Alt liver test normal range: Alanine Aminotransferase (ALT) Test and Results (aka SGPT Test)
Alanine Aminotransferase (ALT) Test and Results (aka SGPT Test)
The alanine aminotransferase (ALT) test is a blood test that checks for liver damage. Your doctor can use this test to find out if a disease, drug, or injury has damaged your liver.
Your liver does a lot of important things for you:
- It makes a fluid called bile that helps your body digest food.
- It removes waste products and other toxins from your blood.
- It produces proteins and cholesterol.
Diseases such as hepatitis and cirrhosis can damage your liver and prevent it from doing its many jobs.
Why Is ALT Important?
This enzyme is found mainly in your liver. Smaller amounts of ALT are in your kidneys and other organs, too.
Your body uses ALT to break down food into energy. Normally, ALT levels in the blood are low. If your liver is damaged, it will release more ALT into your blood and levels will rise. (ALT used to be called serum glutamic-pyruvic transaminase, or SGPT).
Doctors often give the ALT test along with other liver tests.
Why Would My Doctor Order This Test?
Your doctor might recommend ALT if you have symptoms of liver disease or damage, such as:
Here are some reasons you might get this test:
- You’ve been exposed to the hepatitis virus.
- You drink a lot of alcohol.
- You have a family history of liver disease.
- You take medicine that’s known to cause liver damage.
The ALT test can be done as part of a blood panel during a regular exam. If you’ve already been diagnosed with liver disease, your doctor can use the ALT test to see how well your treatment is working.
How Do I Prepare?
You don’t need any special preparation for the ALT test. Your doctor might ask you to stop eating or drinking a few hours before the test.
Tell your doctor what prescription drugs or supplements you take. Some medicines can affect the results of this test.
What Happens During the Test?
A nurse or lab tech will take a sample of your blood, usually from a vein in your arm. They will first tie a band around the upper part of your arm to make your vein fill with blood and swell up. Then they will clean the area with an antiseptic and place a needle into your vein. Your blood will collect into a vial or tube.
The blood test should take only a couple of minutes. After your blood is taken, the lab tech will remove the needle and band, then put a piece of gauze and a bandage over the spot the needle went in to stop the bleeding.
What Are the Risks?
The ALT blood test is safe. Risks are usually minor, and can include:
- Slight pain when the needle is inserted
- Fainting or feeling dizzy
What Do the Results Mean?
You should get your results in about a day. A normal ALT test result can range from 7 to 55 units per liter (U/L). Levels are normally higher in men.
Slightly high ALT levels may be caused by:
Moderately high ALT levels may be because of:
Very high ALT levels can be caused by:
What Other Tests Will I Take?
ALT usually is done as part of a group of liver function tests called a liver panel.
This panel also includes an aspartate aminotransferase (AST) test. AST is another liver enzyme. As with ALT, the levels of AST in your blood rise if your liver is damaged.
Comparing ALT with AST levels gives your doctor more information about the health of your liver. The ALT-to-AST ratio can help your doctor figure out how severe the liver damage is and what might have caused it.
To find out what type of liver disease you have, your doctor might also test the levels of other enzymes and proteins found in your liver, including:
Talk to your doctor to make sure you understand all of your liver test results. Also find out how these results might affect your treatment.
Mildly Elevated Liver Transaminase Levels: Causes and Evaluation
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A systematic review of the prevalence of mildly abnormal liver function tests and associated health outcomes. Eur J Gastroenterol Hepatol.
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Muscular exercise can cause highly pathological liver function tests in healthy men. Br J Clin Pharmacol.
8. Sorbi D,
The ratio of aspartate aminotransferase to alanine aminotransferase: potential value in differentiating nonalcoholic steatohepatitis from alcoholic liver disease. Am J Gastroenterol.
9. Oh RC,
Causes and evaluation of mildly elevated liver transaminase levels. Am Fam Physician.
10. Chalasani N,
The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology [published correction appears in Gastroenterology. 2012;143(2):503]. Gastroenterology.
11. European Association for the Study of the Liver;
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EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol.
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Lifestyle changes for the treatment of nonalcoholic fatty liver disease: a review of observational studies and intervention trials. Therap Adv Gastroenterol.
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Dietary fructose in nonalcoholic fatty liver disease. Hepatology.
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Epidemiology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in the United States and the rest of the world. Clin Liver Dis.
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van Werven JR,
The diagnostic accuracy of US, CT, MRI and 1H-MRS for the evaluation of hepatic steatosis compared with liver biopsy: a meta-analysis. Eur Radiol.
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Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology.
19. Angulo P,
Simple noninvasive systems predict long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology.
20. Castéra L,
Pitfalls of liver stiffness measurement: a 5-year prospective study of 13,369 examinations. Hepatology.
21. Louvet A,
Alcoholic liver disease: mechanisms of injury and targeted treatment. Nat Rev Gastroenterol Hepatol.
22. Toshikuni N,
Clinical differences between alcoholic liver disease and nonalcoholic fatty liver disease. World J Gastroenterol.
23. Dunn W,
Utility of a new model to diagnose an alcohol basis for steatohepatitis. Gastroenterology.
24. Cerović I,
Alcoholic liver disease/nonalcoholic fatty liver disease index: distinguishing alcoholic from nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol.
25. Leise MD,
Drug-induced liver injury. Mayo Clin Proc.
26. Watkins PB,
Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA.
27. Heard KJ,
Serum alanine aminotransferase elevation during 10 days of acetaminophen use in nondrinkers. Pharmacotherapy.
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Drug-related hepatotoxicity. N Engl J Med.
29. U.S. Food and Drug Administration. FDA drug safety communication: important safety label changes to cholesterol-lowering statin drugs. February 28, 2012. https://www.fda.gov/drugs/drugsafety/ucm293101.htm. Accessed March 24, 2017.
30. Centers for Disease Control and Prevention. Surveillance for viral hepatitis—United States, 2014. Updated June 22, 2016. https://www.cdc.gov/hepatitis/statistics/2014surveillance/commentary.htm#summary. Accessed August 6, 2016.
31. U.S. Preventive Services Task Force. Hepatitis C: screening. June 2013. http://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/hepatitis-c-screening. Accessed April 8, 2017.
32. U.S. Preventive Services Task Force. Hepatitis B virus infection: screening, 2014. May 2014. http://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/hepatitis-b-virus-infection-screening-2014. Accessed April 8, 2017.
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Special considerations in interpreting liver function tests. Am Fam Physician.
Alanine aminotransferase (ALT) test: Uses and results
The liver makes several enzymes, including alanine aminotransferase, or ALT. These enzymes help break down proteins so that the body can digest them.
Besides helping the liver break down proteins, ALT helps the liver perform its basic functions. Some of these include:
- filtering toxins from the blood
- storing nutrients and iron
- producing bile, which aids digestion
Most ALT that the liver produces stays within the organ. However, when the liver is damaged or inflamed, it may release ALT into the bloodstream.
When this happens, the level of ALT in the blood rises. Therefore, doctors use an ALT blood test to screen for liver disease or damage. Learn more about the test in this article.
A doctor orders an ALT test to look for problems with liver function. Many people have this test as part of a comprehensive metabolic panel.
The comprehensive metabolic panel is a routine blood test that checks a person’s glucose level, kidney function, and liver function. It is often part of a routine checkup that gives a doctor insight into an individual’s overall health.
Other times, a doctor orders the ALT blood test as part of a series of blood tests called liver panels if they suspect that a person’s liver is damaged or diseased.
Doctors may order liver panels if a person has symptoms of liver disease or damage. Symptoms of liver problems include:
- yellowing of the eyes and skin (jaundice)
- pain in the upper right quadrant of the abdomen
- referred pain in the right shoulder
- easy bleeding or bruising
- intense itching
- pale stools
- swelling in legs or abdomen
These symptoms can indicate liver disease, injury, or another problem that may be affecting the liver.
Medical problems that can cause elevated ALT levels include:
Certain medications can also cause ALT levels in the blood to be high.
Often, these levels are elevated before symptoms of liver damage occur, making the test useful for people at risk of liver damage.
When a doctor can detect liver damage early, they may be better able to treat it and prevent further injury.
People at risk of liver damage or disease include:
- people with a family history of liver disease
- people who have diabetes
- people who are overweight
- people who consume a lot of alcoholic beverages
- people taking certain medications
Doctors routinely order liver panels to monitor diagnosed liver disease or injury. The results of these tests can show how well the treatment plan is working.
A person with a healthy liver will have an ALT level in the normal range. The normal range can vary from laboratory to laboratory.
According to the Mayo Clinic, the normal range for adult males is 7–55 units per liter. Females may have a lower upper limit normal than males.
Age can also affect results. A person should speak with their doctor about what their results mean.
If a person has results above the normal range, this may indicate liver damage.
Causes of elevated ALT levels include:
- the destruction of liver cells
- a lack of blood flow to the liver
- cirrhosis, or severe scarring of the liver
- hemochromatosis, or iron buildup
- mononucleosis, an infection usually caused by the Epstein-Barr virus
- a tumor in the liver
A person should discuss their results with their doctor, who can say if the numbers returned are within a normal range.
If a person’s results are too low or high, a doctor can help determine the appropriate course of treatment.
People with higher ALT levels often need additional tests to discover the underlying cause of the liver damage and treat it.
An ALT blood test helps determine if a person has liver damage. Uncovering the cause of the problem often requires further testing.
