenation and adequate acid-base balance. This can occur in liver failure and sepsis patients before tissue hypoperfusion sets in. The National Surviving Sepsis Campaign recommends that all patients at risk for sepsis have a baseline lactate level drawn upon admission and all patients with a lactate level >4 mmol/L are entered into special early goal-directed therapy. Hyperlactatemia is different from lactic acidosis. Lactic acidosis is the term given when lactate levels are increased and there is a disruption in the acid-base balance creating a state of acidosis. There are two levels of lactic acidosis. Type A is lactic acidosis with poor tissue perfusion and Type B is lactic acidosis with normal tissue perfusion. Type A cases are usually due to events that cut off oxygen supply such as shock, heart attacks, and strokes. Type B cases are usually due to illnesses such as diabetes, liver failure, drugs, toxins, and inborn errors of metabolism. Lactate can also be measured in cerebrospinal fluid. Lactate levels in CSF will be increased in the event of strokes, intracranial hemorrhage, epilepsy, and most importantly bacterial meningitis. Lactate levels in CSF are usually ordered in order to distinguish between bacterial and viral meningitis. Normal levels for lactate CSF are around 0.6-2.2 mmol/L.
Lactate levels are not a diagnostic marker of disease; rather they are another tool provided by the laboratory that clinicians can use to monitor disease states. When used in conjunction with other testing, lactate levels can tell a clinician whether or not a patient is metabolizing glucose correctly. It can also show that the body is metabolizing lactate correctly. A lactate level in conjunction with other testing can show whether or not the body is getting enough oxygen. More importantly this test can be used as a marker for monitoring patient treatment. It is currently the gold standard test to start and monitor treatment for sepsis patients. It is both an interesting metabolite and an insightful test.
References
· Gunnerson, K., Sat, S. (2009). Lactic Acidosis. Emedicine from WebMD. Retrieved on December 20, 2009 from http://emedicine.medscape.com/article/167027-overview
· Lactate. (2009). Lactate: The Test. Lab Tests Online. Retrieved on December 20, 2009 from http://www.labtestsonline.org/understanding/analytes/lactate/test.html
· Serum Lactate Measured. (2009). Implement the Sepsis Resuscitation Bundle: Serum Lactate Measured. Institute for Healthcare Improvement. Retrieved on December 20, 2009 from http://www.ihi.org/IHI/Topics/CriticalCare/Sepsis/Changes/IndividualChanges/SerumLactateMeasured.htm
· Kraviz, L. (2004). Lactate: Not Guilty as Charged. Retrieved on December 20, 2009 from http://www.unm.edu/~lkravitz/Article%20folder/lactate.html
· Burtis, C. A., Ashwood, E. R., Bruns, D. E., Tietz Textbook of Clinical Chemistry & Molecular Diagnostics. St. Louis, Missouri: Elsevier (2006). p. 877-878.
Ammonia
Ammonia is a compound found within the human body. It is a major byproduct of protein catabolism and is required for the anabolism of certain essential cellular compounds. Extra amounts of ammonia are processed by the liver and kidneys in order to keep blood levels within a tightly controlled range. If levels build up and exceed this range then severe neurological damage and even death can occur.
Ammonia is a waste product produced by the body as a byproduct of metabolism. It is mainly produced within the digestive tract however it can also be produced wherever amino acid breakdown occurs within the body. The major areas in the body that produce ammonia are the intestines, skeletal muscle, liver, and kidneys. The body gains energy from proteins via the Kreb’s Cycle which occurs within the mitochondria of all cells. In this process some of the intermediary products produced within the cycle can be converted to glutamate if transaminated for other metabolic processes. It is the conversion of glutamate to α-ketoglutarate via the enzyme glutamate dehydrogenase that creates ammonia. Glutamate can also be produced from glutamine via a hydrolysis reaction; the addition of water and glutaminase produces the compound glutamate. Both of the aforementioned reactions are constantly in flux within the cells as needed producing ammonia as a waste product. In order to rid the body of excess ammonia the hepatocytes in the liver metabolize the ammonia into urea. This is accomplished via the Krebs-Henseleit urea cycle which is a combination of the Krebs and urea cycle that specifically processes ammonia. The urea is then excreted via the kidneys without harming the body. Some ammonia is also produced and excreted by the kidneys. This occurs within the renal tubular cells as they generate ammonia via the glutamate reaction. Because the tubular cells are selectively permeable the ammonia cannot get back through into the blood stream and is excreted directly into the urine. In the event that the liver or kidneys are not working properly urea and ammonia can back up into the system and these cycles will shut down causing toxic amounts of ammonia to build up in the blood stream.
