Liver test levels: Alcoholic hepatitis – Symptoms and causes
Liver Function Tests for Chronic Liver Disease
Liver Function Tests
What are some of the most common liver function tests?
A series of special blood tests can often determine whether or not the liver is functioning properly. These tests can also distinguish between acute and chronic liver disorders and between hepatitis and cholestasis.
The most commonly performed blood tests include the following:
- Serum bilirubin test: This test measures the levels of bilirubin in the blood. Bilirubin is produced by the liver and is excreted in the bile. Elevated levels of bilirubin may indicate an obstruction of bile flow or a problem in the processing of bile by the liver.
- Serum albumin test: This test is used to measure the level of albumin (a protein in the blood) and aides in the diagnosis of liver disease.
- Serum alkaline phosphatase test: This test is used to measure the level of alkaline phosphatase (an enzyme) in the blood. Alkaline phosphatase is found in many tissues, with the highest concentrations in the liver, biliary tract, and bone. This test may be performed to assess liver functioning and to detect liver lesions that may cause biliary obstruction, such as tumors or abscesses.
- Serum aminotransferases (transaminases): This enzyme is released from damaged liver cells.
- Prothrombin time (PTT) test: The prothrombin time test measures how long it takes for blood to clot. Blood clotting requires vitamin K and a protein that is made by the liver. Prolonged clotting may indicate liver disease or other deficiencies in specific clotting factors.
- Alanine transaminase (ALT) test: This test measures the level of alanine aminotransferase (an enzyme found predominantly in the liver) that is released into the bloodstream after acute liver cell damage. This test may be performed to assess liver function, and/or to evaluate treatment of acute liver disease, such as hepatitis.
- Aspartate transaminase (AST) test: This test measures the level of aspartate transaminase (an enzyme that is found in the liver, kidneys, pancreas, heart, skeletal muscle, and red blood cells) that is released into the bloodstream after liver or heart problems.
- Gamma-glutamyl transpeptidase test: This test measures the level of gamma-glutamyl transpeptidase (an enzyme that is produced in the liver, pancreas, and biliary tract). This test is often performed to assess liver function, to provide information about liver diseases, and to detect alcohol ingestion.
- Lactic dehydrogenase test: This test can detect tissue damage and aides in the diagnosis of liver disease. Lactic dehydrogenase is a type of protein (also called an isoenzyme) that is involved in the body’s metabolic process.
- 5′-nucleotidase test: This test measures the levels of 5′- nucleotidase (an enzyme specific to the liver). The 5′- nucleotidase level is elevated in persons with liver diseases, especially those diseases associated with cholestasis (disruption in the formation of, or obstruction in the flow of bile).
- Alpha-fetoprotein test: Alpha-fetoprotein (a specific blood protein) is produced by fetal tissue and by tumors. This test may be performed to monitor the effectiveness of therapy in certain cancers, such as hepatomas.
- Mitochondrial antibodies test: The presence of these antibodies can indicate primary biliary cirrhosis, chronic active hepatitis, and certain other autoimmune disorders.
Liver Function Tests – StatPearls
The liver, located in the right upper quadrant of the body and below the diaphragm is responsible for several functions including primary detoxification of various metabolites, synthesizing proteins, and producing digestive enzymes. The liver also has a significant role in metabolism, regulation of red blood cells (RBCs) and glucose synthesis and storage.
Typically when reviewing LFTs, the discussion includes alanine transaminase (ALT) and aspartate transaminase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), serum bilirubin, prothrombin time (PT), the international normalized ratio (INR) and albumin. These tests can be helpful in determining the area of hepatic injury, and the pattern of elevation can help organize a differential diagnosis.
The term “liver function tests“ is a misnomer as many of the tests do not comment on the function of the liver but rather pinpoint the source of the damage. Elevations in ALT and AST in out of proportion to ALP and bilirubin denotes a hepatocellular disease. Whereas, an elevation in ALP and bilirubin in disproportion to ALT and AST would denote a cholestatic pattern. The actual function of the liver can be graded based on its ability to produce albumin as well as vitamin K dependent clotting factors.
Etiology and Epidemiology
Elevated LFTs are found in approximately 8% of the general population. These elevations may be transient in patients without symptoms with up to 30% elevations resolving after 3 weeks. Thus, care should be taken when interpreting these results to avoid unnecessary testing.
Differential Diagnosis Based on Elevated LFTs
Hepatocellular pattern: Elevated aminotransferases out of proportion to alkaline phosphatase
ALT-predominant: Acute or chronic viral hepatitis, steatohepatitis, acute Budd-Chiari syndrome, ischemic hepatitis, autoimmune, hemochromatosis, medications/toxins, autoimmune, alpha1-antitrypsin deficiency, Wilson disease, Celiac disease
AST-predominant: Alcohol-related, steatohepatitis, cirrhosis, non-hepatic (hemolysis, myopathy, thyroid disease, exercise)
Cholestatic pattern: elevated alkaline phosphatase + GGT + bilirubin out of proportion to AST and ALT
Hepatobiliary causes: Bile duct obstruction, primary biliary cirrhosis, primary sclerosing cholangitis, medication-induced, infiltrating diseases of the liver (sarcoidosis, amyloidosis, lymphoma, among others), cystic fibrosis, hepatic metastasis, cholestasis
Non-Hepatic causes of elevated alkaline phosphatase: Bone disease, pregnancy, chronic renal failure, lymphoma or other malignancies, congestive heart failure, childhood growth, infection or inflammation
Components of Liver Function Test
Aminotransferase includes AST and ALT. They are markers of hepatocellular injury. They participate in gluconeogenesis by catalyzing the transfer of amino groups from aspartic acid or alanine to ketoglutaric acid to produce oxaloacetic acid and pyruvic acid respectively. AST is present in cytosolic and mitochondrial isoenzymes and is found in the liver, cardiac muscle skeletal muscle, kidneys, brain, pancreas, lungs, leucocytes, and red cells. It is not as sensitive or specific for the liver, and elevation in AST may be seen as secondary to nonhepatic causes as well. ALT is a cytosolic enzyme that is found in high concentrations in the liver. Hepatocellular injury and not necessarily cell death is the trigger for the release of these enzymes into the circulation. Both AST and ALT values are higher in normal males than females. They also correlate with obesity with normal reference range higher in those with higher body mass index.
Alkaline phosphatase is part of a family zinc metalloenzymes that are highly concentrated in the microvilli of the bile canaliculus as well as several other tissues (e. g., bone, intestines, placenta). During growth, due to increased osteoblastic activity, elevated levels of ALP are seen in children and adolescents. The normal reference range levels also increase with age in females. Glycoprotein gamma-glutamyltransferase (GGT) is located on membranes of cells with high secretory or absorptive activities. Its main function is to catalyze the transfer of a gamma-glutamyl group from peptides to other amino acids. It is also abundant in many other sources of the body (kidney, pancreas, intestine, and prostate, testicles, spleen, heart, and brain) but is more specific for biliary disease when compared to alkaline phosphatase because it is not present in bone. The levels of GGT are higher in infants.
Bilirubin is the end result of heme catabolism, with 80% being derived from hemoglobin. Unconjugated bilirubin is transported to the liver loosely bound to albumin. Bilirubin is water-insoluble and cannot be excreted in the urine. Bilirubin that is conjugated is water-soluble and appears in the urine. It is conjugated in the liver to bilirubin glucuronide and subsequently secreted into bile and the gut respectively.
Synthetic Function Tests
Albumin is synthesized in the liver, producing approximately 10 grams per day. With any liver disease, there is a fall in serum albumin, reflecting decreased synthesis. If liver function is normal and serum albumin is low, this may reflect on poor protein intake (malnutrition) or protein loss (nephrotic syndrome, malabsorption, or protein-losing enteropathy).
Prothrombin time (PT) measures the rate of conversion of prothrombin to thrombin. Except for factor VIII, all other coagulation factors are synthesized by the liver. Prothrombin time requires factors II, V, VII, and X and, as these are made in the liver, the liver’s function is crucial in coagulation. If the synthetic function of the liver is normal and prothrombin time is delayed this may indicate treatment with warfarin, consumptive coagulopathy (e.g., disseminated intravascular coagulopathy), or deficiency of vitamin K.
Results, Reporting, Critical Findings
Reference ranges for LFTs tend to vary depending on the laboratory. Further, normal reference ranges vary between males and females and may be higher for those with higher body mass index.
Alanine transaminase: 0 to 45 IU/L
Aspartate transaminase: 0 to 35 IU/L
Alkaline phosphatase: 30 to 120 IU/L
Gamma-glutamyltransferase: 0 to 30 IU/L
Bilirubin: 2 to 17 micromoles/L
Prothrombin time: 10.9 to 12.5 seconds
Albumin: 40 to 60 g/L
The levels of LFTs can point to the differentials. Many disease processes have very distinct abnormalities in the liver enzymes. Further investigation is warranted if repeated tests confirm abnormality.
In patients with alcoholism, AST to ALT ratio is generally at least 2:1, showing a high level of AST activity in alcoholic liver disease. Elevated GGT along with AST also suggests alcohol abuse. GGT shall be used alone since it is not very specific for alcohol.
Several medications are known to cause liver damage. Many of these are commonly used in daily practice including but not limited to NSAIDs, antibiotics, statins, anti-seizure drugs, and drugs for tuberculosis treatment. Acute hepatocellular injury can be seen secondary to several drugs including but not limited to acetaminophen, allopurinol, NSAIDs, alcohol, anti-tuberculosis medications such as isoniazid, pyrazinamide, and rifampin, statins, antifungals such as ketoconazole, antibiotics such as tetracyclines, anti-seizure medications such as valproic acid and phenytoin, antidepressants such as fluoxetine, antipsychotics such as risperidone and antivirals such as valacyclovir and ritonavir. Acute cholestasis can be seen secondary to drugs including anabolic steroids, NSAIDs, tricyclic antidepressants, alcohol, antibiotics such as azithromycin, amoxicillin, nafcillin, rifampin, and trimethoprim-sulfamethoxazole. Long-term use of these agents can also lead to chronic hepatocellular and/or cholestatic liver damage. Methotrexate, he commonly used medication for rheumatoid arthritis and other inflammatory arthritis can cause a mild transient elevation in LFTs, and can also cause permanent liver damage in liver fibrosis and cirrhosis, especially with higher cumulative doses. Liver fibrosis can also be seen as secondary to chronic alcohol intake or methyldopa. Ergot alkaloids can result in ischemic necrosis. Oral contraceptives can result in hepatic venous outflow obstruction (Budd-Chiari syndrome). Herbal medications can also cause an elevation in LFTs.
Viral illnesses are a common cause of hepatitis and elevation in LFTs. Viral hepatitis B, C, and D can cause chronic hepatitis, while hepatitis A and E cause acute viral hepatitis. Several other viruses including HIV, Epstein-Barr (EBV) and Cytomegalovirus (CMV) can also cause hepatitis.
Autoimmune hepatitis is a chronic disease that is characterized by continuing hepatocellular inflammation and necrosis and a tendency to progress to cirrhosis. It is more common in young women than men with a 4:1 ratio. The patient usually presents with high LFTs without apparent cause. These patients can have positive autoantibodies including antinuclear antibody, anti-smooth muscle antibody, anti-liver/kidney microsomal antibodies, and antibodies to the liver antigen.
Hepatic Steatosis and Nonalcoholic Steatohepatitis
Fatty liver disease aka nonalcoholic steatohepatitis has gained more attention recently because of its ability to cause chronic hepatic disease as well as hepatocellular carcinoma (HCC). The typical patient with this disease is overweight, has type II diabetes, or has dyslipidemia and no evidence of clinically significant alcohol use. The AST and ALT are usually both elevated with a ratio of 1:1, with other liver function tests being normal.
Hemochromatosis is the abnormal accumulation of iron in parenchymal organs, leading to organ toxicity. It is the most common autosomal recessive genetic disorder and the most common cause of severe iron overload. Clinical manifestations include diabetes, liver disease, and cutaneous hyperpigmentation. A raised serum ferritin level usually raises concerns for possible hemochromatosis, but a transferrin saturation greater than 45% is more reliable. HFE mutations (C282Y, H63D) is pivotal for the diagnosis of hereditary hemochromatosis. Secondary hemochromatosis can also be seen due to increased iron intake.
Wilson disease, a rare autosomal-recessive inherited disorder of copper metabolism, is characterized by excess copper deposition in the liver, brain, and other tissues. It is fatal if not recognized and treated early. A low serum ceruloplasmin level is seen in the majority (up to 85%) of the cases. Kayser-Fleischer rings can be a clinical clue but are not present all the time. The 24-hour urinary copper excretion test is usually abnormal with more than 100 micrograms of copper excretion in the urine indicating Wilson’s disease. A liver biopsy remains the confirmatory test. 
Alpha-1 Antitrypsin Deficiency
Alpha-1 antitrypsin deficiency (AATD) is a relatively common yet often undiagnosed genetic condition. Those with AATD are also predisposed to obstructive pulmonary disease and liver disease (e.g., cirrhosis and hepatocellular carcinoma in children and adults). AATD is one of the most common inherited disorders among Caucasians. Its primary manifestation is early-onset panacinar emphysema.