The normal range for results tends to vary among facilities, and a doctor can discuss what the results mean on an individual basis.
Once they know the underlying cause of the liver damage, based on symptoms and test results, the doctor will discuss appropriate treatment options.
Alanine Aminotransferase (ALT) Test | Michigan Medicine
An alanine aminotransferase (ALT) test measures the amount of this enzyme in the blood. ALT is found mainly in the liver, but also in smaller amounts in the kidneys, heart, muscles, and pancreas. ALT was formerly called serum glutamic pyruvic transaminase (SGPT).
ALT is measured to see if the liver is damaged or diseased. Low levels of ALT are normally found in the blood. But when the liver is damaged or diseased, it releases ALT into the bloodstream, which makes ALT levels go up. Most increases in ALT levels are caused by liver damage.
The ALT test is often done along with other tests that check for liver damage, including aspartate aminotransferase (AST), alkaline phosphatase, lactate dehydrogenase (LDH), and bilirubin. Both ALT and AST levels are reliable tests for liver damage.
Why It Is Done
The ALT test is done to:
- Identify liver disease, such as cirrhosis and hepatitis, caused by alcohol, drugs, or viruses.
- Help check for liver damage.
- Find out whether jaundice was caused by a blood disorder or liver disease.
- Keep track of the effects of medicines that can damage the liver.
How To Prepare
Avoid strenuous exercise just before having an ALT test.
How It Is Done
A health professional uses a needle to take a blood sample, usually from the arm.
How long the test
The test will take a few minutes.
How It Feels
When a blood sample is taken, you may feel nothing at all from the needle. Or you might feel a quick sting or pinch.
There is very little chance of having a problem from this test. When a blood sample is taken, a small bruise may form at the site.
An alanine aminotransferase (ALT) test measures the amount of this enzyme in the blood. Results are usually available within 12 hours.
The normal values listed here—called a reference range—are just a guide. These ranges vary from lab to lab, and your lab may have a different range for what’s normal. Your lab report should contain the range your lab uses. Also, your doctor will evaluate your results based on your health and other factors. This means that a value that falls outside the normal values listed here may still be normal for you or your lab.
High levels of ALT may be caused by:
- Liver damage from conditions such as hepatitis or cirrhosis.
- Lead poisoning.
- Very strenuous exercise or severe injury to a muscle.
- Exposure to carbon tetrachloride.
- Decay of a large tumor (necrosis).
- Many medicines, such as statins, antibiotics, chemotherapy, aspirin, opioids, and barbiturates.
- Growth spurts, especially in young children. Rapid growth can cause mildly elevated levels of ALT.
- Fischbach FT, Dunning MB III, eds. (2009). Manual of Laboratory and Diagnostic Tests, 8th ed. Philadelphia: Lippincott Williams and Wilkins.
Current as of:
September 23, 2020
Author: Healthwise Staff
E. Gregory Thompson MD – Internal Medicine
Adam Husney MD – Family Medicine
Martin J. Gabica MD – Family Medicine
Kathleen Romito MD – Family Medicine
Jerome B. Simon MD, FRCPC, FACP – Gastroenterology
Current as of: September 23, 2020
Medical Review:E. Gregory Thompson MD – Internal Medicine & Adam Husney MD – Family Medicine & Martin J. Gabica MD – Family Medicine & Kathleen Romito MD – Family Medicine & Jerome B. Simon MD, FRCPC, FACP – Gastroenterology
Fischbach FT, Dunning MB III, eds. (2009). Manual of Laboratory and Diagnostic Tests, 8th ed. Philadelphia: Lippincott Williams and Wilkins.
Liver Enzyme Interpretation and Liver Function Tests
Reviewing the interpretation and limitations of serum liver enzyme activity and liver function tests for dogs and cats.
Brigitte B. McAteeDVM
Brigitte B. McAtee received her DVM from Auburn University. She is currently a second-year internal medicine resident at Texas A&M University in College Station, Texas. Her clinical and research interests include infectious and immune-mediated diseases.
Jonathan A. LidburyBVMS, MRCVS, PhD, DACVIM, DECVIM-CA
Jonathan A. Lidbury graduated from the University of Glasgow and completed his internal medicine residency at Texas A&M University. Jonathan is an assistant professor of small animal internal medicine and the associate director for clinical services of the Gastrointestinal Laboratory at Texas A&M University. His clinical interests are small animal hepatology and gastroenterology, and he is involved in a wide range of research in these fields.
Hepatobiliary disease is an important cause of morbidity and mortality in dogs and cats and can present a diagnostic challenge for two main reasons. First, patient signalment varies because liver disease and dysfunction can occur in cats and dogs of any age, sex, or breed (see Case Studies). Despite this, the patient’s signalment can sometimes give important clues because certain breeds have disease predispositions; for example, Labrador retrievers are predisposed to copper-associated chronic hepatitis. Second, elevations of serum liver enzyme activities are commonly encountered in small animal practice but are not specific for primary liver disease. However, early in the course of liver diseases, such as chronic hepatitis, patients may have no or only subtle, nonspecific clinical signs, such as intermittent anorexia or lethargy. In these patients, increased liver enzyme activities may be the first indicator of a problem. More liver-specific clinical signs, such as icterus, ascites, edema, polyuria/polydipsia, and hepatic encephalopathy, tend to occur late in the course of disease, when it is often too late to prevent its progression. Therefore, early diagnosis of liver disease often relies on serum biochemical testing, which may prompt further diagnostics, including liver function testing. This article reviews the interpretation and limitations of serum liver enzyme activity and liver function tests.
Signalment and Presentation
A 3-month-old female intact Irish wolfhound presents for stunted growth and episodes of intermittent lethargy and disorientation.
Results of Diagnostic Testing
A serum biochemistry panel is performed, with the results in Table A. The fasted ammonia concentration is 175 mcg/dL (normal range, 0–50 mcg/dL). Preprandial and postprandial (2-hour) SBA are 40 mcmol/L (normal, 0–8 mcmol/L) and 102 mcmol/L (normal, 0–30 mcmol/L), respectively.
The combination of hypoalbuminemia, decreased BUN, and hypocholesterolemia suggests decreased hepatic synthetic capacity. The ALT and AST activities are within normal limits, making hepatocellular damage unlikely; the ALP activity is only mildly elevated, probably because the dog is growing.
The ammonia concentration and SBA results suggest portosystemic shunting and/or hepatic insufficiency.
Given the patient’s signalment, clinical findings, and laboratory abnormalities, a congenital portosystemic shunt is likely and imaging (ultrasonography and/or computed tomography) is warranted.
Signalment and Presentation
An 8-year-old male neutered Labrador retriever presents for a 3-month history of decreased appetite and weight loss.
Results of Diagnostic Testing
A serum biochemistry panel is performed, with the results in Table B. The fasted ammonia concentration is <15 mcg/dL (normal range, 0–50 mcg/dL). Preprandial and postprandial (2-hour) bile acids are 2.9 mcmol/L (normal, 0–8 mcmol/L) and 14.5 mcmol/L (normal, 0–30 mcmol/L), respectively.
The ALT activity is 2.4 times the upper limit of the reference interval, while the ALP activity is only 1.3 times the upper limit of the reference interval. This, along with the increased serum AST activity, is consistent with a hepatocellular damage pattern.
The ammonia concentration and SBA results rule out portosystemic shunting and do not support the presence of severe liver dysfunction. However, hepatobiliary disease is not excluded and further testing is indicated.
Abdominal ultrasonography would be a logical next step. If the ALT is persistently increased and no evidence supports the presence of extrahepatic disease, liver biopsy would be indicated.
The liver has a wide variety of metabolic functions (Box 1). Because of these diverse metabolic roles, liver dysfunction is associated with a variety of sequelae and clinicopathologic abnormalities.
The liver is unique in that it receives much of its blood supply (75%) from the portal venous system, which drains abdominal organs, such as the gastrointestinal (GI) tract, spleen, and pancreas.1,2 This means that diseases of the pancreas and GI tract can secondarily affect the liver. The liver also metabolizes and/or excretes a variety of exogenous substances (ie, drugs and toxins) that may cause secondary liver injury.
Serum liver enzymes are sensitive but not necessarily specific markers of primary hepatobiliary disease. They are not direct markers of liver function. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are markers of hepatocellular damage, whereas alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT) are markers of cholestasis.3 Each individual enzyme can provide information on whether liver disease is present and may provide clues as to the most likely differential diagnosis.
ALT is a cytoplasmic enzyme found mainly in hepatocytes. However, it is also found in other cells, such as skeletal muscle, renal, and red blood cells, in smaller amounts. ALT is released into the circulation when there is hepatocyte necrosis or increased cell membrane permeability and therefore is a sensitive marker of hepatocellular injury. ALT is the most liver specific of the liver enzymes, but occasionally severe muscle damage or ex vivo hemolysis may increase ALT activity.4 Concurrent evaluation of creatine kinase activity may help discriminate between muscle disease and liver disease because creatine kinase activity is expected to increase with muscle damage. ALT activity can also be increased in patients with extrahepatic diseases that secondarily affect the liver (eg, feline hyperthyroidism). The reported half-life of ALT has been reported to be about 60 hours in dogs and 3.5 hours in cats.3 These relatively short half-lives are useful when monitoring recovery after acute liver injury. Conditions that can cause an increase in ALT activity include those listed in Table 1.