It is normal to have low levels of ammonia in the blood stream as it is constantly being produced by the body, however high levels can hold much clinical significance for a physician. Normal ranges for ammonia can differ between labs. As a general rule patients less than 30 days old have an ammonia level around 64-107 umol/L, 1 month to 12 years old is around 29-57 umol/L, and greater than 12 years old is around 11-32 umol/L. While hyperammonemia has many different causes its overall effect on the body is expressed solely as neurological damage. Ammonia can cross the blood-brain barrier via passive diffusion. It needs to be able to do this because neurons need to use energy from the Kreb’s cycle just like all other cells in the body. The problem occurs when ammonia builds up to toxic levels in the cerebrospinal fluid. At this point all sorts of important brain functions begin to become inhibited causing brain swelling and alteration in cognition. If the situation is left unchecked eventually the body will fall into a coma and die.
Hyperammonemia can be caused by either an inherited disorder or it can be caused by an acquired illness. Inherited causes include inherited deficiencies of urea cycle enzymes such as lysine and ornithine. These disorders usually manifest in infancy however there are rare cases that manifest in adulthood. There are dozens of inherited disorders that affect enzymes related to ammonia metabolism the key is that the outcome is still the same if ammonia levels become toxic. The list of acquired causes of hyperammonemia is a bit more varied. The two big causes are liver and kidney failure. Severe liver failure directly impacts ammonia metabolism whereas kidney failure affects the body’s ability to excrete urea causing a backup of ammonia. A third cause is Reye’s syndrome which occurs in children. This occurs when a child has a viral infection and the liver becomes overloaded due to aspirin toxicity. Once the liver is overworked then the ammonia levels begin to back up to toxic levels and cause damage. Other drugs such as heparin and valproic acid will actually increase ammonia. Tetracycline and diphenhydramine will decrease ammonia. The key to finding the cause of hyperammonemia is determining at what point in the body the metabolic cycle is getting jammed up.
Treatment for hyperammonemia is relatively simple in concept; fix the metabolic cycle. For inherited enzyme deficiencies a change in diet is usually required. For patients with acquired causes of hyperammonemia treatment can be as simple as adhering to a low protein diet to something as drastic as undergoing a liver transplant. In general to treat acute hyperammonemia physicians can give a patient an intravenous solution of sodium benzoate and phenylacetate to remove excess nitrogen from the blood. Dialysis can also be performed if needed to remove excess toxins. These are quick fixes though, the main goal is to treat the underlying condition that created the environment of hyperammmonemia.
References
* Crisan, E., Chawla, J. (2009). Hyperammonemia. Emedicine from WebMD. Retrieved December 20, 2009 from http://emedicine.medscape.com/article/1174503-overview
* Essig, M. (2009). Ammonia. Yahoo Health. Retrieved December 20, 2009 from http://health.yahoo.com/blood-diagnosis/ammonia/healthwise—hw1768.html
* Burtis, C. A., Ashwood, E. R., Bruns, D. E., Tietz Textbook of Clinical Chemistry & Molecular Diagnostics. St. Louis, Missouri: Elsevier (2006). 1765-1766, 1789-1791.
* Glutamic Acid. (2009). Retrieved December 20, 2009 from http://en.wikipedia.org/wiki/Glutamic_acid
Ammonia is a waste product produced by the body as a byproduct of metabolism. It is mainly produced within the digestive tract however it can also be produced wherever amino acid breakdown occurs within the body. The major areas in the body that produce ammonia are the intestines, skeletal muscle, liver, and kidneys. The body gains energy from proteins via the Kreb’s Cycle which occurs within the mitochondria of all cells. In this process some of the intermediary products produced within the cycle can be converted to glutamate if transaminated for other metabolic processes. It is the conversion of glutamate to α-ketoglutarate via the enzyme glutamate dehydrogenase that creates ammonia. Glutamate can also be produced from glutamine via a hydrolysis reaction; the addition of water and glutaminase produces the compound glutamate. Both of the aforementioned reactions are constantly in flux within the cells as needed producing ammonia as a waste product. In order to rid the body of excess ammonia the hepatocytes in the liver metabolize the ammonia into urea. This is accomplished via the Krebs-Henseleit urea cycle which is a combination of the Krebs and urea cycle that specifically processes ammonia. The urea is then excreted via the kidneys without harming the body. Some ammonia is also produced and excreted by the kidneys. This occurs within the renal tubular cells as they generate ammonia via the glutamate reaction. Because the tubular cells are selectively permeable the ammonia cannot get back through into the blood stream and is excreted directly into the urine. In the event that the liver or kidneys are not working properly urea and ammonia can back up into the system and these cycles will shut down causing toxic amounts of ammonia to build up in the blood stream.