Enhancing Healthcare Team Outcomes
The liver function tests are one of the most commonly ordered laboratory tests. Mild isolated elevations in LFTs can be seen as normal fluctuations and shall not trigger expensive and extensive workup. However, physicians shall be aware of various conditions that can lead to an elevation in LFTs. Thorough history taking and physical examination can provide clues to the differential diagnosis. Drug and medication history is of utmost importance. The nursing team shall help with medication reconciliation. Pharmacists can also assist in identifying potentially hepatotoxic agents. Referral to specialists such as hepatologists may sometimes be indicated. An interprofessional team approach can help identify the underlying etiology with appropriate management.[Level 5]
Continuing Education / Review Questions
- Ribeiro AJS, Yang X, Patel V, Madabushi R, Strauss DG. Liver Microphysiological Systems for Predicting and Evaluating Drug Effects. Clin Pharmacol Ther. 2019 Jul;106(1):139-147. [PMC free article: PMC6771674] [PubMed: 30993668]
- Vagvala SH, O’Connor SD. Imaging of abnormal liver function tests. Clin Liver Dis (Hoboken). 2018 May;11(5):128-134. [PMC free article: PMC6385957] [PubMed: 30992803]
- Wilkerson RG, Ogunbodede AC. Hypertensive Disorders of Pregnancy. Emerg Med Clin North Am. 2019 May;37(2):301-316. [PubMed: 30940374]
- Gupta M, Choudhury PS, Singh S, Hazarika D. Liver Functional Volumetry by Tc-99m Mebrofenin Hepatobiliary Scintigraphy before Major Liver Resection: A Game Changer. Indian J Nucl Med. 2018 Oct-Dec;33(4):277-283. [PMC free article: PMC6194760] [PubMed: 30386047]
- Leoni S, Tovoli F, Napoli L, Serio I, Ferri S, Bolondi L. Current guidelines for the management of non-alcoholic fatty liver disease: A systematic review with comparative analysis. World J Gastroenterol. 2018 Aug 14;24(30):3361-3373. [PMC free article: PMC6092580] [PubMed: 30122876]
- Prati D, Taioli E, Zanella A, Della Torre E, Butelli S, Del Vecchio E, Vianello L, Zanuso F, Mozzi F, Milani S, Conte D, Colombo M, Sirchia G. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med. 2002 Jul 02;137(1):1-10. [PubMed: 12093239]
- Ruhl CE, Everhart JE. Trunk fat is associated with increased serum levels of alanine aminotransferase in the United States. Gastroenterology. 2010 Apr;138(4):1346-56, 1356.e1-3. [PMC free article: PMC2847039] [PubMed: 20060831]
- Cabrera-Abreu JC, Green A. Gamma-glutamyltransferase: value of its measurement in paediatrics. Ann Clin Biochem. 2002 Jan;39(Pt 1):22-5. [PubMed: 11853185]
- Moussavian SN, Becker RC, Piepmeyer JL, Mezey E, Bozian RC. Serum gamma-glutamyl transpeptidase and chronic alcoholism. Influence of alcohol ingestion and liver disease. Dig Dis Sci. 1985 Mar;30(3):211-4. [PubMed: 2857631]
- Radovanović-Dinić B, Tešić-Rajković S, Zivkovic V, Grgov S. Clinical connection between rheumatoid arthritis and liver damage. Rheumatol Int. 2018 May;38(5):715-724. [PubMed: 29627896]
- Zhong HJ, Sun HH, Xue LF, McGowan EM, Chen Y. Differential hepatic features presenting in Wilson disease-associated cirrhosis and hepatitis B-associated cirrhosis. World J Gastroenterol. 2019 Jan 21;25(3):378-387. [PMC free article: PMC6343092] [PubMed: 30686905]
Common Liver Tests
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What are some common liver tests?
A series of blood tests can often find out if the liver is inflamed, injured, or working normally. These tests can also tell the difference between acute and chronic liver disorders. And they can tell the difference between hepatitis (infection or inflammation of the liver) and cholestasis (problems with the flow of bile).
The most common blood tests are below.
Liver function tests
Serum bilirubin test. This test measures the levels of bilirubin in the blood. Bilirubin is made by the liver and is excreted in the bile. High levels of bilirubin may mean there is a blockage of bile flow or a problem with how the liver processes bile.
Serum albumin test. This test is used to measure the level of albumin. Albumin is a protein in the blood. The test may help in the diagnosis of liver disease. Low levels of albumin may mean the liver is not working normally.
International normalized ratio (INR). This used to be known as the prothrombin time (PT) test. This test measures how long it takes for blood to clot. Blood clotting needs vitamin K and a protein that is made by the liver. Blood that takes a long time to clot may mean liver disease or low levels of certain clotting factors.
Liver enzyme tests
Serum alkaline phosphatase test. This test is used to measure the blood level of an enzyme called alkaline phosphatase. This enzyme is found in many tissues. The highest amounts are in the liver, biliary tract, and bones. This test may be done to check liver function. And it may be done to find liver lesions that may cause bile blockage, such as tumors or abscesses.
Alanine transaminase (ALT) test. This test measures the level of alanine aminotransferase. This is an enzyme found mostly in the liver. It is released into the bloodstream after acute liver cell damage. This test may be done to check liver function. Or it may be done to check on the treatment of acute liver disease, such as hepatitis.
Aspartate transaminase (AST) test. This test measures the level of aspartate transaminase. This is an enzyme that is found in the liver, kidneys, pancreas, heart, skeletal muscle, and red blood cells. This enzyme is released into the bloodstream after acute liver cell damage.
Gamma-glutamyl transpeptidase (GGT) test. This test measures the level of gamma-glutamyl transpeptidase. This is an enzyme that is made in the liver, pancreas, and biliary tract. This test is often done to check liver function, to give information about liver diseases, and to see if a person has had alcohol.
Lactic dehydrogenase test. This test can find tissue damage and may help in the diagnosis of liver disease. Lactic dehydrogenase is a type of protein. It is also called an isoenzyme. It is involved in the body’s metabolic process. But this is a very nonspecific liver test. It is rarely used for liver disease assessment.
5′-nucleotidase test. This test measures the levels of 5′- nucleotidase. This is an enzyme made only in the liver. The 5′- nucleotidase level is high in people with liver diseases, especially diseases that cause problems with the flow of bile (cholestasis).
Other diagnostic tests
Other diagnostic liver tests may be done if a specific disease is suspected. These tests include:
Alpha-fetoprotein (AFP) test. Alpha-fetoprotein is a blood protein made by fetal tissue and by tumors. This test may be done to predict the risk for primary liver cancer (hepatocellular carcinoma). It is also done to see how well therapy is working to treat certain cancers, such as hepatoma (a type of liver cancer).
Antimitochondrial antibodies (AMAs).These antibodies in the blood can mean primary biliary cirrhosis, chronic active hepatitis, or other autoimmune disorders.
Serum alpha-1 antitrypsin test (A1AT). This test measures the levels of alpha-1 antitrypsin in the blood. This test is done to help find a rare form of emphysema in adults. And it is done to find a rare form of liver disease (cirrhosis) in children and adults.
Viral hepatitis tests. These check if you have or had hepatitis A, B, C, or D.
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Tests and Investigations | Children’s Liver Disease Foundation
Liver function tests explained:
It’s important to note that every child will have their own ‘normal’ and whilst these levels are a guide, it doesn’t necessarily mean a result outside of these ranges is dangerous. Always talk to your child’s medical team if you have any worries about test results. LFTs show the amount of inflammation in the liver, whether the bile ducts are affected and how well the liver is functioning.
|Name of test||Normal range||What does this show?|
a) Total bilirubin
b) Conjugated bilirubin
a) 3 – 20 mmol/l
b) Conjugated less than 7 mmol/l
|The total bilirubin level corresponds to the level of jaundice present.The amount of conjugated bilirubin compared to the unconjugated bilirubin can show whether jaundice is caused by red blood cells breaking up too quickly (not a liver disease) or is due to a reduced flow of bile out of the liver.
Conjugated means that a sugar has been added to the bilirubin.
|Aspartate Aminotransferase (AST)||10 – 40 IU/I||High levels can mean there is liver inflammation present.|
|Alanine Aminotransferase (ALT)|
(GGT, gGT or Gamma GT)
|5 – 55 IU/L||High levels can mean bile duct inflammation or obstruction.The results can sometimes give information about bile production.|
|Alkaline Phosphatase (ALP)||Less than 350 IU/L||High levels can mean there is bile duct inflammation
ALP is not specific to the liver as it is also produced in other organs e.g. bones. Therefore, abnormal levels can be due to processes occurring in other parts of the body.
|Total Protein||60 – 80 g/l||High and low levels can be used in consideration with the other LFT results|
|Albumin||35 – 50 g/l||Low levels can mean the liver is not making enough, that protein is being lost through the stool or a child is not well nourished.|
Another blood test which is helpful to assess how the liver is working is a blood clotting test. Blood is taken, chemicals are added to it in the lab and the time taken for blood to clot is measured.
|Name of test||Normal range||What does this show?|
|Blood Clotting (Coagulation) Test
a) PT (Prothrombin time)
b) INR (International normalised ratio*)
*INR is a standardised version of the PT for comparison, they both measure the same thing
|a) 12 – 15 seconds
b) 0.9 – 1.2
|The liver produces substances needed for blood to clot.Raised levels can mean there is less Vitamin K due to a reduced bile flow.
If Vitamin K is given and the result is still raised, it may mean there is damage to the liver.
Other blood tests include:
|Name of test||What is measured?|
|Full blood count (FBC)||Haemoglobin (Hb)White blood cell count (WBC)
Platelets (Plt) – levels can fall in liver disease if the spleen is enlarged.
|Urea and electrolytes||Urea and creatinine are waste products removed by the kidneys.Electrolytes include sodium, chloride and calcium.|
|Blood glucose||A high or low level of sugar in the blood can sometimes be a sign of liver damage or a metabolic liver disease.|
|Ammonia||Ammonia is a waste product. It is converted into urea in the liver and is then removed in urine.A higher level than usual may mean there is damage to the liver or an underlying metabolic condition.|
Some of these tests may be used to monitor the effects of medications on the body.
This website provides general information but does not replace medical advice. It is important to contact your/your child’s medical team if you have any worries or concerns
Liver Function Tests | HealthLink BC
Some blood tests are used to determine whether your liver is damaged or inflamed. Although these tests help your doctor evaluate how well your liver is working, they cannot tell if you have hepatitis C.
Tests that assess liver function
Your doctor may do tests to measure certain chemicals produced by the liver. These tests can help your doctor check how well your liver is working.
Tests may measure:
Tests that check for inflammation of the liver (liver enzyme studies)
Your liver may be damaged if you have increased levels of:
An increased level of alkaline phosphatase (AP) may indicate blockage of bile ducts.
Why It Is Done
Liver tests are done when a medical history or physical examination suggests that something may be wrong with your liver.
These tests can also help diagnose long-term (chronic) infection. If liver enzymes are high, a test for hepatitis C antibodies may be done to see if you have hepatitis C.
If you are being treated with antiviral therapy, you may have liver tests from time to time to see whether treatment is working.
Findings of liver function tests may include the following:
All levels are within the normal range.
One or more levels are outside the normal range. Abnormal liver function tests may indicate that your liver is inflamed or is not working normally. This can be a sign that you have a viral infection.
What To Think About
Elevated liver enzymes can be caused by many things other than hepatitis C, such as obesity, hepatitis B, autoimmune hepatitis, certain medicines, or long-term alcohol use. So you will need other tests (such as a hepatitis C antibody blood test or a liver biopsy) to confirm a diagnosis of hepatitis C.
People with chronic hepatitis C have abnormal liver enzyme levels most of the time. But the levels can fluctuate between normal and abnormal throughout the course of the disease.
Liver tests can be used to help you and your doctor develop a treatment plan. Signs that you might need treatment include:
- Liver enzyme levels that remain above normal for longer than 6 months, which is evidence of chronic infection.
- Detectable levels of hepatitis C virus in your blood (positive hepatitis C RNA test). This is a sign of an active infection.
- Evidence of serious liver damage. This is detected with a liver biopsy.
Current as of: December 9, 2019
Author: Healthwise Staff
Medical Review: E. Gregory Thompson, MD – Internal Medicine
Brian O’Brien, MD, FRCPC – Internal Medicine
Adam Husney, MD – Family Medicine
Martin J. Gabica, MD – Family Medicine
W. Thomas London, MD – Internal Medicine, Hepatology
Current as of: December 9, 2019
Author: Healthwise Staff
Medical Review:E. Gregory Thompson, MD – Internal Medicine & Brian O’Brien, MD, FRCPC – Internal Medicine & Adam Husney, MD – Family Medicine & Martin J. Gabica, MD – Family Medicine & W. Thomas London, MD – Internal Medicine, Hepatology
Liver function tests – Lab Tests Online AU
Liver Function Tests (LFTs) may be used to screen a person for liver damage, especially someone who has a condition, or is taking a drug, that may affect the liver.
LFTs or one or more component tests may be used to help detect liver disease if a person has symptoms that indicate possible liver dysfunction or if a person is being monitored or treated for a known condition or liver disease. A bilirubin test, for instance, may be ordered to evaluate and monitor a jaundiced newborn.
Abnormal tests on a liver function tests panel may prompt a repeat analysis to see if the elevation or decrease persists and/or may indicate the need for additional testing to determine the cause of the liver dysfunction.
The group of tests may also be ordered to monitor liver function and the effectiveness of treatment in someone who has a liver disease.
LFTs, or one or more components, may be ordered when someone is at risk for liver dysfunction. Some examples include:
- people who have a history of known or possible exposure to hepatitis viruses
- those who are heavy alcohol drinkers
- individuals whose families have a history of liver disease
- people who take drugs that might occasionally damage the liver
LFTs may be ordered when a person has and of liver disease. Some of these include:
- Weakness, fatigue
- Loss of appetite
- Nausea, vomiting
- Abdominal swelling and/or pain
- Dark urine, light coloured stool
- Itching ()
Usually no one single set of liver tests are used to make a diagnosis. Often, several LFTs will be ordered over a few days or weeks to determine if a pattern is present and to help determine the cause of the liver disorder.
When liver disease is detected, it may be monitored on a regular basis over time with the LFTs or with one or more of its components. LFTs may also be ordered regularly to monitor the effectiveness of treatment for the liver disorder.
LFT results are not diagnostic of a specific condition; they indicate that there may be a problem with the liver. In a person who does not have symptoms or identifiable risk factors, abnormal liver test results may indicate a temporary liver injury or reflect something that is happening elsewhere in the body – such as in the skeletal muscles, pancreas, or heart. It may also indicate early liver disease and the need for further testing and/or periodic monitoring.
Results of LFTs are usually evaluated together. Several sets of results from tests performed over a few days or weeks are often assessed together to determine if a pattern is present. Each person will have a unique set of test results that will typically change over time. A doctor evaluates the combination of liver test results to gain clues about the underlying condition. Often, further testing is necessary to determine what is causing the liver damage and/or disease.
The table below shows examples of some combinations of results that may be seen in certain types of liver conditions or diseases.
Type of liver condition or disease
ALT and AST
ALP and GGT
liver damage (due, for example, to infection, toxins or drugs, etc.)
Normal or increased usually after ALT and AST are already increased
Usually greatly increased; ALT is usually higher than AST
Normal or only moderately increased
forms of various liver disorders
Normal or increased
Normal to slightly increased
Normal or increased
AST is usually higher than the level of ALT
Normal or moderately increased, GGT markedly increased
May be increased but this usually occurs later in the disease
AST is usually higher than ALT but levels are usually lower than in alcoholic disease
Normal or increased
Bile duct obstruction, cholestasis
Normal or increased; increased in complete obstruction
Normal to moderately increased
Increased; often greater than 4 times what is normal
Usually normal but if the disease is chronic, levels may decrease
Cancer that has spread to the liver (metastasized)
Normal or slightly increased
Usually greatly increased
Cancer originating in the liver (hepatocellular carcinoma, HCC)
May be increased, especially if the disease has progressed
AST higher than ALT but levels lower than that seen in alcoholic disease
Normal or increased
Normal or increased
Normal or slightly increased
Normal or decreased
If a person is taking drugs that may affect their liver, then abnormal test results may indicate a need to re-evaluate the dosage or choice of medication. When a person with liver disease is being monitored, then the doctor will evaluate the results of the liver panel together to determine if liver function in worsening or improving. For example, increasingly abnormal bilirubin, albumin, and/or PT may indicate a deterioration in liver function, while stable or improving results of these tests may indicate liver function preservation or improvement.