AST is a cytoplasmic and mitochondrial enzyme found in hepatocytes and other cells. Reversible or irreversible damage to the liver causes release of the cytoplasmic AST; however, only irreversible damage to the cell will cause release of mitochondrial AST. These two sources of AST are not distinguishable by measuring serum AST activity on a routine biochemistry panel.
Increases in AST activity generally parallel those of ALT. However, AST is less specific for liver injury than ALT because increases in activity of AST may also be due to cardiac or skeletal muscle injury4 or ex vivo hemolysis. The half-life of AST is about 22 hours in dogs and 80 minutes in cats.3 The shorter half-life compared with ALT means that AST activity decreases and returns to normal before that of ALT in patients with acute liver injury. Conditions that can cause an increase in AST activity include those listed in Table 1.
ALP is an enzyme found in hepatocytes that line the bile canaliculi. It is released into the circulation during intra- or extrahepatic cholestasis. This enzyme is sensitive for hepatobiliary disease in dogs (80%), but because of the possible contributions of bone and glucocorticoid-induced isoenzymes to serum ALP activity, its specificity is low (51%).5 In young, growing animals, ALP activity is normally increased because of the bone isoenzyme, with 71% of dogs younger than 1 year having ALP activity >150 U/L.6 Bone ALP may also be elevated in patients with osteomyelitis or osteosarcoma. Dogs with hyperadrenocorticism and those receiving glucocorticoids can be expected to have increased ALP activity due to the glucocorticoid-induced isoenzyme. Conditions that can cause an increase in ALP activity include those listed in Table 1.
The highest activities of ALP have been reported with conditions such as cholestasis, steroid hepatopathy, chronic hepatitis, and hepatic necrosis.7 This lack of tissue specificity can make increases in activity of ALP hard to interpret. The half-life of ALP is approximately 70 hours in dogs and 6 hours in cats.3 In cats, which lack the glucocorticoid-induced isoenzyme with a shorter half-life, increases of serum ALP activity are more specific for hepatobiliary disease than in dogs and are generally clinically relevant.
GGT is associated with the cell membranes of hepatocytes that form the bile canaliculi and bile ducts, as well as periportal hepatocytes. It is a marker of intrahepatic (eg, feline hepatic lipidosis) or extrahepatic (eg, bile duct obstruction) cholestasis. In dogs, it has a higher specificity (87%) and lower sensitivity (50%) for hepatobiliary disease compared with ALP.7 In general, GGT is a more sensitive marker of feline hepatobiliary disease than ALP. However, in cats with feline hepatic lipidosis, GGT is generally only mildly elevated.8 No definitive studies determining the half-life of GGT have been performed in cats or dogs. However, serum GGT and ALP activities decrease after liver injury at a similar rate in dogs, suggesting that they have a similar half-life.9
Interpreting Liver Enzyme Elevations
The degree of the increase in hepatocellular-damage enzyme activities may help stratify disease severity as follows5:
- Mild: 2- to 3-fold elevation in activity
- Moderate: 5- to 10-fold elevation in activity
- Marked: >10-fold elevation
However, such increases do not always correlate with severity of disease. This is true in dogs and cats with portosystemic shunting and dogs with end-stage chronic hepatitis, in which hepatocytes are replaced by fibrous tissue. Therefore, the degree of liver enzyme increase should be interpreted with caution.
Because the liver has a large regenerative capacity, the degree of liver enzyme elevation should also not be used to indicate prognosis. For example, a dog with acute liver injury may have severely increased serum ALT activity but can still make a full recovery. Longitudinal monitoring trends in liver enzyme activities can help in determining chronicity and monitoring disease progression and/or response to treatment.
In evaluating liver enzymes, it is important to determine what type of elevation pattern is present (ie, hepatocellular damage versus cholestasis). A relatively greater increase in ALT and AST activity indicates hepatocellular damage, while a greater increase in ALP and GGT activity indicates cholestasis, which could be intrahepatic or extrahepatic. Establishing the pattern may help narrow the differential diagnosis. However, some liver diseases can display a mixed pattern (eg, cholangitis, phenobarbital hepatopathy).
LIVER FUNCTION TESTING
Routine biochemical testing can give clinicians an insight into many liver functions. Box 2 presents common abnormal results of biochemical tests that can have liver-related causes as well as important differential diagnoses to consider for these test results. However, because of the liver’s functional reserve capacity, these tests are not sensitive for liver insufficiency. Abnormal results can also be caused by other conditions and thus also lack specificity.
It is important for clinicians to not only look for analytes that are flagged as being outside their respective reference intervals but also look at their actual values. For example, serum albumin, cholesterol, and blood urea nitrogen (BUN) concentrations toward the lower limit of the reference interval suggest hepatic insufficiency or portosystemic shunting. Monitoring trends in these values over time can also be informative.
Because of the limited sensitivity and specificity of biochemical tests, patients with confirmed or suspected liver disease sometimes require additional liver function testing to better characterize their disease.
Serum Bile Acids
Measurement of the total concentrations of serum bile acids (SBA) aids in the diagnosis of patients with portosystemic shunts and in the assessment of hepatic function. Potential indications for SBA measurement include:
- Suspicion for portosystemic shunting (eg, seizures, other signs of encephalopathy)
- Persistently increased liver enzyme activities, especially ALT
- Severe hypoalbuminemia (<2. 0 g/dL) in dogs
- Unexplained ammonium urate urolithiasis
- Hyperbilirubinemia when hemolysis cannot be definitely diagnosed/excluded (uncommon)
In a healthy patient, SBA are synthesized from cholesterol. In dogs, bile acids are conjugated to glycine or taurine and then stored in the gallbladder, whereas in cats they are conjugated almost exclusively with taurine.10 After a meal, the gallbladder contracts because of secretion of cholecystokinin, emptying bile into the duodenum. Bile acids are absorbed in the ileum. They are transported via the portal circulation to the liver, where they are subsequently reabsorbed. Normally this process is about 95% to 98% efficient.
The enterohepatic recirculation of bile acids is impeded in dogs without gallbladders and patients with ileal disease or that have had ileal resection, causing a decrease in SBA concentration. Other conditions that can cause decreased SBA concentrations include GI malabsorption and decreased gastric motility.2 Causes of increased total SBA concentrations are listed in Box 2. Diseases that cause intrahepatic cholestasis (lipidosis, diabetes mellitus, lymphoma, histoplasmosis, cirrhosis) or extrahepatic cholestasis (cholangitis, bile duct carcinoma, liver flukes, cholelithiasis, pancreatitis) can cause decreased bile acid excretion, despite no decrease in functional hepatic mass. In patients with hyperbilirubinemia, once hemolysis has been ruled out, measuring SBA is not indicated because their concentration will be predictably increased.
Compared with plasma ammonia, SBA are easy to measure and do not not require special sample handling. Paired preprandial and 2-hour postprandial SBA measurements are usually performed to increase the sensitivity of this test (Box 3). While SBA measurement is arguably the best test of liver function and portosystemic shunting in dogs and cats, increased concentrations are not specific for any single hepatobiliary disease. Therefore, this test can be helpful for evaluating the likelihood of hepatobiliary disease; however, it cannot definitively determine the underlying liver disease. Additionally, this test does not provide a truly quantitative assessment of hepatic function. Because of the hepatic reserve capacity, it is possible for dogs with normal SBA concentrations to have hepatobiliary disease; therefore, this test should not be used to screen patients for hepatobiliary disease. However, the sensitivity of SBA measurement for portosystemic shunts (congenital and acquired) is high and in one study was reported to be 93% and 100% for dogs and cats with congenital portosystemic shunt, respectively.11
Blood ammonia concentration can be increased because of portosystemic shunting, severe hepatic insufficiency, or urea cycle enzyme deficiencies (Box 4).12 Potential indications for plasma ammonia measurement include:
- Suspicion for portosystemic shunting
(eg, seizures, other signs of encephalopathy)
- Suspicion for urea cycle enzyme deficiency
(eg, cat with feline hepatic lipidosis)
- Unexplained ammonium urate urolithiasis
Ammonia is mainly produced by catabolism of glutamine by enterocytes and bacterial degradation of urea and proteins in the large bowel. Therefore, blood coming from the splanchnic circulation is rich in ammonia.13 The liver detoxifies ammonia through two pathways: (1) the urea cycle, which converts ammonia into urea and (2) consumption of ammonia during glutamine synthesis by hepatocytes. In animals with portosystemic shunting or severe hepatic dysfunction, the liver is unable to synthesize sufficient glutamine or urea, leading to hyperammonemia. Because ammonia freely passes across membranes, including the blood–brain barrier, hyperammonemia contributes to the development of clinical signs of hepatic encephalopathy.
Fasting Ammonia Measurement
Ammonia testing requires heparinized tubes, transfer of the sample on ice, and urgent separation of plasma and is ideally performed within 30 minutes of sample collection. These requirements can make this diagnostic assay difficult to perform in private practice. Increased serum ammonia is a sensitive marker for congenital and acquired portosystemic shunts, with a reported sensitivity of 83% to 98%.11,14 However, in the absence of portosystemic shunting, ammonia is not a sensitive test of liver disease.
Ammonia Tolerance Test
When ammonia is administered orally or rectally to a normal dog, it should be efficiently extracted from the portal circulation by the liver. However, dogs with a portosystemic shunt or decreased hepatic functional mass cannot extract the additional ammonia, leading to an excessive increase in plasma ammonia concentration.