It is normal to have low levels of ammonia in the blood stream as it is constantly being produced by the body, however high levels can hold much clinical significance for a physician. Normal ranges for ammonia can differ between labs. As a general rule patients less than 30 days old have an ammonia level around 64-107 umol/L, 1 month to 12 years old is around 29-57 umol/L, and greater than 12 years old is around 11-32 umol/L. While hyperammonemia has many different causes its overall effect on the body is expressed solely as neurological damage. Ammonia can cross the blood-brain barrier via passive diffusion. It needs to be able to do this because neurons need to use energy from the Kreb’s cycle just like all other cells in the body. The problem occurs when ammonia builds up to toxic levels in the cerebrospinal fluid. At this point all sorts of important brain functions begin to become inhibited causing brain swelling and alteration in cognition. If the situation is left unchecked eventually the body will fall into a coma and die.
Hyperammonemia can be caused by either an inherited disorder or it can be caused by an acquired illness. Inherited causes include inherited deficiencies of urea cycle enzymes such as lysine and ornithine. These disorders usually manifest in infancy however there are rare cases that manifest in adulthood. There are dozens of inherited disorders that affect enzymes related to ammonia metabolism the key is that the outcome is still the same if ammonia levels become toxic. The list of acquired causes of hyperammonemia is a bit more varied. The two big causes are liver and kidney failure. Severe liver failure directly impacts ammonia metabolism whereas kidney failure affects the body’s ability to excrete urea causing a backup of ammonia. A third cause is Reye’s syndrome which occurs in children. This occurs when a child has a viral infection and the liver becomes overloaded due to aspirin toxicity. Once the liver is overworked then the ammonia levels begin to back up to toxic levels and cause damage. Other drugs such as heparin and valproic acid will actually increase ammonia. Tetracycline and diphenhydramine will decrease ammonia. The key to finding the cause of hyperammonemia is determining at what point in the body the metabolic cycle is getting jammed up.
Treatment for hyperammonemia is relatively simple in concept; fix the metabolic cycle. For inherited enzyme deficiencies a change in diet is usually required. For patients with acquired causes of hyperammonemia treatment can be as simple as adhering to a low protein diet to something as drastic as undergoing a liver transplant. In general to treat acute hyperammonemia physicians can give a patient an intravenous solution of sodium benzoate and phenylacetate to remove excess nitrogen from the blood. Dialysis can also be performed if needed to remove excess toxins. These are quick fixes though, the main goal is to treat the underlying condition that created the environment of hyperammmonemia.
References
* Crisan, E., Chawla, J. (2009). Hyperammonemia. Emedicine from WebMD. Retrieved December 20, 2009 from http://emedicine.medscape.com/article/1174503-overview
* Essig, M. (2009). Ammonia. Yahoo Health. Retrieved December 20, 2009 from http://health.yahoo.com/blood-diagnosis/ammonia/healthwise—hw1768.html
* Burtis, C. A., Ashwood, E. R., Bruns, D. E., Tietz Textbook of Clinical Chemistry & Molecular Diagnostics. St. Louis, Missouri: Elsevier (2006). 1765-1766, 1789-1791.
* Glutamic Acid. (2009). Retrieved December 20, 2009 from http://en.wikipedia.org/wiki/Glutamic_acid
Friday, May 28, 2010
Alcohol
Alcohol is the term given to name a family of organic compounds that all have common properties. Ethanol, methanol, isopropanol, and other compounds are all members of the alcohol family. Ethanol is the alcohol that is seen most often ingested by patients. The chemical formula for ethanol is C2H5OH and is usually abbreviated ETOH. The main characteristic of ethanol is that it is very soluble in water, which allows it to be taken up quickly by the human body. There are two types of ethanol, that which is made for human consumption and that which is made for industrial purposes. The difference between the two is the way in which they are processed. Ethanol for human consumption is made from fermenting foodstuffs such as barley or grapes. Ethanol for industrial purposes is made using chemical processes that render the final product unsafe for consumption. In the laboratory testing is done for ethanol that is made for human consumption.