For individual tests:
Alanine aminotransferase (ALT)
A very high level of ALT is frequently seen with acute hepatitis. Moderate increases may be seen with chronic hepatitis. People with blocked bile ducts, cirrhosis, and liver cancer may have ALT concentrations that are only moderately elevated or close to normal.
Alkaline phosphatase (ALP)
ALP may be significantly increased with obstructed bile ducts, liver cancer, and also with bone disease.
Aspartate aminotransferase (AST)
A very high level of AST is frequently seen with acute hepatitis. AST may be normal to moderately increased with chronic hepatitis. In people with blocked bile ducts, cirrhosis, and liver cancer, AST concentrations may be moderately increased or close to normal. When liver damage is due to alcohol, AST often increases much more than ALT (this is a pattern seen with few other liver diseases). AST is also increased after heart attacks and with muscle injury.
Bilirubin is increased in the blood when too much is being produced, less is being removed, due to bile duct obstructions, or to problems with bilirubin processing. It is not uncommon to see high bilirubin levels in newborns, typically 1 to 3 days old.
Albumin is often normal in liver disease but may sometimes be low due to decreased production.
Total protein is typically normal with liver disease.
Gamma-glutamyl transferase (GGT)
A GGT test may be used to help determine the cause of an elevated ALP. Both ALP and GGT are elevated in bile duct and liver disease, but only ALP will be elevated in bone disease. Increased GGT levels are also seen with alcohol consumption and often in patients taking some drugs that are metabolized in the liver such as carbamazepine and phenobarbitone.
Prothrombin Time (PT)
A prolonged or increased PT can be seen with liver disease, vitamin K deficiency, and with coagulation factor deficiencies.
Laboratory Tests of the Liver and Gallbladder – Hepatic and Biliary Disorders
Bilirubin, the pigment in bile, is produced from the breakdown of heme proteins, mostly from the heme moiety of hemoglobin in senescent red blood cells. Unconjugated (free) bilirubin is insoluble in water and thus cannot be excreted in urine; most unconjugated bilirubin is bound to albumin in plasma. Bilirubin is conjugated in the liver with glucuronic acid to form the more water-soluble bilirubin diglucuronide. Conjugated bilirubin is then excreted through the biliary tract into the duodenum, where it is metabolized into urobilinogens (some of which are reabsorbed and resecreted into bile), then into orange-colored urobilins (most of which are eliminated in feces). These bile pigments give stool its typical color.
Hyperbilirubinemia results from one or more of the following:
Increased bilirubin production
Decreased liver uptake or conjugation
Decreased biliary excretion (see Jaundice)
Normally, total bilirubin is mostly unconjugated, with values of < 1.2 mg/dL (< 20 micromol/L). Fractionation measures the proportion of bilirubin that is conjugated (ie, direct, so-called because it is measured directly, without the need for solvents). Fractionation is most helpful for evaluating neonatal jaundice and for evaluating elevated bilirubin when other liver test results are normal, suggesting that hepatobiliary dysfunction is not the cause.
Unconjugated hyperbilirubinemia (indirect bilirubin fraction > 85%) reflects increased bilirubin production (eg, in hemolysis) or defective liver uptake or conjugation (eg, in Gilbert syndrome). Such increases in unconjugated bilirubin are usually < 5 times normal (to < 6 mg/dL [< 100 micromol/L]) unless there is concurrent liver injury.
Conjugated hyperbilirubinemia (direct bilirubin fraction > 50%) results from decreased bile formation or excretion (cholestasis). When associated with other liver test abnormalities, a high serum bilirubin indicates hepatocellular and/or biliary tract dysfunction. Serum bilirubin is somewhat insensitive for liver dysfunction. However, the development of severe hyperbilirubinemia in primary biliary cholangitis (also called primary biliary cirrhosis), primary sclerosing cholangitis, alcoholic hepatitis, and acute liver failure suggests a poor prognosis.
Bilirubinuria reflects the presence of conjugated bilirubin in urine; bilirubin spills into urine because blood levels are markedly elevated, indicating severe disease. Unconjugated bilirubin is water insoluble and bound to albumin and so cannot be excreted in urine. Bilirubinuria can be detected at the bedside with commercial urine test strips in acute viral hepatitis or other hepatobiliary disorders, even before jaundice appears. However, the diagnostic accuracy of such urine tests is limited. Results can be falsely negative when the urine specimen has been stored a long time, vitamin C has been ingested, or urine contains nitrates (eg, due to urinary tract infections). Similarly, increases in urobilinogen are neither specific nor sensitive.
90,000 Evaluation of liver function tests. – obstetrics and gynecology, urology, therapy, endocrinology, ultrasound diagnostics, laboratory diagnostics
Evaluation of liver tests.
1. WHAT ARE LIVER SAMPLES?
Many laboratory tests can be characterized by
as “liver function tests”. These include such biochemical
indicators like alanine aminotransferase (ALT), aspartate aminotransferase
(ACT), gamma glutamyltransferase (GTT), alkaline phosphatase (ALP), bilirubin
and serum proteins (incl.including albumin). These tests also sometimes
called functional liver function tests and liver enzymes;
however, none of the definitions is completely accurate. Only
the first four can be called actually enzymes, and only the last two
reflect the actual function of the liver. Liver tests can be used to characterize
existing violations and approximately evaluate the synthetic function
liver.These tests are not fully diagnostic, although
their various combinations are useful in the diagnosis of specific diseases.
Several other liver function tests are described below. In the end
account, some tests help to identify specific causes of diseases
liver. Neither serological (for example, the determination of antibodies to the virus
hepatitis C), nor biochemical (for example, determination of the level of alpha1-antitrypsin)
tests are usually not used for screening analysis and routine
2. WHAT ARE TRUE FUNCTIONAL LIVER SAMPLES?
By means of true functional liver function tests, synthetic
liver function or its ability to absorb various substances and
remove them from the bloodstream, as well as metabolize and modify
injected diagnostic drugs. Determination of albumin level
– one of the most commonly used indicators in the clinic, although
it is not highly sensitive and is influenced by
malnutrition, kidney disease and other factors.Generally
low albumin levels indicate a decrease in synthetic
liver function. Determination of prothrombin time (PT) – other
a simple test that determines the ability of the liver
synthesize blood clotting factors. Change in prothrombin
time is associated with both a violation of the synthesizing function of the liver, and
and with a deficiency of vitamin K. Increased prothrombin time and lack of
his reactions to the introduction of vitamin K inside (5-10 mg for 3
days) indicates liver disease or vitamin malabsorption
K due to obstruction of the bile duct or intrahepatic cholestasis,
preventing the flow of bile into the duodenum.Subcutaneous
or intravenous vitamin K helps with differential
There are various tests for determining the absorption and excretory
liver function; they use substances such as bromosulfophthalein,
tricarbocyanine dye, aminopyrine, caffeine, monoacylglycinexylidide.
They are often used to assess the severity of liver damage and to predict
the outcome of the disease for research purposes, but for clinical
they are rarely used in practice.
3. WHAT IS THE DIFFERENCE BETWEEN CHOLESTATIC AND LIVER CELL (PARENCHYMATOUS) LOSS?
Two main mechanisms of liver damage are
damage or destruction of hepatocytes (hepatocellular mechanism)
and impaired transport of bile (cholestatic mechanism). The reasons
parenchymal liver damage are most often viral
hepatitis, autoimmune hepatitis, as well as various toxic substances
and medicines.Bile transport is impaired due to extrahepatic
obstruction of the bile ducts (for example, gallstones or when
postoperative stricture), narrowing of the intrahepatic ducts (for example
with primary sclerosing cholangitis), damage to the bile ducts
(for example, with primary biliary cirrhosis) or transport disorders
bile at the level of small bile ducts (for example, when using
chlorpromazine).In some cases, both mechanisms of damage take place.
The most specific indicator of damage to the liver parenchyma is the level
ALT. The ACT level can also be increased (although this indicator
not so specific). On the contrary, about cholestatic liver damage
an increase in the level of alkaline phosphatase is more likely to indicate. Bile
acids stimulate ALP production, but blockage or damage
bile ducts prevent it from entering the duodenum
the intestine, which leads to a significant increase in the concentration of alkaline phosphatase in the serum
blood.The ALP level is slightly increased in the early stages of the lesion
hepatic parenchyma. However, this is due to the release
enzyme from hepatocytes, rather than stimulating its synthesis. Since ALP
produced in other organs (bones, intestines), concomitant
an increase in GGT and 5′-nucleosidase levels indicates cholestatic
mechanism of defeat.
4. WHAT ARE SERUM TRANSAMINASES? WHAT ARE THEY USED FOR?
In clinical practice, the level of
two serum trans-aminases – ALT and ACT.It is used to this day,
usually the old terminology for which ALT is called serum
glutamate pyruvate transaminase, and ACT serum glutamate oxalate transaminase.
The new names more accurately reflect the function of these enzymes, which is
in the transfer of amino groups from one compound to another.
As noted above, an increase in ALT and / or ACT levels indicates
about damage to hepatocytes.It is necessary to understand how the
these tests and what factors can alter their results. Most
ALT cases are determined by the following reaction:
This reaction requires ALT and pyridoxal phosphate
(vitamin B6). It is important to understand that with the help of enzymatic reactions it is determined
not the level of the enzyme itself, but (indirectly) its catalytic activity.This analysis does not show the level of ALT, but the rate of catalyzed
reactions. The result obtained is evaluated as follows: the higher
the reaction rate, the greater the amount of ALT. The lack of response is
in the inability to determine the amount of its products when increasing
ALT level. Therefore, a reaction with a bound enzyme is used instead:
which takes place in the presence of another enzyme
– lactate dehydrogenase.During the reaction, oxidation of the reduced
nicotinamide adenine dinucleotide (N ADN), and as a by-product
its unreduced form (NAD +) is formed. OVER + absorbs light
wavelength 340 nm. Absorption is recorded using a spectrometer
and is used to determine the activity of ALT. As a result, the number
the enzyme can only be estimated indirectly. On the speed of reaction
several factors affect: temperature, concentration of substances, quantity
enzymes or cofactors, the presence of impurities inhibiting the reaction, and
See also the sensitivity of the spectrometer.For example, if the patient has
deficiency of pyridoxal phosphate, that is, it is not enough for staging
test reaction, its speed will slow down, and ultimately there will be
a false result of low ALT activity was obtained. This effect is often
observed in alcoholics (whose nutrition is reduced), since a deficiency
vitamin B6 leads to a limitation of the reaction rate to a greater extent,
than the ALT level.
The second controversial issue: what can be considered a normal level, and what
– a deviation from the norm? This is usually done in a local laboratory.
in an arbitrary way, for which a small group of “healthy” patients is selected
(often from a blood bank) that have their ALT levels determined and calculated
mean and standard deviation.Borders are randomly selected;
they usually correspond to the maximum and minimum values,
which were obtained from 2.5% of the selected population. However, such
the technique is unsuccessful, since the ALT level depends on many demographic
factors. In men, it is higher than in women. Obese women
have higher ALT levels than people whose weight is close to ideal.
Some racial groups have a level of
ALT is also higher.Therefore, if the examined group of patients consists of
of thin women (especially of the Caucasian race) who had
donate blood, the limits of the norm will be very low, as a result
many overweight men will have high ALT levels
even in the absence of disease. This is typical for all enzymatic
reactions described in this chapter. Therefore, the higher the level
(speed) of enzymatic reactions deviates from the norm, the more
the presence of the disease is likely.Conversely, in patients with asymptomatic
the course of liver diseases even with significant lesions of the parenchyma
ALT levels may be normal.
Therefore, the ALT level is an unreliable marker of pathological
process in the liver. With massive lesions of the hepatic parenchyma
(for example, with viral hepatitis, toxic hepatitis – poisoning
paracetamol, solvents, or fly agaric) ALT levels may be
significantly increased.In particular, with a severe overdose of paracetamol
ALT value often reaches 2000 U / L (which is about 50 times higher than
the upper limit of the norm). This indicates a significant yield
enzyme from damaged hepatocytes. In patients with chronic viral
hepatitis, ALT levels are usually higher than normal
5. WHAT IS THE CAUSE OF THE ALP ALP LEVEL INCREASING?
TIF – an enzyme that catalyzes the transfer of phosphate
groups.Its various isoenzymes are produced in the liver, bones and
intestines. Most hospital laboratories have equipment for
there is no separate determination of various forms of alkaline phosphatase and its source,
which leads to some difficulties in diagnosis. According to the survey
a large group of hospitalized patients, only in 65% of cases high
ALP was associated with liver disease. Increase in the level of the “hepatic” fraction
enzyme is a consequence of stimulating its synthesis with a local increase
concentration of bile acids.This occurs when cholestasis occurs,
caused by drugs, and with intra- or extrahepatic
obstruction of the biliary tract. Test reaction for the determination of alkaline phosphatase:
The detection of nitrophenyl indicates the presence of
ALF. Although this reaction is not associated with an enzyme, however, problems
arising from the determination of enzyme activity and the establishment of boundaries
norms are similar to those of serum transaminases.Simultaneous
increased levels of TIF and gamma-glutamyl transpeptidase (or 5′-nucleosidase)
testifies in favor of liver disease and indicates the presence
6. WHAT DOES AN INCREASE IN THE LEVEL OF BILIRUBIN MEAN?
– a decay product of erythrocytes – exists in two forms: conjugated
and unconjugated. Unconjugated bilirubin appears in plasma,
when the rate of destruction of red blood cells exceeds reserve capacity
liver by its transformation (which is often found in patients with hemolytic
anemia).A genetically determined deficiency of certain enzymes leads to
to the fact that the process of conjugation of bilirubin in the liver is wrong
or incomplete. This is most often observed with Gilbert’s syndrome.