The main indication for this test is concern for hepatic insufficiency that is not supported by routine laboratory testing. This test is unnecessary for dogs with increased baseline ammonia, in addition to posing a risk for hepatic encephalopathy in these patients. Disadvantages of oral ammonia administration include15:
- Absorption depends on gastric emptying.
- Vomiting can occur.
- It is stressful to the patient.
- The taste of the ammonium chloride is unpleasant.
The rectal ammonia tolerance test avoids these problems (Box 5).16 However, we do not routinely perform either test in dogs or cats.
Postprandial Venous Ammonia Tolerance Test
The postprandial ammonia tolerance test involves a procedure similar to that of the oral or rectal ammonia tolerance test except that digested food provides the ammonia challenge and the disadvantages of oral administration are avoided. The patient is fed a commercial diet containing about 30% protein to provide 33 kcal/kg, and a blood sample is collected 6 hours after feeding. This test was reported to have 91% sensitivity for the detection of portosystemic shunting, but in the absence of portosystemic shunts it is not as sensitive for detecting hepatic insufficiency. 17
Protein C is an anticoagulant protein produced by the liver. Measurement of protein C provides information regarding liver function and perfusion. In one study,18 dogs with congenital and acquired portosystemic shunts, hepatic failure, and chronic hepatitis had decreased levels of protein C, which distinguished them from dogs with microvascular dysplasia (portal vein hypoplasia) and those without hepatobiliary disease. With use of a cutoff value of 70% activity, protein C could distinguish dogs with congenital portosystemic shunt from those with microvascular dysplasia with a sensitivity of 93% and a specificity of 88%.
Increased liver enzyme activities are common results in small animal practice and can suggest patterns of liver disease, including hepatocellular damage, cholestasis, or both. Liver enzymes, especially ALP, are not specific for primary liver disease. To evaluate their clinical significance, a combination of history, clinical signs, physical examination, diagnostic imaging, and other liver function test results must be considered. Changes such as hypocholesterolemia or hypoalbuminemia can suggest hepatic dysfunction. Measuring SBA or ammonia concentrations provides a more accurate assessment of liver function, but it is important to be aware that patients with normal liver function test results can still have liver disease. Although these laboratory tests play an important role in diagnosing canine and feline liver disease, definitive diagnosis usually requires a combination of diagnostic imaging and cytologic or histologic assessment of liver tissue.
- Hall JE, Guyton AC. Guyton and Hall Textbook of Medical Physiology, 12th ed. Philadelphia: Saunders/Elsevier; 2011.
- Allison RW. Laboratory evaluation of the liver. In: Thrall M, Weiser, G, Allison RW, Campbell TW (eds): Veterinary Hematology and Clinical Chemistry, 2nd ed. Oxford: John Wiley & Sons; 2012:401-424.
- Lidbury JA, Steiner JM. Diagnostic evaluation of the liver. In: Washabau RJ, Day MJ, eds: Canine & Feline Gastroenterology. St. Louis, MO: Elsevier Saunders; 2013:863-875.
- Valentine BA, Blue JT, Shelley SM, et al. Increased serum alanine aminotransferase activity associated with muscle necrosis in the dog. J Vet Intern Med 1990; 4(3):140-143.
- Webster CRL, Cooper JC. Diagnostic approach to hepatobiliary disease. In: Bonagura J, Twedt D, eds. Kirk’s Current Veterinary Therapy, 15th ed. St. Louis, MO: Elsevier; 2014:569-575.
- Comazzi S, Pieralisi C, Bertazzolo W. Haematological and biochemical abnormalities in canine blood: frequency and associations in 1022 samples. J Small Anim Pract 2004; 45(7):343-349.
- Center SA, Slater MR, Manwarren T, et al. Diagnostic efficacy of serum alkaline phosphatase and gamma-glutamyltransferase in dogs with histologically confirmed hepatobiliary disease: 270 cases (1980-1990). JAVMA 1992; 201(8):1258-1264.
- Center SA, Baldwin BH, Dillingham S, et al. Diagnostic value of serum gamma-glutamyl transferase and alkaline phosphatase activities in hepatobiliary disease in the cat. JAVMA 1986; 188(5):507-510.
- Kaneko JJ, Harvey J, Bruss ML. Diagnostic enzymology of domestic animals. In: Clinical Biochemistry of Domestic Animals, 6th ed. St. Louis, MO: Elsevier; 2008:358-361.
- Rabin B, Nicolosi RJ, Hayes KC. Dietary influence on bile acid conjugation in the cat. J Nutr 1976; 106(6):1241-1246.
- Ruland K, Fischer A, Hartmann K. Sensitivity and specificity of fasting ammonia and serum bile acids in the diagnosis of portosystemic shunts in dogs and cats. Vet Clin Pathol 2010; 39(1):57-64.
- Center SA, ManWarren T, Slater MR, et al. Evaluation of twelve-hour preprandial and two-hour postprandial serum bile acids concentrations for diagnosis of hepatobiliary disease in dogs. JAVMA 1991; 199(2):217-226.
- Lidbury JA, Cook AK, Steiner JM. Hepatic encephalopathy in dogs and cats. J Vet Emerg Crit Care (San Antonio) 2016; 26(4):471-487.
- Gerritzen-Bruning MJ, van den Ingh TS, Rothuizen J. Diagnostic value of fasting plasma ammonia and bile acid concentrations in the identification of portosystemic shunting in dogs. J Vet Intern Med 2006; 20(1):13-19.
- Meyer DJ, Strombeck DR, Stone EA, et al. Ammonia tolerance test in clinically normal dogs and in dogs with portosystemic shunts. JAVMA 1978; 173(4):377-379.
- Rothuizen J, van den Ingh TS. Rectal ammonia tolerance test in the evaluation of portal circulation in dogs with liver disease. Res Vet Sci 1982; 33(1):22-25.
- Walker MC, Hill RC, Guilford WG, et al. Postprandial venous ammonia concentrations in the diagnosis of hepatobiliary disease in dogs. J Vet Intern Med 2001; 15(5):463-466.
- Toulza O, Center SA, Brooks MB, et al. Evaluation of plasma protein C activity for detection of hepatobiliary disease and portosystemic shunting in dogs. JAVMA 2006; 229(11):1761-1771.
What is Alanine Aminotransferase (ALT)? Test & Normal Range
Alanine aminotransferase (ALT) is an important marker of liver health. Keep reading to find out why this marker is often part of liver function tests – and when you should be concerned about your levels.
What is ALT?
Alanine aminotransferase or ALT (also known as SGPT) is an enzyme your body needs to break down proteins into energy [1, 2].
Healthy liver cells store most of ALT, but small amounts are also found in the kidneys, heart, muscles, fat tissue, intestines, and pancreas .
Normally, blood ALT levels are low. However, when liver cells are damaged due to illness, injury, or medication, they release ALT, increasing its blood levels .
Therefore, ALT blood levels are a marker of liver health: low levels typically indicate a healthy liver, while high levels suggest liver damage .
Most of ALT is safely stored in the liver. When there is liver damage, ALT leaks into the bloodstream.
Before we talk about the ALT blood test, let’s take a look at what ALT normally does in the body.
ALT helps turn L-alanine and alpha-ketoglutarate into glucose that can be used for energy (via pyruvate) and L-glutamate which can be eliminated as waste or used to build new proteins [6, 7, 8, 9].
ALT Blood Test
An ALT blood test may be ordered to [10, 11, 12, 13]:
- Assess liver health
- Investigate symptoms of liver disease, such as abnormally yellow skin or eyes (jaundice), or pain in the upper-right section of the abdomen
- Monitor progression of a liver disease
- Evaluate the effectiveness of a treatment for liver disease
- Determine if the liver is involved in or damaged by a health condition, such as diabetes or heart disease
Since ALT is an enzyme, its levels are typically determined by measuring its activity (the rate at which ALT transforms L-alanine and α-ketoglutarate into pyruvate and L-glutamate) .
ALT levels are often measured together with the liver enzyme aspartate transaminase (AST). The ratio of AST/ALT is also sometimes used as a marker of liver health.
While ALT levels can signal the presence of liver damage, they cannot determine the type of damage, such as scarring, infection, or inflammation .
Your doctor will typically order an ALT test along with AST to assess your liver function. High levels can signal liver damage, but they don’t reveal its type or cause.
ALT is measured in units per liter of blood or U/L.
The normal range is around 7-35 U/L in women and 7-40 U/L in men. There may be some lab-to-lab variability in ranges due to differences in equipment, techniques, and chemicals used.
ALT levels typically do not change much during pregnancy. They may slightly increase during the final trimester, but generally still remain below 40 U/L [16, 17, 18, 19].
Low ALT levels are expected and normal – they are just uncommon in the general population. This is because reference ranges are based on where 95% of a healthy population falls into, which means that there are 5% of the people who are healthy and not within the reference range!
There are some factors that can decrease ALT, but they are not common. These include:
- Vitamin B6 deficiency [20, 21]
- Smoking 
- Regular exercise 
- Oral contraceptives or hormone replacement therapy [22, 24]
- Chronic kidney disease [25, 26]
Find out more about low ALT levels and associated conditions here.
High ALT levels often signal a problem with the liver. However, a result that’s higher than normal, doesn’t necessarily mean that you have a health condition that needs treatment. Your doctor will interpret your ALT result, taking into account your medical history, symptoms, and other test results.