Ethanol is the member of the alcohol family that is normally consumed by people. When it enters the body it is absorbed into the bloodstream by the stomach and the small intestine. Ethanol is readily absorbed into the bloodstream due to its high affinity for water. Once in the bloodstream it is carried throughout the body and will affect all tissues that contain water. Once all the ethanol in a person’s system has been absorbed equilibrium will be reached throughout the body so that all tissues in a person’s system will have the same concentration of ethanol. When a person consumes ethanol the stomach absorbs approximately 20% of the ethanol and the small intestine absorbs approximately 80%. The longer ethanol remains in the stomach, say when you eat a big meal and drink, the slower the rate of absorption. If a person drinks ethanol on an empty stomach the ethanol is quickly absorbed into the blood stream via the small intestine. The rate of absorption affects the rate that ethanol takes to affect the system. Ethanol is considered a central nervous system depressant. It affects the body by reducing inhibitions, reducing response to stimuli, and impairs a person’s thought process. Ethanol is toxic to the body and is metabolized via the liver. Ninety-five percent of ethanol in the body is metabolized by the liver. The remaining ethanol is excreted through the lungs and in the urine. The liver metabolizes alcohol through a variety of pathways, however the main enzyme that breaks ethanol down is alcohol dehydrogenase. This enzyme breaks ethanol down into acetaldehyde, which is then broken down into acetic acid. Finally the acetic acid is broken down into carbon dioxide and water. Ethanol acts as a diuretic which causes the body to lose water through urination. Since the liver needs water in order to metabolize ethanol it will divert water from all areas of the body if there is a not sufficient amount of water present. This lack of water available to the liver and the toxicity of the metabolite acetaldehyde both contribute to the systemic affects of ethanol on the body. These affects include the common hangover complaints such as nausea, vomiting, and headaches. The rule of thumb is that a healthy individual will eliminate approximately 15 mL of ethanol (one beer or glass of wine) per hour. Chronic alcoholics generally will metabolize ethanol at a higher rate so long as the liver is still relatively healthy. With age, our ability to process alcohol diminishes.
In the laboratory there are several ways to test for ethanol. Ethanol can be found in the blood, in the urine, and in a person’s breath. These are good samples for ethanol testing. Generally laboratories will process blood and urine to determine ethanol concentrations while field workers, such as the police, will use a breathalyzer to determine ethanol concentration in a person’s breath. The results produced by the lab are used by doctors to determine ethanol intoxication and poisoning. The method used on the Siemens Dimension system is based on an enzymatic reaction. The reagent used contains alcohol dehydrogenase and the co-enzyme NAD (nicotinamide adenine dinucleotide). If ethanol is present in a serum sample it reacts with the NAD in the presence of the enzyme alcohol dehydrogenase to produce acetaldehyde and NADH. The amount of NADH produced is read via absorbance at 340nm and is proportional to the amount of ethanol in the sample. In general the normal range for ethanol is zero however some laboratories will report out less than ten to rule out samples that have been contaminated with alcohol wipes. Positive results are reported out in mg/dL for the Siemens Dimenson system. The national blood alcohol concentration (BAC) values that define legal limits for alcohol intoxication are reported out in a percentage. The legal limit of 0.08% means that there are eight grams of alcohol per every hundred mL of blood in a person’s system. To compare this value to the values reported out on the Siemens Dimension system a 0.08% BAC level would be equivalent to a value of 80 mg/dL. It is generally accepted that values over 0.40 BAC or 400 mg/dL can be fatal in a normal healthy person.
Ethanol is the most commonly abused substance in the country. Here in Virginia the legal limit for alcohol intoxication is 0.08% BAC. In some instances an ethanol level can be used for legal purposes, however in these cases samples have to be collected and tested following chain of custody protocols. The role of the laboratory is to test samples for the presence of ethanol so that doctors can treat patients for intoxication or poisoning.
References
· Ethanol. (2010). Ethanol. Lab Tests Online. Retrieved on February 27, 2010 from http://www.labtestsonline.org/understanding/analytes/ethanol/sample.html
· Measuring BAC. (2010). Measuring BAC. Blood Alcohol Content. Retrieved on February 27, 2010 from http://www.bloodalcoholcontent.org/measuringbac.html
· SIEMENS Dimension Flex reagent cartridge. (2009). Ethanol. (REF DF22). Newark, DE: Siemens Healthcare Diagnostics Inc.