(Gilbert), which is characterized by a relative deficiency of glucuronyl transferase
and mild hyperbilirubinemia. When fasting or
reducing the calorie intake of food (for example, in patients with viral
gastroenteritis), the level of bilirubin in the blood rises in the first place
due to its unconjugated form.If the bilirubin fractions are not tested,
a patient with abdominal pain, nausea, vomiting and hyperbilirubinemia
may be misdiagnosed as cholecystitis. Researching factions
bilirubin helps to avoid unnecessary cholecystectomy
when misdiagnosed. Most often level research
bilirubin includes a biochemical reaction with the calculation of the so-called
excess time.In most laboratories, only
total bilirubin. The amount of indirect (unconjugated) bilirubin
can be calculated if the reaction is stopped at a certain time and
subtract the resulting value from the value that determines the total bilirubin.
Accurate measurement of the amount of bilirubin and its fractions is possible using
chromatography, the equipment for which is far away
not in all laboratories.Conjugated bilirubin levels rise
for many diseases: viral, toxic, medicinal and alcoholic
hepatitis, liver cirrhosis, metabolic disorders, obstruction
intra- and extrahepatic bile ducts.
7. WHAT TESTS ARE USED TO DIAGNOSE THE MOST COMMON METABOLIC DISORDERS?
In patients with liver diseases in a planned manner
specific laboratory tests are used to identify
some metabolic disorders.Hemochromatosis is a disease characterized by
excessive deposition of iron in the liver and other organs. Most likely
the cause of this disease is a violation of the regulatory mechanism
absorption of iron in the small intestine. For years, its reserves
increases in the liver, pancreas, heart and other organs.
Most often, as a screening test for hemochromatosis, they use
determination of serum ferritin levels.Its rise indicates
on the possibility of excess iron content in the body. but
ferritin levels also increase in the acute phase of inflammatory
process, so the results obtained can often be false positive.
When ferritin levels rise (usually => 400 μg / L), it is necessary to
determine the level of serum iron and iron binding capacity
(TIBC) blood. If the ratio of serum iron to TIBC exceeds
50-55%, then, most likely, the patient has hemochromatosis (and
not hemosiderosis – secondary excess iron deposition in tissues).The most reliable is the quantitative determination of iron in
biopsy of liver tissue. Then the age adjustment is calculated,
Iron Age Index:
Data has been obtained that in establishing a diagnosis can
help magnetic resonance imaging. MRI allows you to limit
range of indications for liver biopsy.
Alpha1-antitrypsin – an enzyme produced by the liver,
which helps break down trypsin and other tissue proteases.Described
many modifications (isoforms) of this enzyme, which depend on
alleles obtained from both parents, and therefore in one person
one or two forms of alpha1-antitrypsin can be found in the blood.
Z-form (so called because of its special electrophoretic activity
in gel) is a product of a genetic mutation of one of
amino acids of a widespread type of proteins – M-protein.Z-protein
is hardly released from liver cells and causes local damage,
which can lead to hepatitis or cirrhosis. To diagnose
three tests help. The first is the electrophoretic study of proteins
serum (EBS). Under the influence of an electric field, blood proteins move
in a gel and are separated; in this case, several bands are formed. One of
them, the alpha! band consists predominantly of alpha1-antitrypsin.Therefore, the deficiency of alpha! -Antitrypsin leads to its decrease. Second
the test consists in a direct assessment of the amount of enzyme using
monoclonal antibodies. The degree of binding is measured with a spectrophotometer
by the method of nephelometry. The third way is to determine the phenotype of alpha1-antitrypsin.
Only a few laboratories in the USA have the ability to do this.
research aimed at recognizing the alleles of the protein contained
in serum (MM, ZZ, MZ, FZ).Patients with type ZZ protein have
homozygous alpha! -antitrypsin deficiency. This form is most often
accompanied by severe liver disease. If in hepatocytes
contains Z-protein, it can be found in liver tissue in the form
small globules stained with Schiff’s dye (PAS-positive
reaction) and resistant to the enzyme diastase. In some
in hospitals, the immunofluorescence reaction is also used.
Wilson’s disease – impaired assimilation
and the accumulation of copper associated with a deficiency of the enzyme contained
in liver cells. Like iron, copper can be deposited in
many tissues of the body. Nevertheless, it accumulates mainly
in certain places. Copper deposits are found in the cornea (rings
Kayser-Fleischer) and some parts of the brain.Many
chole-static liver disease (for example, primary biliary
cirrhosis) also lead to excess copper accumulation, but copper deposits
never reach the same size as in true Wilson’s disease.
The main screening test is to determine the level of ceruloplasmin in
serum, which is reduced in 95% of individuals with Wilson’s disease. Ceruloplasmin
is a protein of the acute phase of inflammation, therefore its content increases
in patients with inflammatory processes, in whom its baseline level
was normal or low.In the process of monitoring patients regularly
the level of copper in urine and blood serum is estimated. Liver biopsy
with the subsequent quantitative assessment of the copper content in it allows
make a final diagnosis. Copper deposits in tissues are stained
special dyes (for example, rhodanine).
Diagnostic tests for the most common
metabolic disorders of the liver
|DISEASE||BASIC TEST||AUXILIARY TEST||TEST TO DELIVER FINAL DIAGNOSIS|
|Hemochromatosis||Serum ferritin level> 400 μg / L||TIBC> 55%||Iron Age Index> 2|
|Alpha1-antitrypsin deficiency|| Serum protein electrophoresis or determination of the level of monoclonal
antibodies to alpha 1-antitrypsin
|Phenotype determination (Pi-type)|| Liver biopsy with detection of PAS-positive, diastase-resistant
|Wilson’s disease||Ceruloplasmin level <10 mg / dL||Urine / serum copper> 80 μg / 24h|| Liver biopsy (quantitative content of copper in tissue> 50
μg / g)
To many other hereditary
liver diseases include Gaucher disease, Niemann-Pick disease
(Niemann-Pick) and hereditary tyrosinemia.These rare diseases
usually diagnosed in children. Specific diagnostic methods
studies not covered in this chapter
8. WHAT ARE AUTOIMMUNE MARKERS? HOW ARE THEY ASSOCIATED WITH THE DIAGNOSIS OF LIVER DISEASES?
markers – antibodies to specific cellular components that
epidemiologically associated with the development of specific diseases
liver.These include antinuclear antibodies (ANA), antibodies
to smooth muscle (ASMA, also called anti-actin antibodies),
antibodies to liver and kidney microsomes type 1 (LKM-1), antimitochondrial
antibodies (AMA), soluble hepatic antigen (SLA) and antibodies
to sialoglycoprotein receptors. Most commonly used tests
to determine ANA, ASMA and AMA; they allow you to diagnose
the most common autoimmune liver diseases.In the present
time definition of SLA in the USA is not always possible. Antibodies are detected
using the following reaction: the cell culture is treated with serum
the patient, after which the formed antigen-antibody complex (AG-AT) is “labeled” bound
with fluorescein human antibodies. The resulting triple
the complex is detected by fluorescence microscopy. Separation
cells are carried out in accordance with the intensity of the luminescence and
with which part of the cell binds antibodies.Thus, the definition
the level of antibodies and the division of the results into positive and negative
very subjective. Most hepatologists make these tests in
diagnostic algorithm only if positive
results with titers greater than 1: 80 – 1: 160. ANA and ASMA
more often found in the elderly, women, and also in patients
with many other liver diseases.Therefore, the diagnosis of autoimmune
liver disease is based on the general clinical picture; at
this takes into account the age, sex of the patient, the presence of other autoimmune
processes, levels of gamma globulins and the results of liver biopsy.
It should be noted that with various autoimmune diseases, it is possible
detection of the same antibodies. The table is presented in general
features one of the classifications of autoimmune liver diseases.Was
a new scoring system is also proposed, in which the authors have tried
take into account the factors mentioned above.
Classification of autoimmune liver diseases
|Type I, classic lupoid hepatitis||ANA and / or ASMA|
|Type II, autoimmune hepatitis||LKM-1|
|Type III, autoimmune hepatitis||SLA|
|Primary biliary cirrhosis||AMA|
9.IN WHAT CASES ARE SCREENING OR DIAGNOSTIC TESTS PERFORMED IN PATIENTS WITH SUSPECTED LIVER DISEASE?
research methods performed in case of suspicion of the presence of diseases
liver, include the determination of levels of transaminases, bilirubin
and alkaline phosphatase. History, physical examination and assessment
risk factors help to decide which specific diagnostic
tests are required on a case-by-case basis.Sometimes
there are patients with latent liver diseases, the level
enzymes in which it is normal or slightly different
from such. In some patients with isolated elevation
the level of enzymes fails to diagnose any disease.
As a rule, before proceeding with a full (detailed) examination
the patient, you should double check the level of liver enzymes for
excluding laboratory error.With many diseases (for example
hepatitis B and hepatitis C) it is necessary to prove the presence of chronic
process (when pathological changes persist for more than 6
months) before starting treatment or to confirm
diagnosis or staging of the disease plan implementation
liver biopsy. Typically, the standard waiting period may vary.
depending on the severity of enzyme disorders and the likelihood
detection of a curable process.For example, a woman with increased
10 times the level of transaminases, an autoimmune thyroid disease
a history of glands and an increased globulin fraction,
apparently, exacerbation of a previously unrecognized autoimmune
hepatitis A. Determination of the autoimmune profile and early biopsy
liver will help to confirm this assumption and to start in a timely manner
treatment with steroid hormones and other immunosuppressants.
diagnostic methods, biochemical parameters, interpretation of results
The liver is an organ adapted to high loads. Up to 1.5 liters of blood is pumped through it every minute. Liver diseases occur with a serious infection of the body, a stably unhealthy lifestyle, pathologies of other vital organs. Diagnosis of liver diseases is quite difficult and, as a rule, requires a large number of laboratory tests.
In the list of tests shown for suspected liver disease, in the first place is a biochemical blood test.It allows you to identify cirrhosis and hepatitis. In special cases, the doctor may prescribe immunological tests, tests for tumor markers and histological studies.
Biochemical analysis for liver diseases: indicators and norms
A blood test for biochemistry is the main laboratory test, in addition to urine and feces tests, which helps to diagnose liver cirrhosis, hepatitis, metabolic disorders. Based on this study, additional tests for tumor markers may be prescribed.
Let’s consider each of the indicators determined in the course of the research.
A number of enzymes necessary for the normal functioning of the body are synthesized in the liver. Tests for liver enzymes can be part of a biochemical blood test or carried out separately if serious deviations from the norm (reference values) are detected. When diagnosing, it is necessary to take into account the general clinical picture, since the studied indicators may indicate pathologies of other organs – for example, the heart.
Aspartate aminotransferase (AsAt) is an enzyme involved in the exchange of amino acids. Reference values:
- young children – 36 U / l;
- girls 12-17 years old – 25 U / l;
- boys 12-17 years old – 29 U / l;
- men – 37 U / l;
- women – 31 U / l.
Exceeding the norm is observed with damage to liver cells (hepatocytes) or heart muscle. At high concentrations of AsAt for several days and / or a sharp increase in the number of enzymes, urgent hospitalization is required in order to identify necrotic foci, which may even be a consequence of myocardial infarction.In pregnant women, a slight excess of the norm is possible without any pathologies.
Alanine aminotransferase (AlAt) participates in the formation of glucose from proteins and fats. Normal indicators:
- newborns – 5–43 U / l;
- children under 1 year old – 5–50 U / l;
- children under 15 years old – 5–42 U / l;
- men under 65 years old – 7–50 U / l;
- women under 65 years old – 5–44 U / l;
- elderly people after 65 years – 5–45 U / l.
The limits of the norm are quite wide, on different days the indicator can vary within 10-30%. With serious liver pathologies, the value exceeds the norm by several times.
Alkaline phosphatase (ALP) . Participates in the reactions of elimination of the remainder of phosphoric acid from its organic compounds. It is found mainly in the liver and bones. Blood norm:
- for women – up to 240 U / l;
- for men – up to 270 U / l.
An increased indicator may indicate, in addition to diseases of the skeletal system, liver cancer or tuberculosis, cirrhosis, infectious hepatitis.
Lactate dehydrogenase (LDH). Required for glycolysis reactions (release of energy through the breakdown of glucose). The rate varies depending on age:
- children of the first year of life – up to 2000 U / l;
- up to 2 years old – 430 U / l;
- from 2 to 12 years old – 295 U / l;
- adolescents and adults – 250 U / l.
Exceeding the norm can be observed with damage to liver cells.
Glutamate dehydrogenase (GDH) .Participant in the exchange of amino acids. Deviations from the norm are observed with severe lesions of the liver and biliary tract, acute intoxication.
- in the first month of life – no more than 6.6 U / l;
- 1–6 months – no more than 4.3 U / l;
- 6–12 months – no more than 3.5 U / l;
- 1-2 years – no more than 2.8 U / l;
- 2-3 years – no more than 2.6 U / l;
- 3–15 years old – no more than 3.2 U / l;
- boys and men – no more than 4 U / l;
- girls and women – no more than 3 U / l.
Sorbitol dehydrogenase (SDH) . A specific enzyme, the detection of which in the blood indicates acute liver damage (hepatitis of various etiologies, cirrhosis). Together with the indicators of other enzymes, it helps in the diagnosis of the disease.
Gamma Glutamyl Transferase (GGT) . Contained in the liver and pancreas, it is actively released into the bloodstream with liver pathologies and alcohol intoxication. After giving up alcohol in the absence of hepatic pathologies, the level of GGT returns to normal in a month.
- the first six months of life – no more than 185 U / l;
- up to 1 year – no more than 34 U / l;
- 1-3 years – no more than 18 U / l;
- 3–6 years old – no more than 23 U / l;
- 6–12 years old – no more than 17 U / l;
- boys under 17 years old – no more than 45 U / l;
- girls under 17 years old – no more than 33 U / l;
- men – 10–71 U / l;
- women – 6–42 U / l.
Fructose monophosphate aldolase (FMFA). Normally can be found in blood in trace amounts. An increase in FMFA is characteristic of acute hepatitis and occupational intoxication of workers in hazardous industries.
Any enzyme is a protein molecule that accelerates one specific biochemical reaction in the body at a certain temperature and acidity of the environment. By the totality of the analysis data for enzymes, one can judge about metabolic disorders associated with certain pathologies. An enzyme test is a very informative method for diagnosing the state of the liver.
Proteins, fats and electrolytes
In addition to the level of enzymes for the diagnosis of liver pathologies, other biochemical parameters of the blood are of great importance.
Total protein . Normally, the concentration of total protein in the blood is 66–83 g / l. The liver actively synthesizes various protein molecules, therefore, deviations from the norm can occur when the liver cells – hepatocytes – do not work properly.