ALT can increase due to various underlying issues. Causes shown below are commonly associated with high ALT levels. Work with your doctor or another health care professional to get an accurate diagnosis. Aforementioned conditions include:
- Liver diseases, such as fatty liver, viral hepatitis, other infections that affect the liver (mononucleosis), or liver cancer [27, 28]
- Liver damage due to toxins such as lead, mercury, or pesticides [11, 29, 30]
- Liver damage due to prescription and over-the-counter drugs and supplements [11, 31, 32, 33]
- Alcohol abuse 
- Anorexia 
- Obesity [36, 34, 37]
- Gallstones and gallstone-induced inflammation of the pancreas (pancreatitis) [38, 39]
- Muscle damage due to strenuous exercise, injury, or muscle disease [40, 41, 42]
- Tissue damage due to surgery or burns [43, 44]
- Heart attack or heart failure [45, 31]
- Underactive thyroid gland (hypothyroidism) 
- Abnormal red blood cell destruction (hemolysis) [46, 47]
Read through this post to learn more about the causes of high ALT and what you can do to decrease high ALT levels.
While one elevated ALT test doesn’t necessarily mean that you have a health condition that needs treatment, several high ALT tests or a high ALT test in conjunction with symptoms of liver damage or disease are a reason for concern. Your doctor should work on finding the underlying cause and treatment options .
Tests of other liver enzymes such as AST, ALP, bilirubin, and GGT can help create a more complete picture of liver health .
ALT is an enzyme your body needs to turn proteins into energy. Most of it is stored in your liver. Your levels will usually remain stable and relatively low if your liver is healthy, while liver damage causes ALT to leak into the bloodstream in higher amounts. Thus, doctors typically order ALT to check liver function. However, various other conditions beyond liver health can also affect your levels. That’s why doctors will analyze ALT alongside other markers of liver health like AST, ALP, bilirubin, and GGT.
Liver Function Test – About, Normal Range, Preparation, Test Results & More
what is a liver function test?
It is a group of tests that gives a statement on the health of a patient’s liver. It determines the health of the liver by evaluating the level of liver enzymes, proteins or bilirubin in the blood. The main tests in the liver function tests are prothrombin time, APTT, albumin, bilirubin.
A liver function test is recommended for the following reasons:
- To screen for any infections such as hepatitis C in the liver
- If you are consuming any medications that might have a side effect on the liver functions
- To monitor an already existing liver disease and its status during treatment
- If you have any symptoms of any liver problems or liver disease
- Planning for pregnancy
causes of liver problem:
There may be many liver damage causes. Some of them are:
- Immune system abnormality
- Habits such as excessive alcohol intake
why do i need liver function test?
The liver is a vital organ of the human body and liver functions play a vital role in the overall health of your body.
A liver function test helps in determining the condition and health of your liver in order for it to perform the following liver functions efficiently.
what is the function of a liver?
- Cleanses your blood by removing contaminants eliminating liver infections
- Helps in converting nutrients from your food intake
- Stores vitamins and minerals in your body
- Regulates blood clot
- Produces enzymes, proteins and bile
- Produces infection fighting factors
- Removes bacteria from the blood
- Processes harmful substances from the body
- Helps in balancing hormones
With so much liver functions, a problem caused in the liver can cause life-threatening diseases to the person.
what do my test results mean?
The most common blood test taken for liver function test is aminotransferases.
If your liver function test results range between 7-56 units/litre for ALT and 10-40 got AST, your liver function is normal. Anything outside the liver function test normal range means there might be some liver problems or liver infection and needs to be diagnosed and treated.
how is liver function test done?
The liver function test is like any other blood test. It may be taken at a hospital, clinic or specialised testing facility. You can administer the test by checking if the following steps are done:
- Your skin will be cleaned by the blood test technician to prevent any substances on your skin to avoid contamination of the test.
- They will wrap your arm with some sort of pressure device to make the veins more visible. They will then insert the needle into the vein to draw enough blood samples for the test.
- Once the blood is drawn, they will cover the pierced area to avoid any infection and will send the blood samples for testing to the laboratory.
does liver function test pose any risk?
Blood tests are a very common routine to check several diseases and diagnosis like the liver disease. The rare cases of risks that might happen while giving a blood sample are:
- Internal bleeding under the skin
- excessive bleeding
- fainting due to weakness after blood withdrawal
how do i prepare for the test?
You will be guided by the doctor with instructions to follow before taking the tests. You may have to avoid certain foods and medicines before the test as they might affect the levels of enzymes and proteins present in your blood.
how can we help?
Do you find yourself searching for “Liver function test near me” on google? Worry no more. We now provide services for home liver function test. If you have noticed any symptoms of a liver problem or liver infection and your doctor can recommended you to take this tests, all you have to do is contact us!
We will have a health care expert sent to your house and do the necessary procedures. The samples will be sent for testing and you will receive your liver function test report at your doorstep.
Understanding results ofLiver Function
|SGOT||The normal range for the AST test is 10 to 34 IU/L (international units per liter)|
|GGT||The normal range for GGT in blood is 0 to 51 international units/liter.|
|Total Protein||The total protein is between 6 and 8.3 gm/dL (grams per deciliter)|
|Albumin||The typical value for albumin is 3.4 to 5.4 g/dL of blood|
|Bilirubin||In an older child or adult, normal values of direct (conjugated) bilirubin are from 0 to 0.3 milligrams per deciliter (mg/dL). Normal values of total bilirubin (direct and indirect) are from 0.3 to 1.9 mg/dL. In a newborn, higher bilirubin is normal due|
‘*A Reference range is a set of values which helps the healthcare professional to interpret a medical test. It may vary with age, gender, and other factors. Reference ranges may also vary between labs, in value & units depending on instruments used and method of establishment of reference ranges’
Cow’s milk (F2), allergen-specific IgG
Method of determination
Determination of immunoglobulins of the IgG class to cow’s milk antigens.
See also test # 608 – IgE cow’s milk.
Cow’s milk is one of the most common causes of allergic reactions in children.Cow’s milk sensitization occurs in 75% of children with food allergies.
Milk allergens can be divided into caseins (curdled proteins) and milk whey proteins. Caseins (see tests No. 650, 6602 – Casein IgE, IgG) are quantitatively about 80% of all proteins in cow’s milk (in breast milk they are about 40%).
About 20% of the proteins in unprocessed milk are whey proteins. The main allergens in milk serum are beta-lactalbumin, beta-lactoglobulin (the main milk allergen, see.tests No. 649, 6601 – beta-lactoglobulin IgE, IgG), bovine serum albumin, immunoglobulins. Milk proteins, due to a deficiency of digestive enzymes and permeability of the intestinal wall in children, can enter the bloodstream unchanged. Sensitization to cow’s milk proteins can occur even in the womb or during breastfeeding against the background of intensive use of dairy products by the mother.
The most common clinical manifestations of milk allergy can be skin manifestations (itchy rash, eczema, dermatitis), gastroenteric symptoms (abdominal pain, vomiting, diarrhea, flatulence, constipation).Sometimes – respiratory symptoms (cough, asthma attacks, rhinitis). If you are allergic to cow’s milk, you may experience cross-allergic reactions when eating beef. An allergic reaction to milk proteins should be distinguished from milk intolerance associated with enzyme (lactase) deficiency (see test # 236 – Carbohydrates in the feces).
The vast majority of food allergy cases are IgE-mediated allergic reactions. Basic laboratory diagnostic allergy tests are based on detecting the presence of specific IgE antibodies in the blood (see.determination of specific IgE).
IgG antibodies are often found in food allergies, the detected IgGs are not necessarily reactive to the same proteins as IgE, their role is not fully understood. They can potentially participate in food hypersensitivity reactions: it has been shown that degranulation of mast cells and basophils can be induced not only by a complex of IgE and antigen, but also by other stimuli, for example, anaphylotoxins C3a and C5a, which are produced during the alternative (IgG4 is involved) or classical ( involved IgG1, IgG2, IgG3) pathways of complement activation.
But it is also known that IgG antibodies to an allergen can also perform the function of blocking antibodies that reduce the severity of allergic reactions involving specific IgE. IgG antibodies to food allergens can be detected in healthy people as evidence of increased consumption of certain foods without the presence of allergies to them.
The diagnostic value of the fact of detecting an increased amount of IgG to food allergens in the patient’s blood is controversial.IgG testing for food allergens is usually performed in addition to IgE testing, in order to select the optimal dietary change with the exclusion or rotation of certain food components, which can significantly improve the patient’s condition.
The purpose and interpretation of the test results should be made by a specialist who represents the limitations of this study and considers it in combination with clinical and anamnestic data and the results of other tests.
Casein, IgG (Food – Casein, IgG, F78)
Method of determination
Determination of immunoglobulins of the IgG class to one of the main milk proteins – casein.
See also test # 650 – Casein, IgE.
Casein (lat.caseus – cheese) is a complex protein formed from the precursor of casein – caseinogen when milk is curdled under the action of proteolytic enzymes. It is the main protein of milk, its content in cow’s milk during lactation is 2.8 – 3.5%, about 80% of all proteins in cow’s milk (the content of casein in human milk is half as much).
Casein contains all amino acids necessary for a person, is the main component of cottage cheese and cheese. Cow’s milk sensitization occurs in 75% of children with food allergies.also tests No. 608, 6648 – Cow’s milk IgE, IgG; No. 649, 6601 – Beta-lactoglobulin IgE, IgG).