· Alcohol and the Human Body. (2010). Alcohol and the Human Body. Intoximeters Incorporated. Retrieved on February 27, 2010 from http://www.intox.com/physiology.asp
· Body Effects. (2008). Body Effects. ALAC. Retrieved on February 27, 2010 from http://www.alac.org.nz/BodyEffects.aspx
Ethanol is the member of the alcohol family that is normally consumed by people. When it enters the body it is absorbed into the bloodstream by the stomach and the small intestine. Ethanol is readily absorbed into the bloodstream due to its high affinity for water. Once in the bloodstream it is carried throughout the body and will affect all tissues that contain water. Once all the ethanol in a person’s system has been absorbed equilibrium will be reached throughout the body so that all tissues in a person’s system will have the same concentration of ethanol. When a person consumes ethanol the stomach absorbs approximately 20% of the ethanol and the small intestine absorbs approximately 80%. The longer ethanol remains in the stomach, say when you eat a big meal and drink, the slower the rate of absorption. If a person drinks ethanol on an empty stomach the ethanol is quickly absorbed into the blood stream via the small intestine. The rate of absorption affects the rate that ethanol takes to affect the system. Ethanol is considered a central nervous system depressant. It affects the body by reducing inhibitions, reducing response to stimuli, and impairs a person’s thought process. Ethanol is toxic to the body and is metabolized via the liver. Ninety-five percent of ethanol in the body is metabolized by the liver. The remaining ethanol is excreted through the lungs and in the urine. The liver metabolizes alcohol through a variety of pathways, however the main enzyme that breaks ethanol down is alcohol dehydrogenase. This enzyme breaks ethanol down into acetaldehyde, which is then broken down into acetic acid. Finally the acetic acid is broken down into carbon dioxide and water. Ethanol acts as a diuretic which causes the body to lose water through urination. Since the liver needs water in order to metabolize ethanol it will divert water from all areas of the body if there is a not sufficient amount of water present. This lack of water available to the liver and the toxicity of the metabolite acetaldehyde both contribute to the systemic affects of ethanol on the body. These affects include the common hangover complaints such as nausea, vomiting, and headaches. The rule of thumb is that a healthy individual will eliminate approximately 15 mL of ethanol (one beer or glass of wine) per hour. Chronic alcoholics generally will metabolize ethanol at a higher rate so long as the liver is still relatively healthy. With age, our ability to process alcohol diminishes.
In the laboratory there are several ways to test for ethanol. Ethanol can be found in the blood, in the urine, and in a person’s breath. These are good samples for ethanol testing. Generally laboratories will process blood and urine to determine ethanol concentrations while field workers, such as the police, will use a breathalyzer to determine ethanol concentration in a person’s breath. The results produced by the lab are used by doctors to determine ethanol intoxication and poisoning. The method used on the Siemens Dimension system is based on an enzymatic reaction. The reagent used contains alcohol dehydrogenase and the co-enzyme NAD (nicotinamide adenine dinucleotide). If ethanol is present in a serum sample it reacts with the NAD in the presence of the enzyme alcohol dehydrogenase to produce acetaldehyde and NADH. The amount of NADH produced is read via absorbance at 340nm and is proportional to the amount of ethanol in the sample. In general the normal range for ethanol is zero however some laboratories will report out less than ten to rule out samples that have been contaminated with alcohol wipes. Positive results are reported out in mg/dL for the Siemens Dimenson system. The national blood alcohol concentration (BAC) values that define legal limits for alcohol intoxication are reported out in a percentage. The legal limit of 0.08% means that there are eight grams of alcohol per every hundred mL of blood in a person’s system. To compare this value to the values reported out on the Siemens Dimension system a 0.08% BAC level would be equivalent to a value of 80 mg/dL. It is generally accepted that values over 0.40 BAC or 400 mg/dL can be fatal in a normal healthy person.
Ethanol is the most commonly abused substance in the country. Here in Virginia the legal limit for alcohol intoxication is 0.08% BAC. In some instances an ethanol level can be used for legal purposes, however in these cases samples have to be collected and tested following chain of custody protocols. The role of the laboratory is to test samples for the presence of ethanol so that doctors can treat patients for intoxication or poisoning.
References
· Ethanol. (2010). Ethanol. Lab Tests Online. Retrieved on February 27, 2010 from http://www.labtestsonline.org/understanding/analytes/ethanol/sample.html
· Measuring BAC. (2010). Measuring BAC. Blood Alcohol Content. Retrieved on February 27, 2010 from http://www.bloodalcoholcontent.org/measuringbac.html
· SIEMENS Dimension Flex reagent cartridge. (2009). Ethanol. (REF DF22). Newark, DE: Siemens Healthcare Diagnostics Inc.
· Alcohol and the Human Body. (2010). Alcohol and the Human Body. Intoximeters Incorporated. Retrieved on February 27, 2010 from http://www.intox.com/physiology.asp
· Body Effects. (2008). Body Effects. ALAC. Retrieved on February 27, 2010 from http://www.alac.org.nz/BodyEffects.aspx
Thursday, May 27, 2010
Welcome
Welcome to the Clinical Laboratory Sciences Review. Each week I will be posting articles about testing done in a basic hospital laboratory in order to educate and refresh the memory. It is my hope that the information provided can help educate the general public as well as refresh the minds of those of us working behind the scenes in the lab.
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