Albumin .The main protein in blood plasma is synthesized in the liver. The concentration in a healthy adult is normally 65–85 g / l. A decreased level may indicate cirrhosis, hepatitis, liver tumor, or the presence of metastases in the organ.
Bilirubin . Yellow pigment, a breakdown product of hemoglobin. Total bilirubin in the blood normally ranges from 3.4–17.1 µmol / l, direct – 0–7.9 µmol / l, indirect – up to 19 µmol / l. Exceeding the norm may indicate pathological processes in the liver.
Cholesterol and its fractions . It can enter the body both with food and be synthesized by liver cells. Normal cholesterol levels, depending on age and gender, can range from 2.9-7.85 mmol / l. Deviations from the norm are observed in a number of diseases, including an increase in values typical for those suffering from alcoholism and cirrhosis of the liver.
Triglycerides . Similarly, cholesterol enters the bloodstream as a result of digestive processes or is synthesized in the liver.Normal rates vary greatly depending on gender and age. The limiting values are in the range of 0.34–2.71 mmol / L. Elevated triglyceride levels can occur with cirrhosis or viral hepatitis. Decreased levels may be associated with malnutrition and various extrahepatic pathologies.
Ammonia . It is formed during the breakdown of amino acids and is found in the blood when hepatic metabolism is impaired due to severe liver damage.
- for children in the first days of life – 64–207 μmol / l;
- up to two weeks – 56–92 μmol / l;
- further up to adolescence – 21-50 µmol / L;
- in adolescents and adults – 11–32 μmol / l.
Iron . Acute hepatitis is accompanied by an increase in the level of iron in the blood, cirrhosis of the liver – by a decrease.
- in children in the first year of life – 7.16-17.9 μmol / l;
- in the period 1-14 years – 8.95-21.48 μmol / l;
- in adult women – 8.95-30.43 μmol / l;
- in adult men – 11.64-30.43 μmol / l.
Urea . Normal blood urea levels:
- in the first month of life – 1.4–4.3 mmol / l;
- under 18 years old – 1.8–6.4 mmol / l;
- up to 60 years old – 2.1-7.1 mmol / l;
- after 60 years – 2.9-8.2 mmol / l.
Decreased urea levels indicate liver problems, this happens in cirrhosis, acute hepatic dystrophy, hepatic coma, hepatitis.
Tests for proteins, fats and electrolytes can help clarify the diagnosis in case of suspected liver disease.
Prothrombin is a protein produced in the liver and is a precursor of thrombin, which is necessary for the formation of blood clots. The prothrombin index reflects the state of the blood coagulation system and the liver itself (in relation to protein synthesis). The most modern and informative is the prothrombin index according to Quick. The reference values are 78-142%. An increase in the level of prothrombin can be observed in malignant liver tumors, a decrease is noted when taking certain medications (for example, heparin), vitamin K deficiency, and also due to hereditary factors.
Liver diseases provoke a whole complex of changes in blood biochemistry, and their direction depends on the type of pathology. There are no liver pathologies that would affect only one parameter. However, some values change more, others less, and when evaluating the tests, the doctor focuses on the most pronounced shifts and on the mutual proportions of individual indicators.
Immunological tests for autoimmune liver damage
Autoimmune liver damage includes autoimmune hepatitis, biliary cirrhosis, sclerosing cholangitis.Laboratory markers of these diseases are AMA (antimitochondrial antibodies), SMA (antibodies to smooth muscle), anti-LKM1 (autoantibodies to microsomes
5 9000 type 1) (antinuclear antibodies).
The results of the research are presented in credits. The titers of the content of AMA, PCA, SMA and anti-LKM1 in the blood should normally be less than 1:40, the ANA titer – up to 1: 160. In small amounts, these antibodies can also be present in healthy people.
An increased AMA titer is observed in viral or autoimmune hepatitis, as well as oncological diseases and infectious mononucleosis. In 70% of cases, SMA grows with autoimmune or viral hepatitis, malignant neoplasms. The concentration of LKM1 antibodies is high in autoimmune hepatitis, less often in viral hepatitis C and D. However, the result may be incorrect if the patient took phenobarbital, thienam, carbamazepine and other anticonvulsants.
Research on markers of cancer and hepatitis
Markers of liver cancer are AFP (alpha-fetoprotein), CEA (cancer-embryonic antigen), ferritin .AFP is specific for primary hepatocarcinoma, its concentration in blood serum also increases in the presence of liver metastases in cancers of other organs. The CEA test allows distinguishing between these two cases; this antigen appears in the blood in increased concentrations precisely with metastatic liver damage. Increased ferritin is characteristic of liver carcinoma and liver metastases: in 76% of all patients with tumor metastases in the liver, its concentration exceeds 400 μg / l.
AFP can increase with liver cirrhosis, CEA – with hepatitis, ferritin – with damage and decay of liver cells.Therefore, for the diagnosis of liver cancer, it is necessary to correlate all three indicators.
- AFP for men and non-pregnant women – 0.5-5.5 IU / ml. In pregnant women, AFP can fluctuate within the normal range of 0.5–250 IU / ml, gradually increasing and reaching its maximum before childbirth.
- CEA – up to 5.5 ng / ml.
- Ferritin in women – 13–150 mcg / l; in men – 30–400 mcg / l.
When receiving the results of the analysis for tumor markers, the patient should not panic, the diagnosis of liver cancer is carried out on the basis of the complete clinical picture.Histological analysis may be required.
Histological analysis of liver tissue
Until recently, histological analysis could only be performed invasively, with microscopic examination of the harvested tissues. However, there are already patented methods that provide more complete information by calculation. Although they are not inherently histological, their high information content, comparable only to histology, assigns them to this category of research.
- Conventional biopsy . The method of puncture sampling of liver tissue through the intercostal space for further research. Differs in high information content in relation to severe liver diseases. The disadvantage of this method is that a small part of the tissue is taken, which may not be affected by pathological processes. In addition, biopsy is contraindicated and cannot be performed frequently.
- FIBROTEST® .A set of computational tests, comparable to biopsy in terms of information content. Non-invasive method based on data from blood tests and anamnesis. Allows you to get an accurate quantitative and qualitative assessment of fibrosis and necroinflammatory hepatic changes at any stage, regardless of localization. The possibility of errors in the local examination of the material by the biopsy method is excluded.
- FIBROMAX® . Additional set of design tests for FIBROTEST®. Allows you to determine the degree of steatosis of any etymology.
Modern medicine generally follows the trend of decreasing invasiveness, therefore FIBROTEST® and FIBROMAX® are the future in the diagnosis of hepatic pathologies.
When deciding to see a doctor with symptoms of liver pathologies, you should be aware of the full range of studies that you may be prescribed. Their number will be greatly reduced with early medical attention.
Liver tests with up to 50% discount
Liver tests are a set of tests that evaluate damage to cells in the liver and biliary tract.The liver is a vital gland in the body that performs several thousand different functions.
The complex is recommended at any age with suspicion of liver damage and inflammation, before and against the background of taking hepatotoxic drugs, to control the treatment of liver diseases, cholelithiasis. Also, the complex is suitable for the initial assessment of the state of the liver against the background of diseases of other organs, for example, kidneys, stomach, intestines, diabetes mellitus, rheumatological diseases, parasitic infections.
In the absence of complaints, this complex is recommended prophylactically, as part of an annual laboratory examination, especially against the background of gallbladder dyskinesia, chronic gastrointestinal diseases, and taking dietary supplements.
Material for research
– Blood serum
Composition and Results
Analysis will be ready in
within 1 day, excluding the day of collection.The term can be extended by 1 day if necessary.
You will receive the results by email. mail immediately when ready.
Deadline: 2 days, excluding Saturday and Sunday (except for the day of taking biomaterial)
Preparation for analysis
Do not take a blood test immediately after radiography, fluorography, ultrasound, physiotherapy.
The day before
24 hours before blood collection:
- Limit fatty and fried foods, do not drink alcohol.
- Eliminate strenuous physical activity.
From 8 to 14 hours before donating blood, do not eat, drink only clean non-carbonated water.
On the day of donation
Before taking blood
- No smoking for 60 minutes,
- Be quiet for 15-30 minutes.
Comprehensive screening study, including the study of bilirubin and its fractions and the activity of liver enzymes: ALT, AST, GGTP, ALP. Allows you to suspect liver and / or biliary tract disease.
Depending on the cause of liver damage, different functions of the liver may suffer.
Look for symptoms that are suspicious of possible damage to the liver and bile ducts:
- pain or discomfort in the right hypochondrium,
- nausea, decreased appetite,
- darkening of urine,
- fecal discoloration,
- the appearance of icteric discoloration of the skin, sclera,
- the appearance of edema, increased bleeding, fatigue.
Many types of metabolism take place in liver cells. Protein metabolism involves enzymes of liver cells (hepatocytes) called transaminases (ALT and AST). An increase in transaminases in the blood can be observed during cytolysis (destruction) of hepatocytes. An increase in ALT more often indicates liver damage, while an increase in AST can also be observed with muscle damage, myocardial infarction, and erythrocyte hemolysis. In acute viral hepatitis, the levels of enzymes exceed the upper limit of the norm by 5-10 times, and in chronic hepatitis by 1.5-2 times, increasing about the same.With alcoholic hepatitis, cirrhosis, liver metastases, there is a predominant increase in AST.
The enzymes alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (GGTP) help evaluate the biliary function of the liver and biliary tract. In the case of their simultaneous increase, first of all, obstruction (blockage) of the biliary tract is excluded, for example, with gallstone disease. High levels of GGTP are characteristic of cirrhosis and liver metastases. A moderate increase in GGTP (2-5 times) is observed in viral hepatitis.Unlike GGTP, ALP is also increased in diseases of the bones and intestines.
For hepatic jaundice and obstruction of the biliary tract, an increase in total bilirubin is also typical, more due to the direct fraction. With hemolysis of erythrocytes, an increase in the indirect fraction of bilirubin is expressed.
The complex of liver tests includes the main indicators reflecting damage to the liver cells (hepatocytes) and biliary tract. In some situations, additional tests may be required.Suitable for preventive examinations, before and against the background of taking hepatotoxic drugs, in the control of drug therapy for liver diseases.
The general assessment of the research results, the establishment of the diagnosis and the appointment of therapy are carried out by the attending physician.
Hepa-Merz – Smart assistant for the liver
Action Hepa-Merz in granules
Action 1: Promotes the removal of toxins (ammonia)
As a result of taking Hepa-Merz granules, the following improvements can occur *:
- Improve concentration at work and while driving
- Pass the feeling of fatigue, speed up energy recovery
- Improve your mood
- Normalize sleep
Action 2: Promotes the restoration of the energy of liver cells
As a result of taking Hepa-Merz can:
- Increase the production of energy in the liver cells, which allows the liver to normalize its work and perform its functions more efficiently
Step 3: Enables liver function
As a result of taking Hepa-Merz, the following improvements can occur **:
- Normalized liver function indicators in analyzes (ALT, AST, GGTP)
- Pass unpleasant symptoms: heaviness, discomfort in the right side and / or in the abdomen
- Improve overall well-being
Action 4: Promotes metabolic improvement
Hepa-Merz promotes ***:
- Reducing fatigue
- Improving well-being
- Normalization of increased body weight (with steatosis and steatohepatitis)
- Production of insulin and growth hormone
- Improving protein metabolism
* P.O. Bogomolov, A.O. Bueverov, O.V. Uvarova, M.V. Matsievich, “Hyperammonemia in patients with liver disease at the pre-cirrhotic stage: is it possible?”, Clinical Perspectives of Gastroenterology, Hepatology, No. 5 2013.
E. Yu. L-Ornithine in Sports Medicine, Sports Medicine: Science and Practice, No. 4 2016.
Mika Miyake et al. “Randomized controlled trial of the effects of L-ornithine on stress markers and sleep quality in healthy workers”
** Grungreiff K., Lambert-Baumann J., Die Medizinische Welt, 2001; 52: 219-226.
Instructions for use of the drug Hepa-Merz granules.
*** L.Yu. Ilchenko, L.I. Melnikova, M.V. Zhuravleva “Experience of using ornithine aspartate (hepa-merz) and probiotic bioflorum forte
in the treatment of mild forms of alcoholic and non-alcoholic fatty liver disease”, Archive of Internal Medicine, No. 5, 2016
E. Yu. Plotnikova, M. R. Makarova, T Y. Gracheva “Possibilities of using L-ornithine in sports medicine”, Sports medicine: science and practice, No. 4 2016.
Instructions for use of the drug Hepa-Merz granules.
90,000 Hepatic encephalopathy symptoms and diagnosis HE
Liver failure occurs when the liver has completely lost its function due to cirrhosis caused by various liver diseases.
What are the common causes of cirrhosis?
- Hepatitis B and C
- Alcohol-related liver disease
- Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH)
- Autoimmune hepatitis
- Bile duct diseases such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC)
- Metabolic diseases such as hemochromatosis, Wilson’s disease and alpha-1 antitrypsin deficiency.
Liver failure is a life-threatening condition that requires hospitalization. Many people do not have symptoms of liver damage until serious liver problems develop slowly and unnoticed.
What are the symptoms and signs of liver failure caused by cirrhosis?
Some people are unintentionally diagnosed with cirrhosis. Cirrhosis often does not show any specific signs and symptoms at an early stage. Nonspecific symptoms may include:
- Loss of appetite
- Upset stomach
- Jaundice (yellowing of the skin and whites of the eyes)
As cirrhosis progresses, symptoms and complications may appear indicating that the liver is not working properly.These can be symptoms of hepatic encephalopathy (HE) and other complications caused by liver cirrhosis. In addition to hepatic encephalopathy (HE), the following complications are signs of liver damage or cirrhosis:
- Accumulation of fluid and painful swelling of the legs (edema) and abdomen (ascites)
- Easy bruising and bleeding
- Dilated veins in the lower esophagus (esophageal varices) and stomach (gastropathy).
- Enlarged spleen (splenomegaly)
- Stones in the gallbladder and bile duct (stones in the gallbladder)
- Liver cancer (hepatocellular carcinoma)
Chronic liver failure indicates that the liver is failing gradually, possibly over many years.
If the liver is not working, in some cases a liver transplant may be required.
What is a liver transplant?
Liver transplantation is the process of replacing a diseased liver with a healthy liver. For liver transplantation, it is necessary that the blood type and body size of the donor match the person receiving the transplant. The donated liver comes from living and non-living donors. Liver transplant surgery usually takes four to twelve hours.Most patients stay in the hospital for up to three weeks after surgery. More than 17,000 to 5,000 patients are currently awaiting liver transplantation here in the United States. Historically, 6,000 to 10 liver transplants are performed annually.