Clinical signs of such an allergy can be skin manifestations (itchy rash, eczema, dermatitis), gastroenteric symptoms (abdominal pain, vomiting, diarrhea, flatulence and constipation), and sometimes respiratory symptoms (cough, suffocation, rhinitis). Allergy to milk proteins should be distinguished from milk intolerance, which is associated with an enzyme deficiency (see test for lactase deficiency # 236 – The content of carbohydrates in feces).The vast majority of food allergy cases are IgE-mediated allergic reactions. Basic laboratory diagnostic allergy tests are based on detecting the presence of specific IgE antibodies in the blood (see definition of specific IgE).
IgG antibodies are often found in food allergies, the detected IgGs are not necessarily reactive to the same proteins as IgE, their role is not fully understood. They can potentially participate in food hypersensitivity reactions: it has been shown that degranulation of mast cells and basophils can be induced not only by a complex of IgE and antigen, but also by other stimuli, for example, anaphylotoxins C3a and C5a, which are produced during the alternative (IgG4 is involved) or classical ( involved IgG1, IgG2, IgG3) pathways of complement activation. But it is also known that IgG antibodies to an allergen can also perform the function of blocking antibodies that reduce the severity of allergic reactions involving specific IgE. IgG antibodies to food allergens can be detected in healthy people as evidence of increased consumption of certain foods without the presence of allergies to them.
The diagnostic value of the fact of detecting an increased amount of IgG to food allergens in the patient’s blood is controversial. IgG testing for food allergens is usually performed in addition to IgE testing, in order to select the optimal dietary change with the exclusion or rotation of certain food components, which can significantly improve the patient’s condition.The appointment and interpretation of test results should be made by a specialist who represents the limitations of this study and considers it in combination with clinical and anamnestic data and the results of other tests.
90,000 Clinical Trial Malignant Melanoma: Vincristine Sulfate Liposomes for Injection – Clinical Trials Register
– Patients must have histologically proven, surgically inoperable stage III or IV.metastatic melanoma of the skin, mucous membrane or choroid and does not meet the criteria of the highest priority treatment protocol.
– Patients must have a secondary liver tumor confirmed by CT scan and a bilirubin level of 1.6-3.0 mg / dL (National Cancer Institute, General Terminology Grade 2 Adverse Events Criteria) (Anderson Cancer Center’s normal range is 0-1, 0 mg / dl).
– Patients must have a disease that can be measured in two dimensions.
– Patients with non-choroidal melanoma should undergo prior chemotherapy for metastatic disease using cytotoxic or biological agents. Patients with choroidal melanoma may or may not receive chemotherapy for metastatic disease with cytotoxic or biological drugs.
– Patients should have health status 0, 1, 2 or 3 (Zubrod scale).
– Patients must recover from the side effects of previous chemotherapy (including cytotoxic agents and biological response modifiers) and / or radiation therapy.
– Patients should have an absolute neutrophil count of ≥1.0 x 10 * 9 / L and a platelet count of ≥100 x 10 * 9 / L.
– Patients should have adequate renal function, as demonstrated by creatinine levels ≤2.0. mg / dl.
– Patient life expectancy should be> 8 weeks.
– Patients must provide a signed informed consent document confirming that they are aware of the research nature of this study in accordance with hospital policy.
– Patients undergoing radiation therapy, chemotherapy, immunotherapy, vaccinations and / or alternative cancer treatments (including investigational drugs) within 3 weeks prior to training.
– Patients who received liver chemoembolization in the 4 weeks prior to the enrollment study.
– Patients with severe hepatic impairment, plasma ammonia> 105 mmol / L or serum albumin 3.0 mg / dL.
– Patients with severe intercurrent diseases.
– Patients undergoing major surgery within 4 weeks of inclusion.
– Patients with severe symptomatic lesions of the central nervous system (CNS) melanoma and patients taking phenytoin or requiring steroids for brain metastases, spinal cord compression, or meningeal “carcinomatosis”. Patients with an asymptomatic and stable course may be reported metastatic disease of the central nervous system.
– Patients receiving phenytoin and / or corticosteroid treatment within 1 week of registration. Patients should not take these medications during the entire treatment period. treatment phase of the study.
– Patients with a history of neurological disorders not related to chemotherapy (including familial neurological diseases and acquired demyelinating disorders).
– Patients with Grade 3 or higher sensory, motor, or autonomic neuropathy at screening for any reason.
– Patients receiving treatment with drugs known to inhibit or induce hepatic drugs metabolism with cytochrome P450-3A4 isoenzymes and / or P-glycoprotein within 1 week after enrollment. Patients should not take these drugs prior to collecting Cycle 4 of the PC sample pretreatment.
– Patients with a past or current history of parenchymal or hepatobiliary liver disease not associated with cancer (including but not limited to conditions such as cirrhosis of the liver, acute / chronic hepatitis, ascending cholangitis, etc.)etc.).
– Patients who are pregnant or breastfeeding. Women of childbearing age should have a negative urine or blood pregnancy test at screening. Both men and women should be Practicing an adequate method of birth control at the time of the study. Acceptable methods of birth control include the use of an oral intrauterine device (IUD). birth control pills, implanted, transdermal or injectable contraceptives, spermicide barrier methods and abstinence.
– Patients unable to return for re-examination and assessment of response to VSLI.
13C-Metacetin breath test | Clinic “Consilium”
13 C-METHACETIN RESPIRATORY TEST FOR ESTIMATION OF LIVER FUNCTIONAL RESERVE
Bakulin I.G., Medvedev Yu.V.
North-Western State Medical University named after V.I. I.I. Mechnikov
Bakulin I.G. – Doctor of Medical Sciences Professor, Head of the Department of Propedeutics of Internal Diseases, Gastroenterology and Dietetics, North-Western State Medical University named after I.I. Mechnikov.
Medvedev Yu.V. – Postgraduate student of the Department of Propedeutics of Internal Diseases, Gastroenterology and Dietetics, North-Western State Medical University named after I.I. Mechnikov.
Due to the increase in the number of chronic liver diseases, it is necessary to revise the existing methods of screening diagnostics of these diseases. None of the widely used methods gives an idea of the functional reserve of the liver.Modern non-invasive diagnostic methods, primarily the 13C-metacetin breath test, can solve this problem. It is necessary to study the possibilities of these methods, as well as their place in the diagnosis of chronic liver diseases at the present stage.
Keywords: non-invasive methods for diagnosing fibrosis, liver fibrosis, non-invasive method for liver fibrosis, chronic liver diseases, 13C-metacetin breath test, functional reserve in chronic liver diseases
The liver performs many functions, such as synthetic, detoxification, barrier-protective, hematopoietic, endocrine, participates in the regulation of metabolic, antigenic and temperature homeostasis of the body.The liver has great reserve capabilities, clinical signs of liver dysfunction are manifested when a significant part of its cell mass is lost, when the changes that have occurred become, as a rule, irreversible. In this regard, clinical practice requires screening tests to assess the functional state of the liver.
Among a number of causes of chronic liver diseases, the most common are: hepatitis B and C viruses, alcohol abuse, fat metabolism disorders and diabetes mellitus, leading to the development of non-alcoholic fatty liver disease (NAFLD).Often these factors are present in the same patient, which accelerates the progression of the disease.
There are more than 2 billion carriers of various viral hepatitis in the world. Of these, about 400 million people suffer from chronic hepatitis B and about 170-200 million – from chronic hepatitis C . A quarter of patients with hepatic steatosis develop liver fibrosis . A number of studies have shown that in 10% of cases, within about 10 years, liver steatosis progresses to non-alcoholic steatohepatitis (NASH).In 5–25% of cases, NASH is transformed into cirrhosis of the liver (LC). It is noted that 60–80% of all cryptogenic LC are outcomes of NAFLD , and in 10% of cases referral to liver transplantation is due to the cirrhotic stage of NASH. It should be noted that NAFLD and other chronic liver diseases are at risk of developing hepatocellular carcinoma (HCC) [20,25]. The development of HCC is observed in approximately 10% of patients with cirrhotic NASH within 10 years .
Modern methods of diagnostics of liver diseases
- Laboratory tests (biochemical blood test with assessment of “liver function tests”)
- Instrumental methods: ultrasound of the abdominal cavity organs, gastroscopy, computed tomography, magnetic resonance imaging
- Methods for assessing the stage of fibrosis: puncture biopsy of the liver, fibrotests, fibroelastometry
- Calculated prognostic indices: APRI, FIB-4, MELD, FibroFast, FibroIndex, FibroMeter, Hepascor.
Methods that determine the stage of liver fibrosis are the most demanded in the clinic in terms of prognosis, as well as the choice of treatment tactics. Puncture liver biopsy is a method that is considered to be the reference method for determining the stage of liver fibrosis and the activity of inflammation . Currently, intravital morphological examination of liver tissue remains widespread in clinical practice. The methods of functional diagnostics used up to now are not able to answer questions about the actual nature of morphological changes in the liver with various lesions.Liver biopsy allows you to confirm, clarify, and often change the clinical diagnosis . It should be noted that the method has a high specificity (81-99%), but insufficiently high sensitivity (36-57%)  .