More people in the US need liver transplants than donated ones. The main cause of liver transplants here in the US is Hepatitis C.
Liver transplant procedure:
- The doctor directs the person for an appointment at the transplant center;
- At a transplant center, a transplant team is assessing a person’s overall physical and mental health, plans to pay for the medical costs associated with the transplant, and provide emotional support to family and friends;
- Based on the results, the team decides if a person is eligible for liver transplantation;
- If the person meets the criteria, the center will add him or her to the transplant waiting list.
The waiting list has priority, so the sickest people are at the top of the list. The time a person spends in line depends on:
- Blood group
- Body size
- Stage of liver disease
- General well-being
- Having a suitable liver
Most patients return to their normal lives within six months to a year after a successful liver transplant. Some patients have liver disease that they had before the transplant returns and may need treatment or another transplant.
For more information on cirrhosis and liver transplants, call our support team at 1-800-465-4837 or talk to your healthcare professional.
For more information on the stages of hepatic encephalopathy, consult your healthcare professional.
Non-invasive diagnostics of non-alcoholic steatogenic hepatitis Text of a scientific article in the specialty “Clinical medicine”
Problems of health and ecology
1.Barbakadze, GG Treatment of patients with chronic hepatitis C with pegylated interferon / GG Barbakadze, GV Pipia, GK Kamkamidze // Ter. archive. – 2005. – No. 1. – S. 73-75.
2. Klyuchareva, AA Modern drugs and antiviral therapy regimens for chronic hepatitis C / AA Klyuchareva // Medical panorama. – 2003. – No. 6. – S. 3-7.
3. Krel, P. Ye. Antiviral therapy of chronic liver diseases.E. Krel // Ros. zhurn. gastroenterol., ge-patol. and coloproctol. – 1997. – No. 3. – S. 84-88.
4. Treatment of viral hepatitis / A. A. Klyuchareva [and others]; ed. A. A. Klyuchareva. – Minsk: DoctorDesign, 2003 .– 216 p.
5. Maltsev, VI Types and methods of pharmacoeconomic research / VI Maltsev, TK Efimtseva, D. Yu. Belousov // Apteka weekly. – 2002. – No. 37.
6. Podymova, SV The problem of chronic viral hepatitis (diagnosis and treatment) / SV Podymova // Ros. honey. zhurn. – 1996. – No. 11. – S. 74-77.
7. Podymova, S. D. Modern view of the prospects for diagnostics and treatment of hepatitis C / S. D. Podymova, A. O. Buyerov // Klin. pharmacol. and rub. – 1996. – No. 1. – S. 28-31.
8.The need for an economic approach to assessing the effectiveness of treatment in patients with chronic viral hepatitis / VM Tsyrkunov [et al.] // Prescription. – 2001. – No. 1-2. – S. 40-45.
9. A randomized comparative study of three dosing regimens of interferon-alpha-2a in chronic viral hepatitis C / L Chemello [et al.] // Hepatology. – 1995. — Vol. 22.—P. 700-706.
10. Interferon alpha therapy for chronic hepatitis: effectiveness of two different dose based on HCV genotype / O.Fracassem [et al.] // J. Hepatol. – 1997. – Vol. 20, No. 1. – 211 p.
11. Hoofnagle, J. H. The treatment of chronic viral hepatitis / J. H. Hoofnagle, A. M. Di Bisceglie // N. Engl. J. Med. – 1997. – Vol. 336 (5). – P. 347-356.
12. National Institute of Health Consensus development conference statement: Management of hepatitis C: 2002 // Hepatology. – 2002. – Vol. 36, No. 5. – P. 2-20.
13. Pegylated Interferon alfa-2b (PEG-INTRON) Monother-apyis Superior to Interferon alfa-2b (INTRON A) for the Treatment of Chronic Hepatitis C / C. Trepo [et al.] // J. Hepatol. – 2000. – Vol. 32, No. 2. – P. 29.
14. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group / J.McHutchison [et al.] // N. Engl. J. Med. – 1998. – Vol. 339. – P. 1485-1492.
15. Efficacy and safety of peginterferon alfa-2a or -2b plus ribavirin in the routine daily treatment of chronic hepatitis C patients in Germany: the practice study / T. Witthoeft [e al.] // 43rd Annual Meeting of the European Association for the Study of the Liver (EASL). – Milan, Italy, 2008.
NON-INVASIVE DIAGNOSTICS OF NON-ALCOHOLIC STEATOGENIC HEPATITIS
A. L. Kalinin1, E. V. Tsitko2, E. N. Snitsarenko2, T. V. Khvatik2
1 Gomel State Medical University Republican Scientific and Practical Center for Radiation Medicine and Human Ecology, St.Gomel
Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of elevated serum enzymes in chronic liver disease (CKD). The incidence is rapidly increasing due to the ongoing epidemic of obesity and type 2 diabetes mellitus (DM 2). This multifaceted metabolic disorder occurs in the clinical practice of various healthcare professionals: primary care physicians and gastroenterologists, cardiologists, radiologists and gynecologists.NAFLD consists of a spectrum of liver diseases ranging from simple steatosis to steatohepatitis, which is characterized by steatosis, lobular inflammation, balloon dystrophy, and fibrosis. Over the past few years, significant progress has been made in our understanding of its risk factors, pathogenesis, course, non-invasive markers and treatment. This review is aimed at clinicians treating patients with NAFLD, and practical issues related to certain aspects of its diagnosis are discussed.
Keywords: non-alcoholic steatohepatitis, diagnostics.
NONINVASIVE DIAGNOSTICS OF NON-ALCOHOLIC STEATOHEPATITIS
A. L. Kalinin1, E. V. Tsitko2, E. N. Snitsarenko2, T. V. Hvatik2 1 Gomel State Medical University
2Republican Research Center for Radiation Medicine and Human Ecology, Gomel
Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of the increased contents of serum enzymes in chronic liver diseases.Its incidence rate is associated with the ongoing epidemics of obesity and diabetes of type 2. This multifaceted metabolic disorder is commonly encountered in clinical practice of various health care professionals ranging from primary care providers and gastroenterologists to cardiologists, radiologists and gynecologists. NAFLD comprises a spectrum of liver diseases from simple steatosis to full blown steatohepatitis that is characterized by steatosis, lobular inflammation, ballooning and fibrosis.Over the last several years, much progress has been made in terms of our understanding of its risk factors, pathogenesis, natural history, non-invasive markers and treatment. This review is tailored to clinicians caring for patients with NAFLD and it covers practical issues related to the certain aspects of its evaluation and management.
Key words: non-alcoholic steatohepatitis, diagnostics.
Problems of health and ecology
Non-alcoholic fatty liver disease (NAFLD) includes a spectrum of diseases with insulin resistance and associated metabolic disorders such as obesity, type 2 diabetes mellitus (DM 2) and dyslipidemia.NAFLD ranges from simple hepatic steatosis (LH), which is benign, to non-alcoholic steatohepatitis (NASH), which is more severe, with necrotic inflammation and fibrosis, which can progress to cryptogenic cirrhosis and end-stage liver disease.
NASH was first described in 1980 by Ludwig et al.  in patients with impaired liver biochemical tests and fatty infiltration, accompanied by inflammatory changes in histological examination.
The prevalence of NAFLD has increased significantly over the past two 10 years; it is detected in about 30% of adults in the United States  and almost a third of the total population. The most common form of NAFLD encountered in clinical practice is SP, also known as NAFLD, if this pathology develops in the absence of significant alcohol consumption (no more than 10 g / day in women and 20 g / day in men) . Research by Liu et al. confirmed that overweight increases the incidence of cirrhosis of the liver (LC). In middle-aged women in the UK, about 17% of LC deaths are associated with being overweight compared to 42% associated with alcohol .
NAFLD is characterized by a benign clinical course until necrotizing inflammatory liver damage develops. It is very important to differentiate between SP, associated with a favorable long-term prognosis, and NASH, with a progressive natural course, in which about 20% of patients will develop cryptogenic LC and even end-stage liver disease.The outcome of LC associated with NASH may even be hepatocellular carcinoma  and death associated with NASH: in 12-25% of patients within 7-10 years .
NAFLD is an important cause of cryptogenic CPU, although other causes lead to this type of CPU.
Another important issue related to NAFLD is related to the internal mechanisms of the disease. Although SP is a favorable stage and NASH is progressive, the underlying mechanisms appear to be similar.This is confirmed by the report of Tarantino et al. , who found a similar level of transforming growth factor-p1 (TGF-P1) in the serum of patients with NAFLD and NASH.
The pathogenesis of NAFLD and especially NASH is not completely clear; several mechanisms have been proposed to explain liver damage associated with metabolic syndrome (MS) . Identifying these mechanisms is important because targeted treatment can prevent the progression of NAFLD to fibrosis and LC.Insulin resistance (IR) plays a central role in the pathogenesis of NASH. IR is the main feature of MS, which is characterized by obesity, hypertension, diabetes mellitus 2, and dyslipidemia. NAFLD is considered the hepatic component of MS [9, 10, 11]. Although overweight and obesity are present in the majority of patients with NASH, steatohepatitis can also occur in people with normal body weight . There was a direct correlation between the degree of development of obesity and NASH , but not all obese patients have NAFLD.
Ultrasound examination (US) reveals a more pronounced SP in cases of IR compared with healthy people . IR promotes the development of lipid metabolism disorders with increased delivery of free fatty acids to the liver, impaired mitochondrial P-oxidation, de novo lipogenesis, and a decrease in P-export from the liver , all this leads to the development of fatty liver. Some authors suggest that hyperinsulinemia in NAFLD is the result of a decrease in insulin extraction in the liver.NASH is also associated with mitochondrial pathology, enlargement or elongation of mitochondria with crystalline inclusions [12, 15].
Liver lipid overload initiates several pathways, including lipid peroxidation, the generation of reactive oxygen species, oxidative stress, and the production of inflammatory cytokines. Oxidative stress is the trigger for lipid peroxidation in hepatocytes, followed by the secretion of proinflammatory cytokines and activation of fibrosis-producing stellate cells, which are the main mediators of liver fibrosis.
Increased production of tumor necrosis factor TNF-a in NAFLD patients, which plays a central role in liver damage and disease progression from SP to NASH and liver fibrosis by activating both Kupffer and stellate liver cells . According to this hypothesis, targeted anti-TNF-a therapy may be useful in the treatment of NASH . Another concept suggests the effect of adipocytokines secreted by adipose tissue (WAT), known as white adipose tissue, on the development of visceral obesity.WAT is responsible for the release of several adipokines and cyto-
Problems of health and ecology
kines such as adiponectin, leptin, TNF-a and interleukin (IL) -6, which are involved in the hepatic inflammatory process [17, 18].
There is a theory about drug-induced iatrogenic NASH.Dilthiazem, amiodarone, tamoxifen, steroids and antiretroviral drugs cause NAFLD or the development of insulin resistance .
In addition to the widely recognized risk factors for NASH: type 2 diabetes, IR, hyperlipidemia, and obesity, other metabolic disorders are associated with NAFL, namely polycystic ovary syndrome and lipodystrophy [19, 20]. Other rare causes, due to which NAFL develops, are hypobetalipoproteidemia, Weber-Christian syndrome, prolonged parenteral nutrition, toxic effects of organic solvents, dimethyl formamide, gastric bypass anastomoses .
The main goal is the early diagnosis of NASH to identify patients before fibrosis begins. Liver biopsy (LB) is now considered the gold standard for assessing liver fibrosis. Liver puncture reflects the state of a small area of the liver, while fibrosis is diffuse in diffuse liver diseases. In PD, only 1/50000 of the liver is removed, which carries significant errors in subsequent interpretation.PD is an invasive procedure with some unavoidable risks and complications . In this regard, the development of non-invasive tests to assess hepatic inflammation and fibrosis has become an active area of research.
NAFLD is primarily a diagnosis of exclusion, so other specific causes of liver disease should be excluded: viral hepatitis B and C, alcoholic liver disease, Wilson’s disease, hemochromatosis, autoimmune hepatitis, etc.[nine]. The most difficult is the exclusion of alcoholic liver disease, because the histological picture of both diseases is similar. It is necessary to obtain accurate information about the patient’s daily alcohol consumption, while taking into account that consumption of more than 10 g / day in women and 20 g / day in men can damage the liver in the absence of other risk factors such as obesity, diabetes mellitus and viral hepatitis . Clinical manifestations in patients with NAFLD or NASH are nonspecific.
Most patients are asymptomatic, but some of them may complain of fatigue or pain in the right upper quadrant of the abdomen, discomfort.Hepatomegaly is diagnosed in 50% of patients on physical examination. Na-
Fatigue does not correlate with the severity of liver damage. These patients share a common clinical feature: obesity and possibly other components of MS, such as hyperglycemia, dyslipidemia, and hypertension. Liver dysfunctions can be discovered incidentally during routine screening.
Approximately 80% of patients with NAFLD have liver function within the normal range, only a small part show a slight increase in aminotransferases .The ratio between aspartate aminotransferase (AST) and alanine aminotransferase (ALT) is used to assess the severity of liver disease, and an AST / ALT ratio> 1 suggests CP or liver fibrosis . The increase in aminotransferases does not increase more than four times the upper limit of normal and does not correlate with the severity of steatosis or fibrosis . In most cases, the ALT / AST ratio is> 1. Can aminotransferase levels be used to differentiate between NASH and NAFLD? Higher AST and ALT levels and the AST / ALH ratio are more characteristic of NASH.A stronger relationship was found between AST and NASH levels. However, the use of a multivariate model with an assessment of the level of AST and ALT made it possible to separate patients with NASH and NAFLD in only 26% of cases. These data support the need to use additional non-invasive methods to confirm the diagnosis. Fracanzani et al.  examined 455 patients with NAFLD and divided them into two groups depending on their ALT level. They compared the clinical and histological features of patients with and without elevated serum ALT.NASH was diagnosed in 62% of patients with normal and 74% with elevated ALT levels. There were no significant differences in the degree of fibrosis in patients in the two groups, which emphasizes the need for liver biopsy to diagnose and determine the stage of fibrosis in patients with NASH . Laboratory signs of progressive liver disease such as hyper-bilirubinemia, hypoalbuminemia, and decreased prothrombin time have been observed in cases associated with LC.
Other biochemical disorders: hyperglycemia and hypertriglyceridemia are associated with concomitant metabolic disorders.Laboratory assessment of dyslipidemia and IR should be performed. A simple laboratory test has been developed to assess the insulin profile. It is known as the Homeostasis Assessment Model (HOMA) and is defined as the fasting insulin level (cC / ml) times the fasting glucose level (mmol / L) divided by 22.5 . HOMA not perfect, but easy way
Problems of health and ecology
estimates of IR.The possibility of a connection between HOMA and the joint venture was confirmed .
Determining the effects of small amounts of alcohol in patients with liver disease remains a major challenge. Given the difficulty of distinguishing between alcoholic and non-alcoholic liver disease based on patient history, attempts have been made to assess alcohol consumption using serum markers.
Currently, several laboratory markers of alcoholism have been proposed: high serum concentration of γ-glutamyltransferase, increased mean erythrocyte volume, increased AST, AST / ALT ratio> 2, and carbohydrate-deficient transferrin / total transferrin ratio> 1 .
NAFLD is also accompanied by changes in serum iron levels, ferritin levels are increased in 20-50% of patients and an increase in transferrin saturation with iron is observed in 5-10% of cases . If ferritin levels are significantly elevated, testing for the hemochromatosis gene is recommended.
In general, these indicators are non-specific for the diagnosis of NAFLD and reflect liver dysfunction.Levels of increased aminotransferases do not provide an etiological distinction between NAFLD and NASH .
The amount of lipid accumulated in the liver cannot be estimated using liver function tests, but the degree of liver fat infiltration can be determined using various imaging methods.
The most common non-invasive method is ultrasound examination (ultrasound).
Ultrasound reveals the presence of SP as hyperechoicity of the liver parenchyma, known as “bright liver” and “blurred vascular pattern”. The echogenicity of the liver is increased diffusely, which is easy to assess by comparing with the echogenicity of the kidneys and spleen. To assess the severity of the joint venture, hepatorenal contrast is used.
The normal liver has an echo structure similar to the renal parenchyma. An increase in hepatic echogenicity in SP causes hepatic-renal contrast.Webb et al.  assessed the severity of SP by differences in ultrasound density of the liver and kidneys in a study of 93 patients with histologically confirmed CKD. They showed that the hepato-renal index can quantitatively reflect the severity of the joint venture, with a lower limit of difference of 5%.
A simple parameter to determine is the definition of the length of the spleen. In a recent study by Tarantino and
dr. showed that determination of the spleen diameter makes it possible to distinguish NAFLD from NASH better than determination of IL-6 and vascular endothelial growth factor. At values greater than 116 mm, NASH is predicted .
Doppler ultrasound is another method useful in the diagnosis of joint ventures. NAFLD is associated with impaired hepatic parenchyma perfusion. Several parameters reflecting changes in hepatic hemodynamics have been described, the most important is the Doppler study of the hepatic veins .Recently, a new parameter in assessing NAFLD has been proposed: the Doppler perfusion index (PDI), defined as the ratio between hepatic arterial blood flow and total liver blood flow. IDP has been used in the detection of liver metastases
. Dugoni et al.  reported that PID was highly informative in the diagnosis of fatty liver in patients with NAFLD. Further research is needed to assess the role of FID in the diagnosis of NAFD.
The sensitivity of ultrasound in detecting SP varies between 60 and 94% , varies depending on the degree of SP.The sensitivity is very low when the degree of SP is less than 30% . Another difficulty lies in the impossibility of detecting inflammatory changes in the hepatic parenchyma and differentiating a simple SP from NASH. In addition, it is difficult to distinguish liver fibrosis from SP, because they have similar manifestations on ultrasound . This limitation has been overcome by introducing the latest contrast-enhanced ultrasound technology. Lim et al.  studied the value of the transit time through the hepatic veins using microbubbles as a contrast agent and found that this indicator is informative in predicting the severity of the disease in patients with hepatitis C.
The value of ultrasound with left-hand contrast enhancement for the diagnosis of NASH was studied . The intensity of the signal from the regions of interest from the contrasted image was estimated using the measurement of the intensity curves. A statistically significant decrease in signal intensity in patients with NASH compared with NAFLD was found due to a decrease in the uptake of levovista by the liver tissue due to cell damage.
Since this method has only been used in small samples, it is necessary to conduct a study in a larger number of patients to establish the role of contrast ultrasound in the diagnosis of NASH in clinical practice.However, the sensitivity of ultrasound decreases with morbid obesity, since it is difficult to perform in such cases . Ultrasound is an inexpensive, simple, easily reproducible method,
Problems of health and ecology
it can be reused to assess the dynamics of SP, in combination with the assessment of ALT and changes in BMI.The specificity of the method in detecting fatty liver infiltration is high and amounts to about 90% .
Computed tomography (CT) and magnetic resonance imaging (MRI) can be considered as alternatives, but their use is limited due to the high cost and limited amount of information they provide.
CT and MRI are superior to ultrasound in diagnostic value when fat deposition is focal .In other cases, abdominal ultrasound is more sensitive in diagnosing fatty liver disease [12, 30].
CT can also be used to assess thickened abdominal subcutaneous adipose tissue and to measure liver fat . Enhanced CT cannot detect SP using changes in signal intensity. Liver density, as measured by CT, decreases with increasing severity of the joint venture. CT can also visualize splenomegaly in the presence of portal hypertension, which suggests progression of fibrosis in patients with NAFLD.CT allows grading of SP by calculating the weakening of the liver-to-spleen ratio .
Non-contrast CT is preferred for detecting LB because the imaging is enhanced . Focal fatty lesions can be identified by dual-energy CT. The limitations of CT are the difficulties in identifying intermediate stages of fibrosis and its reuse due to radiation exposure.
MRI provides an accurate and rapid assessment of SP with a lower limit of differences of 3% .Phase contrast image correlates with the quantitative assessment of fatty infiltration for the entire spectrum of liver diseases. Assessing the intensity reduction on T1-weighted images can be helpful in identifying focal fat deposits.
A new technique for MRI – proton magnetic resonance spectroscopy (MRS) evaluates the proton fraction of fat and the level of hepatic triglycerides (TG). The level of hepatic triglycerides> 5% makes it possible to diagnose SP [35, 36].MRS characterizes the metabolic processes of cell regeneration and thus can assess the severity of the disease in NASH. An increase in the ATP / phosphate ratio may signal progression to severe fibrosis in NASH. MRS is probably more accurate for the diagnosis of NAFLD than the imaging methods presented above, but it needs research in patients.
None of these imaging modalities are able to conclusively distinguish between SP and NASH, therefore a liver biopsy is required to accurately assess hepatic impairment .
Biomarkers for the assessment of steatohepatitis and fibrosis
Several biological markers have now been studied in connection with NAFLD to assess the degree of SP, the presence of necrosis, inflammation and the development of fibrosis in order to avoid liver biopsy. The most important parameter identified by non-invasive methods is inflammation, which plays a central role in the progression of NAFLD.
C-reactive protein (CRP) is an acute phase of inflammation protein produced in the liver, and its concentration in serum increases in various inflammatory diseases.Assessment of its levels was found to be useful in differentiating between SP and NASH. Moreover, it seems that high concentrations of highly sensitive CRP are associated with advanced liver fibrosis in patients with NASH .
A new serum marker is pentraxin-3 (PTX-3), which appears to be promising in differentiating between patients with and without NASH, as well as in assessing the severity of fibrosis . PTX-3 is an acute phase protein and, together with CRP, is part of the proteins of the pentraxine family.PTX-3 levels increase in NASH and other diseases: vasculitis, cardiovascular and inflammatory conditions .
Another biomarker with an important role in liver disease is interleukin-6. Interleukin-6 is a chemokine that increases in NAFLD; it is synthesized by hepatocytes and immune cells, endothelial cells and adipocytes [8, 39]. Serum levels of IL-6 are directly proportional to their hepatic concentration and reflect the inflammatory activity and degree of fibrosis .
The pro-inflammatory properties of interleukin TNF-a have long been recognized, and its role in the progression of NASH and in other inflammatory diseases has been clearly established. There is a pronounced increase in the level of TNF-a in NASH and it has been shown that anti-TNF-a-therapy with pentoxifylline leads to an improvement in the histological picture of the liver and normalization of aminotransferases .
Cytokeratin-18 is a relatively new marker derived from the caspase-3 dependent apoptosis pathway.Today it has limited clinical use and is only used for research purposes. Cytokeratin-18 is a marker of hepatocyte apoptosis and its value as a potential biomarker for NASH os-
Problems of health and ecology
is new on the observation that apoptosis is expressed in NASH and absent in SP .Tarantino et al.  found that polypeptide specific antigen (PSA), a protein released during apoptosis, is an important marker of fibrosis, more accurate than ALT levels. Determination of PSA, the serological analogue of which is cytokeratin-18, is widely used as a marker for the detection of various types of cancer. Tissue PSA appears to be useful in clinical evaluation in obese patients with NASH, since a significant decrease in serum concentrations of this marker has been associated with weight loss .
A number of studies have shown the role of oxidative stress in the pathogenesis of NASH, studied several parameters: the activity of glutathione peroxidase and superoxide dismutase, levels of vitamin E . Apparently, none of these markers is of significant importance in assessing the histological picture of NASH . The clinical relevance of these biomarkers has not yet been established, and their accuracy in the non-invasive assessment of NASH is under debate.
Evaluation of fibrosis is critical in patients with NASH.Fibrosis is characteristic of the progressive stage of liver damage. A number of studies have evaluated some matrix components, such as transforming growth factor β, hyaluronic acid, tissue inhibitors of metalloproteinases, etc. , but they have not found their daily use. Endothelin-1 mediates fibrosis in NASH with an established correlation in serum and the degree of fibrosis .
Diagnostic panels for the assessment of steatosis, steatohepatitis and fibrosis
Serological marker panels have been developed for non-invasive assessment of SP and necroinflammatory process in the liver.BP has disadvantages: errors during material sampling, the subjective factor of the researcher . The “Biopredictive” company has developed a NASH test, it is approved for the assessment of NASH in patients who do not drink alcohol. It includes the determination of the following parameters: total bilirubin, gammaglutamyl transpeptidase (GGT), a-2-macroglobulin, apolipoprotein A1, haptoglobin and ALT – taking into account age and sex, as well as weight, height, AST, serum glucose, triglycerides, cholesterol and steato test . The NASH test is performed when the steato test is positive.The Steato test is a quantitative analysis for assessing SP, especially in cases associated with metabolic syndrome . The NASH test is a modification of the steato test and the activity test to differentiate SP from NASH. The acti test was developed to detect necrotic inflammation in vi-
hepatitis C and B . Research on these biomarkers should reduce the need for PD .
Evaluation of serologic markers of fibrosis is often used in Europe, in contrast to the USA, where PD is preferred.Various tests have been used to assess fibrosis, such as the ACT / ATT ratio and the APRI test, which measures platelet count and AST levels . Currently, the most commonly used are Fibro-Test (BioPredictive) in Europe and FibroSpect and FibroSure in the USA . FibroTest was first developed for patients with viral hepatitis C and then used for NAFLD . The advantages over PD are: the study of the entire liver and the absence of risks associated with invasive procedures.FibroSpect evaluates liver fibrosis based on the analysis of the following markers: hyaluronic acid, a tissue inhibitor of matrix metalloproteinase-1, and a-2-macroglobulin . Using FibroTest, GGT, haptoglobin, bilirubin, apolipoprotein and a-2-macroglobulin are determined. The biggest drawback of these types of studies is their inability to distinguish between mild and moderate fibrosis. Early detection of fibrosis is valuable in preventing disease progression .The usefulness of these tests is limited in cases with advanced fibrosis.
Fibroscan, or transient elastography, is a non-invasive technique that evaluates liver stiffness using echo ultrasound [22, 48]. It has several advantages over liver biopsy: it is non-invasive, assesses most of the liver and appears to be more sensitive than serologic markers .The main disadvantage of fibroscan is the inability to distinguish the change in liver stiffness measured by determining the wave velocity in fibrosis from the presence of fatty infiltration in SP . Some authors argue that there is a positive correlation between liver stiffness, assessed by fibroscan, and the degree of fibrosis in NAFLD patients [49, 50]. Importantly, if liver elasticity is used to measure fibrosis in NAFLD, then LB can make the liver less rigid and therefore the reference ranges may be different.Fibroscan can also be unreliable in obese people for technical reasons .
Sonoelastography with acoustic pulse force radiation (ARFI sonography) has recently been proposed as an alternative method for assessing the elasticity of the liver.
Problems of health and ecology
one hundred fibroscans.This alternative method uses sound waves to analyze the mechanical properties of liver stiffness. One of the advantages of imaging with ARFI sonography is that it is integrated with conventional ultrasound systems and therefore can be performed during a routine examination, which is usually done in patients with CKD. Preliminary results indicate that image analysis by ARFI sonography can be used to diagnose severe liver fibrosis [52, 53].The role of ARFI elastography in the diagnosis of NAFLD is still poorly understood. Magnetic resonance elastography is another method used to detect moderate to severe liver fibrosis in obese people with NAFLD. It has a higher accuracy in diagnosing fibrosis in cases not associated with BMI . Further research is needed to clearly define the role of liver elastography in patients with NAFLD.
Test of total nocturnal salivary secretion of caffeine
An interesting idea regarding the assessment of liver function in CKD was proposed and developed by a working group of Tarantino et al.. The systemic clearance of caffeine, determined by measuring the concentration of caffeine in saliva, was used as a liver function test with compensated CP. The test for total nocturnal salivary caffeine secretion is a reliable method for assessing liver function, and also allows you to distinguish between viral and cryptogenic (probably metabolic) CP.
Dynamic breath tests
Dynamic breath tests can detect specific changes in various metabolic pathways.) and 13C-octanoate breath test (ODT), which assess cytochrome P450 and mitochondrial dysfunction activity. Both mechanisms increase oxidative stress and appear to be involved in the pathogenesis of NASH. Non-invasive ODT can reliably distinguish between NAFLD and NASH, and MDT can predict the degree of liver fibrosis.
Liver biopsy remains the standard procedure for assessing the extent of necrosis, inflammation and fibrosis, as well as for quantifying hepatic steatosis.However, this invasive procedure comes with inevitable risks and limitations. In addition, in most cases of NAFLD
Liver biopsy results do not influence the choice of treatment, which is still determined by metabolic syndrome. Hence, it becomes necessary to use a non-invasive strategy in order to cover the entire spectrum of NAFLD manifestations. Non-invasive studies such as biomarkers, fibrosis panels, and imaging techniques are the most promising for detecting steatosis and stages of liver fibrosis.