Unfortunately, this technique is invasive and can lead to the development of such complications as: intra-abdominal bleeding (0.24%) , intrahepatic hematoma (2%) , pneumothorax (0.08%) , biliary peritonitis (0.04%) , lethal outcome (0.01%) , local metastasis with targeted biopsy of malignant tumors (0.0005%) . The reason for the impossibility of performing a liver biopsy is also the fear of patients about the procedure. Fear of pain at the puncture site and side effects on anesthesia make up to a third of patients refuse to perform a liver biopsy. This leads to a slowdown in the decision to initiate specific therapy and prolongation of hospitalization [23, 32].
In addition, it is necessary to indicate the requirements for the amount of material for puncture biopsy of the liver, which may lead to insufficiently correct conclusions: the length of the column of hepatic tissue should be more than 15 mm, and the number of portal tracts should be at least 6-8 [2, 10] …It should be emphasized that liver biopsy does not provide information on liver function.
In recent years, non-invasive methods for assessing liver fibrosis, such as elastometry and fibrotests, have become widespread in clinical practice.
Conditions limiting the use of elastometry: BMI ≥ 28 kg / m 2 , active hepatitis, presence of ascites, cholestasis, presence of venous stasis in the portal vein system, operator experience, which requires further technical improvement of the method.At the same time, elastometry can be used both for screening and early diagnosis, and for clarifying the stage of liver damage and monitoring the effectiveness of therapy .
Fibrotest refers to non-invasive methods for diagnosing fibrosis and the activity of the pathological process in the liver. Fibrotest is a special biochemical blood test based on the determination of markers of fibrosis, inflammation and steatosis in the patient’s blood. For example, Fibrotest (Fibromax) includes computer processing of 5 biochemical parameters: alpha 2-macroglobulin (AMG), haptoglobulin (Hp), apolipoprotein A1 (Apo A1), gamma-glutamyltranspeptidase (GGT), total bilirubin bilirubin, albanizina …
Conditions limiting the study: acute hepatitis (any etiology), extrahepatic cholestasis. In addition, the method cannot be considered reliable in chronic inflammatory diseases of the connective tissue (rheumatism, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, etc.), hereditary hyperbilirubinemia like Gilbert’s syndrome, hemolytic anemia. Fibrotests can be considered as an alternative to another method when the latter cannot be performed due to contraindications (for example, biopsy) or due to obesity, ascites (elastometry).
It should be noted that the sensitivity and specificity of these tests is high only when they are combined (elastometry + fibrotest)  , only in this case these diagnostic methods are able to show a result similar to the result obtained with puncture liver biopsy . Despite the possibility of assessing the degree of activity and the stage of fibrosis, these methods do not allow assessing the functional state of the liver.
Breathing tests and their role in the diagnosis of liver disease
Recently, non-invasive methods for determining the functional activity of the liver, its functional reserve, using isotopic respiratory tests have been actively used abroad (tab.1) .
Table 1. The most common compounds for the diagnosis of liver function isotope breath test
|13 C 2 -aminopyrine||CYP – CYP1A2||Assessment of the activity of P450 microsomal enzymes. Assessment of the functional mass of the liver. Differential diagnosis of cirrhosis.Control of liver transplants.|
|13 C-Metacetin||CYP – CYP1A2||Assessment of the activity of P450 microsomal enzymes. Assessment of the functional mass of the liver. Differentiation of cirrhosis. Control of liver transplants.|
|13 C-phenacetin||CYP – CYP1A2||Assessment of the activity of P450 microsomal enzymes. Assessment of the functional mass of the liver. Differentiation of cirrhosis. Control of liver transplants.|
|13 C 2 – erythromycin||CYP3A4||Assessment of CYP3A enzyme activity. Pharmacological research. Individual pharmacotherapy|
|1,3,7- 13 C-caffeine||CYP1A2||Assessment of CYP1A2 enzyme activity. Pharmacological research. Individual pharmacotherapy|
|1- 13 C-phenyalanine||Cytosolic enzymes||Assessment of the functional mass of the liver.Assessment of the dynamics of the disease. Diagnosis of congenital metabolic disorders.|
|1- 13 C-galactose||Cytosolic enzymes||Assessment of the functional mass of the liver. Assessment of the dynamics of the disease. Diagnosis of congenital metabolic disorders.|
|1- 13 C -methionine.|| Mitochondrial
|Assessment of mitochondrial metabolic function of the liver.|
|1- 13 C-ketoiso-caproic acid|| Mitochondrial
|Assessment of mitochondrial metabolic function of the liver.Differential diagnosis of alcoholic steatohepatitis and non-alcoholic steatohepatitis.|
|1- 13 C-Caprylic acid|| Mitochondrial
|Assessment of mitochondrial metabolic function of the liver.|
13C-breath tests, in contrast to puncture liver biopsy , provide information on the functional reserve and metabolic capacity of the liver and can reflect the dynamics of the process, being non-invasive, safe and easily repeatable.Breath tests could play an important role in the treatment and management of chronic liver diseases, as well as in pre- and postoperative transplantation [16, 51].
However, not all 13C-labeled drugs used in breath tests to assess liver microsomal function have been thoroughly investigated. For example, there is very little information on the 13C-phenacetin breath test. Phenacetin is a highly extractive drug, therefore, its metabolism depends on blood flow in the liver, which may affect the values of breath tests in patients with liver disease, portal hypertension and hepatic shunts .
The 13C-caffeine breath test may be an adequate method for assessing the metabolic function of the liver in chronic liver disease and can be used to predict fibrosis in chronic hepatitis C and NAFLD patients, but further research is needed to evaluate the test’s convenience and ease of use  …
The 13C-methacetin and 13C-aminopyrine breath tests have been the most extensively studied and may be particularly useful in the early diagnosis of liver disease and prognosis.In contrast to aminopyrine, methacetin has a high extraction ratio, which can affect the 13C-metacetin breath test values, especially in patients with chronic liver disease with portal hypertension and portosystemic shunts .
At the same time, 13C-labeled breath tests can be performed anywhere, at any time and repeated without affecting the patient and his health.
It should be emphasized that breath tests are not an alternative to methods that assess the stage of fibrosis and inflammation (eg puncture liver biopsy ).In many cases, the most important is the assessment of the functional state of the liver, for example, in acute liver failure, when both fibrosis and inflammatory activity can be minimal. In the case of verified liver cirrhosis, information on functional reserve can also be extremely important and indicate indications for liver transplantation. These techniques can reduce the need for liver biopsies, especially when used in conjunction with other routine diagnostic tests.
Thus, it seems that breath tests such as 13C-aminopyrine and 13C-metacetin may be important in assessing the potential of the liver microsomal systems and play a decisive role in assessing the patient’s prognosis and choosing therapy for chronic liver diseases .
Role of 13C-metacetin breath test in the diagnosis of liver diseases
The most popular is the 13C-metacetin breath test (13C-MDT), due to its safety, sensitivity and specificity (Table 2) .
Table 2. Sensitivity and specificity of 13C-MDT in fibrosis and cirrhosis
|Cirrhosis of the liver||13C-metacetin breath test||<14.6%||92.6%||84.1%|
|Fibrosis||13C-metacetin breath test||<21 ‰||75.4%||79.5%|
The 13C-methacetin liver breath test was first described by Krumbiegel et al.in 1985 . Since then, it has been considered a useful tool for assessing the extent of liver damage and assessing liver functional reserve. The test of the functional activity of the liver is based on the metabolism of 13C-metacetin by its enzyme systems (CYP450), also with the formation of 13CO 2 (Fig. 1)  .
Cytochrome P450 1A2 (CYP1A2) is a hepatic enzyme that plays an important role in the metabolism of xenobiotics, including metacetin, theophylline, caffeine and clozapine .The breath test can easily assess liver function based on labeled substrates that are used and metabolized in the liver [27, 45]. 13C-MDT is the most appropriate test for assessing liver functional reserve compared to other tests [3, 31]. Compared to other molecules that are used for breath tests, 13C-methacetin is safe, cheap, and has a fast clearance [24, 31].
The test allows to determine with high accuracy the pharmacokinetic parameters of metacetin demethylation and, on this basis, to assess the degree of liver detoxification activity and even its mass.The developed mathematical models make it possible to distinguish the stage of cirrhosis, the severity of hepatitis and other diseases .
Data on obtaining quantitative characteristics of the effect of obesity in the liver on a decrease in its detoxification activity are presented. The results of the metacetin test in metastatic lesions of the liver and in the postoperative period make it possible to accurately determine the activity of intact tissue, as well as to observe the recovery of its biochemical parameters.There is information about the possibility of using 13C-MDT to study the functional activity of the liver under conditions of stagnation in the venous system of the abdominal cavity (venous plethora), achieved by placing the patient in the so-called antiorthostatic position (at an angle of -15 o to the horizon) [41 ].
The method allows to study the activation of the biliary function of the liver, as well as to determine its full (total) metabolic capacity, including the functioning and non-functioning (reserve) parts of the liver [52 ].
Studies in the antiorthostatic position -15 ° (ANOP) have shown that the mechanism of increasing excretory activity in the digestive system and activation of bile secretion in the liver are due to the onset of plethora in the venous system of the liver and abdominal cavity [39, 40]. Radioisotope methods and endoscopic studies in ANOP confirmed the role of venous stasis in the liver in activating bile secretion and showed features associated with a decrease in the excretory activity of hepatocytes and the concentration function of the bile secretion system .A decrease in the functional activity of the liver under conditions of venous plethora is not always accompanied by changes in the biochemical parameters of blood [48, 49], since its reserve capacity can mask the suppression of functional activity [55 , 56].
There are data on strong direct positive correlation (r = 0.706) between the 13C-metacetin breath test and the results of dynamic hepatoscintigraphy in patients with primary and metastatic liver damage.The authors believe that the use of 13C-MDT will improve the preoperative assessment and results of anatomical resections in these patients  .
The data presented in table 3 convincingly indicate that 13C-MDT is quite effective in stage 3-4 of liver fibrosis.
Table 3. Threshold values of 13C-MDT depending on the level of fibrosis (according to puncture biopsy of the liver)
|“Dose hour” indicator for 10 minutes|
|Fibrosis AUC (95% CI)||Cut-off||Sensitivity||Specificity||VPP||VPN|
|F1||0.822 (0.719 – 0.924)||29.75||85.7%||76.7%||64.29%||91.67%|
|F3||0.923 (0.837 – 1.000)||16.40||92.9%||86.4%||92.86%||86.36%|
|F4||0.965 (0.919 – 1.000)||11.95||96.2%||91.7%||98.04%||84.62%|
|Cumulative dose (CUM) in 60 minutes|
|Fibrosis AUC (95% CI)||Cut-off||Sensitivity||Specificity||VPP||VPN|
| 0.824 (0.723 – 0.926)
0.900 (0.820 – 0.980)
0.936 (0.868 – 1.000)
0.973 (0.935 – 1.000)
Note : “Dose / hour” indicator for 10 minutes: percentage of the administered dose per hour for 10 minutes; CUM in 60 min: Accumulation percentage (%) of the injected 13C dose released in 60 min.VPP is the predictive value of a positive result; VNP – negative predictive value .
It seems that it is necessary to continue to study the possibilities of using this method in relation to chronic liver diseases of various etiologies.
Also, according to the conclusions of the researchers, 13C-MDT can be used to assess the effectiveness of the therapy. The study was carried out on 96 patients with chronic liver diseases of various etiology; the 13C-MDT parameters were assessed over time while taking Losartan (an angiotensin II receptor blocker) as an antifibrotic agent .
The data are given that 13C-MDT has a high sensitivity in various liver lesions, the level of inflammatory activity has an effect during the test .
There are separate reports on the use of 13C-MDT in NAFLD . The authors studied 13C-MDT indices in patients with NAFLD and noted a significant decrease in liver function compared to controls (18.03% ± 0.6 and 26.46% ± 0.67, respectively). At the same time, it is indicated that the test makes it possible to assess the mass of functioning hepatocytes [5, 9].
According to the conclusions of a number of researchers, the introduction of 13C-MDT into practice will expand knowledge of the pathogenesis of liver steatosis, improve its diagnosis and treatment . At the same time, other authors note that 13C-MDT does not show differences between the control group and patients with early stages of fibrosis, and also cannot show the level of inflammation or the degree of fibrosis .
Non-invasive breath tests can serve as a valuable diagnostic tool in medicine, since they can determine the features of enzymatic and metabolic functions “in vivo” .
It should be noted that the metabolism of metacetin occurs exclusively in the liver, therefore this method has a very high specificity and sensitivity, it should also be taken into account that this method is non-invasive, it can be carried out on mass spectrometers, infrared gas analyzers used for other breathing tests with tagged carbon. The active introduction of this method into clinical practice seems to be expedient both from a scientific point of view and from an economic point of view, since this method is non-invasive, relatively easy to use and use, does not require special skills and abilities from the operator, and does not provide for special conditions for material collection.
Noteworthy is the correlation between the “liver” tests and 13C-MDT (Table 4). The most pronounced correlation was observed with the following indicators: bilirubin, GGTP, INR, prothrombin time, prothrombin index (%), factors 5 and 7.
Table 4. Relationship between 13C-MDT and “liver” tests
|PDR peak||Pico at the same time||PDR10||PDR 15||PDR 20||PDR 30||PDR 60||CPDR 10||CPDR 15||CPDR 20||CPDR 30||CPDR 60|
Note.The results obtained are expressed as a percentage of the 13C administered dose (PDR) and the allocated 13C percentage. Measured (CPDR) at 10, 15, 20, 30 and 60 minutes after methacetin intake, as well as PDR peak, and peak time. PDR refers to the rate at which 13C is output. The substrate is metabolized and exhaled, expressed as a percentage per hour. PDR is based on changing the 13C / 12C ratio for each patient. CPDR Numeric. Integral of PDR, and describes the total percentage of substrate metabolized at any given time.Data are expressed in units of percent. ALT: Alanine aminotransferase; AST: aspartate aminotransferase; GGT: Gamma Glutamyl Transpeptidase; AP: alkaline phosphatase; F-V, F-VII: Factor 5 and 7;
PDR: Percentage of dose allocated at various points in time in minutes; CPDR: Sum of percent of dose delivered at various points in time .
The authors note that the correlation between indicators of 13C-MDT and biochemical markers of hepatitis ranged from 0.2 to 0.7 (tab.five). Comparisons showed a tendency towards correlation; however, statistical significance was not achieved due to the small number of patients and tests. Based on the data presented in Table 4, the use of 13C-MDT is relevant for various chronic liver diseases, since there is a correlation between 13C-MDT and biochemical markers of hepatitis. It is indicated that more studies are needed for statistically significant results .
The principle of the breath test is based on the evaluation of the determination of the metabolizable substrate in the exhaled air.When the substrate enters the body, it passes through the bloodstream, is metabolized in the liver, and then excreted through the lungs as C 13 0 2 . The rate and volume of substrate excretion determine the metabolic function of the liver.
The drug is administered orally with a fixed dose of 75 mg per study as a solution in 200 ml of water. The first metabolic process that the drug undergoes is O-demethylation – the cleavage of the isotope-labeled 13 C-methyl group, which occurs during the catalytic action of enzymes of the liver cytochrome P450 system with the synthesis of formaldehyde.Subsequently, the label is part of formic acid and bicarbonate ion and is excreted through the lungs in the form of CO 2 . By measuring the isotopic composition of carbon in the carbon dioxide of the exhaled air, information on the rate of hepatic metabolism can be obtained.
Samples of exhaled air are taken within 2 hours – before taking the drug, every 10 minutes in the first hour of the study and every 20 minutes during the second hour. The results of each study are presented in the form of dependences of the rate of exogenous carbon label removal (PDR) on time and the total fraction of the removed label on time [29, 50].For a quantitative assessment of liver functional reserves in cirrhosis, a number of European clinics use 13C-MDT [4, 37].
In violation of the metabolic function of the liver of various origins, there is a decrease in the rate of removal of the isotope label and an increase in the time after taking the drug, during which the maximum rate is reached. In severe forms of liver disease, the rate of removal of the isotope tag is at a very low level and practically does not change within two hours, when samples of exhaled air are taken.There are studies that show a good correlation of 13C-MDT with the severity of liver damage in liver cirrhosis, depending on the Child-Pugh class [19, 36, 37].
Table 5. Interpretation of test results 
|% Cumulative dose, 120 min||Indication / Correlation|
|31.0 (25.9 – 38.7)||Standard|
|13.6 (5.7 – 22.3)||Cirrhosis of the liver, Child-Pugh Class A|
|3.1 (1.1 – 16.5)||Cirrhosis of the liver, Child-Pugh Class B|
|0.6 (-1.1 – 3.5)||Cirrhosis of the liver, Child-Pugh Class C|
Examples of clinical application of 13C-MDT
Patient O., male 55 years old, with verified Child-Pugh class A cirrhosis, HCV-etiology, non-responder (underwent a course of triple antiviral therapy).
Cirrhosis was confirmed by liver puncture biopsy.
Concomitant diseases: type 2 diabetes mellitus, insulin-required. Glycated hemoglobin 11.6%. It is noteworthy that in the presence of ultrasound signs of portal hypertension, varicose veins of the esophagus were not detected. Table 6 presents the data of laboratory and instrumental examination.
Table 6. Data of laboratory examination of patient O.
|Survey||Result||Reference values |
|ALT||96 units||6-43 Unit|
|AST||66 Unit||11-36 Unit|
|SHF||83 units||35-131 Unit|
|GGTP||114 unit||10-61 Unit|
|Bilirubin||15 μmol||3-21 μmol|
|Albumin||48 hl||33-49 hl|
|Creatinine||85 μmol||40-119 μmol|
(data from 7.11.16)
The results were evaluated according to the following indicators:
- Parameter DOB-20 (delta over base at the 20th minute of the study) is an indicator of the difference between the initial and the obtained level, i.e. % ratio of the allocated 13C label at the 20th minute of the study and the basal (background) level of 13C. In healthy patients, this indicator is 20.84 ± 1.11.
- Parameter CUM-60, CUM-120 cumulative dose by the 60th and 120th minute of the study, respectively, shows the amount of metabolized metacetin in percent, calculated based on the total released 13C during the study.
Normally, CUM-60 is 20.4%, and CUM-120 ranges from 25.9 to 38.7%.
- The Dose / h parameter shows the metabolic rate of metacetin in the liver based on the level of 13C excretion in the exhaled air. In healthy people, this value should reach a peak between the 10th and 20th minutes, then it decreases. Up to 20 minutes inclusive, the Dose / h (%) indicator for liver cirrhosis should be below 14.