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Received February 28, 2011
EXPERIMENTAL MEDICINE AND BIOLOGY
FEATURES OF TISSUE RESPIRATION OF THYMUS IN RATS AT DIFFERENT TIMES AFTER EXPOSURE TO GAMMA RADIATION
Gomel State Medical University
The article presents the characteristics of tissue respiration in the thymus tissues of white rats after exposure to ionizing radiation. It was found that in the short term after irradiation, the level of respiration on endogenous substrates sharply decreases and the adaptive potential of the electron transport chain practically disappears. Subsequently, a wave-like restoration of the level of respiration and the state of the electronic transport chain occurs with an excess of the indicators of the state of the mitochondrial respiratory system in control animals by 90 days.
Keywords: tissue respiration, thymus, gamma radiation.
Features of a necrotic and inflammatory process in different forms of nonalcoholic fatty liver disease | Kurbatova
Aim. To identify the features of development of a necrotic and inflammatory process in different forms of nonalcoholic fatty liver disease (NAFLD), by comparatively analyzing a full set of clinical and laboratory parameters, including the cytokine status and the expression level of enzyme genes controlling the apoptosis of peripheral leukocytes.Subjects and methods 86 patients with NAFLD, including 8 (9.3%) with hepatic steatosis (HS), 70 (81.4%) with nonalcoholic steatohepatitis (NASH), 40, 19, and 11 with mild, moderate, and high disease activity, respectively , and 8 (9.3%) with liver cirrhosis (LC), were examined. A control group consisted of 34 healthy donors. Clinical and biochemical blood indices, cytokine profile, and the level of caspase gene transcripts in the peripheral blood leukocytes (PBL) were estimated. Results. As compared to the controls, the patients with HS had higher tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) levels and lower caspase 3, 6, and 8 mRNA in PBL.The concentration of IL-10 in NASH was higher than that in steatosis and positively correlated with the level of proinflammatory cytokines. The levels of TNF-α and IL6 were higher in the patients with NASH than in the controls. Those of C-reactive protein, γ-globulin, IL-6, and cytokeratin-18 fragment increased with the progression of NASH. In the latter, the transcriptional activity of caspase-3 gene decreased relative to the reference value and negatively correlated with the level of proinflammatory cytokines.In the patients with LC, the gene expression profile of caspases in PBL was similar to that in the control group; the level of IL-6 was higher than that in steatosis and NASH, that of IL-1β was higher than in HS and positively correlated the concentration of IL-6 and the activity of alanine aminotransferase and aspartate aminotransferase. Conclusion. The features of a necrotic and inflammatory process were identified in different forms of NAFLD. When the latter progressed, the cytokine profile and gene expression levels of caspases in PBL altered along with a change in the general clinical picture.
ALT – alanine aminotransferase AST – aspartate aminotransferase IL-10 – interleukin 10 IL-1β – interleukin 1beta IL-6 – interleukin 6 ELISA – enzyme-linked immunosorbent assay HDL – high-density lipoproteins PBL – peripheral blood leukocytes LDL – low-density lipoprotein NAHAL -VA – non-alcoholic steatohepatitis of high activity NASH-CA – non-alcoholic steatohepatitis of low activity NASH-UA – non-alcoholic steatohepatitis of moderate activity TCh – total cholesterol CRP – C-reactive protein SP – liver steatosis TG – triglycerides TPS – tissue circulatory disease – alkaline phosphatase TNFα (tumor necrosis factor alpha) – tumor necrosis factor α Non-alcoholic fatty liver disease (NAFLD) is a common chronic metabolic multifactorial disease, the main clinical and morphological forms of which are steatosis, steatohepatitis, fibrosis and liver cirrhosis (LC).The main links in the complex pathogenesis of NAFLD are represented by the formation of insulin resistance, the cytotoxic effect of excess free fatty acids, and inflammation . Currently, the mechanisms of progression of NAFLD remain unclear. The increasing attention of researchers is attracting the study of a sluggish inflammatory response associated with obesity as one of the main components of the development of NAFLD [2, 3]. It is known that the main mediators of the inflammatory process in the progression of NAFLD are cytokines, some of them, for example, interleukin-6 (IL-6) and tumor necrosis factor α (TNFα), play a key role in this process [4, 5].It has been shown that proinflammatory cytokines are also involved in the regulation of programmed cell death, in particular, caspase-dependent apoptosis, which plays an important role in the development of liver diseases . In addition to the processes of inflammation and apoptosis, cytokines are also involved in the regulation of necrosis and fibrogenesis [7, 8]. Despite the accumulated knowledge of the pleiotropic action of cytokines, the biochemical and molecular mechanisms of cytokine involvement in the progression of NAFLD remain unclear. A number of researchers have attempted to assess the role of some cytokines in the development of NAFLD [5, 9, 10], but, as a rule, the authors do not conduct a comparative analysis of the studied parameters in patients with different clinical and morphological forms of NAFLD.In addition, there is little information in the literature on the intensity of apoptosis of peripheral blood leukocytes (PBL) in NAFLD, while they are the main cells that implement the immune-inflammatory process in the liver and are responsible for the progression of hepatocellular failure. The aim of the study was to identify the features of the development of the necrotic-inflammatory process in different forms of NAFLD using a comparative analysis of a whole range of clinical and laboratory parameters, including the cytokine status and the level of gene expression of enzymes that regulate apoptosis of LPK.Materials and methods 86 patients with NAFLD were examined: 8 (9.3%) with hepatic steatosis (L), 70 (81.4%) with non-alcoholic steatohepatitis (NASH): 40 weak activity (SA), 19 moderate activity (UA) and 11 – high activity (VA) and 8 (9.3%) – with CP. The control group consisted of 34 healthy donors. The clinical characteristics of the groups are given in table. 1. The diagnosis was verified on the basis of traditional clinical, laboratory, instrumental and histological data. Liver functional tests were evaluated: activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), the level of total and direct bilirubin, albumin, γ-globulin, prothrombin, total cholesterol (TC), high density lipoproteins (HDL), low density (LDL), triglycerides (TG), C-reactive protein (CRP) (on the analyzer Random Access F-15 (BioSystems, Spain).An ultrasound examination of the abdominal organs was performed (Vivid Pro-7 apparatus, General Electric, USA) with an assessment of the echogenicity and size of the liver, the size of the spleen, and the presence of ascites; Doppler sonography determined the diameters of the portal and splenic veins and the linear blood flow velocity in them to detect portal hypertension. During esophagogastroscopy, the presence of varicose veins of the esophagus and the cardiac part of the stomach was assessed. A number of patients underwent spiral computed tomography of the liver with an assessment of the density of the liver and a blind percutaneous puncture biopsy of the liver with an assessment of the degree of activity and fibrosis using the Brunt method .All patients excluded viral, alcoholic, drug and autoimmune genesis of liver damage. There were no patients with diabetes mellitus among the surveyed. Table 1. Clinical characteristics of groups Note. Here and in table. 2: data are presented as M ± m. Significant differences (according to the Wilcoxon-Mann-Whitney U test) compared to the group * – control, ** – SP, # – NASH-SA, ## – NASH-UA, ◊ – NASH-VA. ND – no data. The content of tissue polypeptide specific antigen (TPA) (fragments of cytokeratin-18) in the blood was determined by the method of non-competitive enzyme-linked immunosorbent assay (ELISA) using the TPS ELISA test system (Biotech, Sweden).The concentration of cytokines in the blood was determined by non-competitive ELISA using test systems Interleukin-1beta (IL-1β) – ELISA-Best, Interleukin-6 – ELISA-Best, Interleukin-10 (IL-10) – ELISA-Best (“Vector- Best “, Russia) and Human TNFα Platinum ELISA (” eBioscience “, Austria). ELISA results were recorded on a Sunrise analyzer (Tecan, Switzerland). To determine the level of caspase gene transcripts, PBL was isolated from whole blood by a method based on the ability of an isotonic solution of ammonium chloride to hemolyze erythrocytes.Total RNA was isolated from LPK using the ExtractRNA reagent (Evrogen, Russia). The first strand of complementary DNA was synthesized from 5 μg of total RNA using the MMLV RT kit (Evrogen, Russia). The purity and concentration of cDNA were determined using a SmartSpecPlus instrument (Bio-Rad, United States). The level of gene transcripts in PBL was assessed by real-time polymerase chain reaction (RT-PCR) on an iCycler device with an iQ5 optical attachment (Bio-Rad, USA) using an amplification kit with an intercalating dye SYBR Green (Evrogen, Russia ).For the amplification of the caspase-3, -6, and -9 genes, the primers indicated in [12, 13] were used. Primers for amplification of the GAPDH gene: forward 5′-gaaggtgaaggtcggagtc-3 ‘, reverse 5′-gaagatggtgatgggatttc-3’. Primers for amplification of the caspase-8 gene: forward 5′-ggtcacttgaaccttgggaata-3 ‘, reverse 5′-cagatcttcactgtccagttgt-3’. The specificity of the amplification products was checked by melting PCR fragments. The level of transcripts of the studied genes was calculated relative to the level of GAPDH gene transcripts according to . In the analysis using PCR, two replicates were used.The studies were carried out on the scientific equipment of the Shared Use Center of the Institute of Biology, KarRC RAS Informed consent was obtained from all examined. The study was approved by the Medical Ethics Committee of the Ministry of Health and Social Development R.K. and PetrSU. Statistical processing of the obtained data was carried out using StatGraphics 2.1 software. Conducted a test for compliance of the results with a normal distribution. To assess the differences in biochemical parameters in the study groups, the nonparametric Wilcoxon-Mann-Whitney U test was used.The relationship between indicators was assessed using the Spearman rank correlation method. Differences were considered significant at p <0.05. Data are indicated as arithmetic mean (M) ± standard error of the mean (m). Results The results of a comparative analysis of clinical and laboratory data in healthy donors and patients with different forms of NAFLD are presented in table. 1. In donors of the control group, the values of all studied biochemical parameters are within the clinical norm. In patients with progression of NAFLD from steatosis to NASH-VA, there is an increase in the level of markers of cytolytic and cholestatic syndromes - ALT, AST, Shch.F. The concentration of total and direct bilirubin increases significantly only in patients with LC, while the level of prothrombin significantly decreases in these patients. With an increase in NASH activity, a higher level of total cholesterol is recorded, mainly due to an increase in the concentration of LDL. As NAFLD progresses, markers of mesenchymal-inflammatory syndrome - CRP and γ-globulins naturally increase, reaching a maximum level in NASH-VA and slightly decreasing in CP. The same pattern is observed for TPS, the level of which increases by more than 5 times with NASH-VA compared with that with SP.In patients with NAFLD at the LC stage, all functional liver tests, with the exception of LDL and γ-globulins, significantly differ from those in healthy individuals (see Table 1). Due to a decrease in the mass of parenchymal tissue in CP, the activity of aminotransferases decreases in comparison with that in NASH-VA, and the level of alkaline phosphatase does not significantly differ from that in NASH-UA and NASH-VA. The content of HDL in patients with LC does not significantly differ from that in patients with NASH of moderate and high activity, but is significantly lower than in individuals of other groups.Comparative analysis of the cytokine profile in healthy donors and patients with different forms of NAFLD revealed the following features (Table 2). The content of TNFα in patients with NAFLD increases compared to controls and does not differ depending on the form of NAFLD. The concentration of IL-10 at SP corresponds to the norm, but significantly increases with NASH and CP. There is a slight increase in the level of IL-1β in patients with LC compared with healthy individuals and patients with S.P. The level of IL-6 in general in NAFLD exceeds that in the control group, and among the forms of NAFLD, the content of this cytokine is significantly higher in NASH-VA than in SP, and reaches a maximum in LC.Table 2. The content of cytokines in blood plasma in patients with NAFLD and in donors of the control group The results of a comparative analysis of the levels of caspase gene transcripts in PBL in donors and patients with NAFLD are shown in the figure. It is clearly seen (figure, a) that with SP and NASH of all degrees of activity, the mRNA level of the caspase-3 gene is lower than in the control. The same pattern can be traced in relation to caspase-6, with the exception of NASH-VA (see figure, b). The expression level of the caspase-8 gene in PBL during SP and NASH-CA is significantly lower than in the control (figure, c), and the levels of caspase-9 transcripts in NASH-CA and NASH-VA are also lower than in the control (figure, d ).At the same time, the expression profile of caspase genes in patients with LC is similar to that of donors in the control group. In general, despite the almost complete absence of significant differences in the levels of mRNA genes in patients with different forms of NAFLD, it is possible to reveal a tendency to an increase in their expression in patients with LC (to the control level) compared with patients with NASH. This is due to the fact that the maximum mRNA levels of caspase-3, -6, and -9 genes in CP are significantly higher than in NASH. The level of mRNA expression of the genes caspases-3 (a), -6 (b), -8 (c), -9 (d) in PBL in patients with NAFLD and donors of the control group.Significant differences (according to the Wilcoxon-Mann-Whitney U test) compared to * —control, # — NASH-UA. Columns represent averages, bars - a range of values from minimum to maximum, ♦ - median. To identify the relationships between the expression of caspase genes in PBL, blood parameters and cytokine levels in different forms of NAFLD, we carried out a Spearman correlation analysis between these parameters. At the same time, NASH-SA revealed a negative correlation between the level of mRNA of the caspase-3 gene in PBL and the TNFα concentration (rs = -0.589; p = 0.034), a positive correlation between the levels of IL-10 and IL-1β (rs = 0.809; p = 0.005).In NASH-VA, a negative correlation was found between the level of caspase-3 gene transcripts and the concentration of IL-6 (rs = –0.711; p = 0.020), positive correlations between the levels of IL-10 and IL-6 (rs = 0.690; p = 0.015) and between IL-10 and IL-1β (rs = + 0.712; p = 0.008). With Ts.P. a positive correlation was observed between the concentration of IL-6 and the activity of ALT (rs = 0.803; p = 0.020) and AST (rs = 0.799; p = 0.024). Discussion In patients with the very initial stage of development of NAFLD - with PS - altered liver function tests were already detected: the activity of ALT and ALP increased and the HDL level decreased.This indicated damage to the cytoplasmic membranes, the formation of intrahepatic cholestasis, and a decrease in HDL synthesis. At the same time, an increase in the level of TNFα was noted with a normal level of IL-6. It is known from the literature that these cytokines serve as markers of the immune-inflammatory process , their overproduction is often observed in patients with NAFLD, and they play a leading role in the progression of this disease . In the examined patients with different forms of NAFLD, we did not detect an increase in the concentration of TNFα with the development of NAFLD from SP to C.P. Considering the important role of TNFα as a marker of cellular immune responses and an inducer of macrophage activity, it can be concluded that a significant progression of cellular-type immune responses during the development of NAFLD from PS to CP did not occur, and humoral effector mechanisms played an important role. This was confirmed by an increase in the concentration of IL-10, which suppresses Th2-helpers and macrophages, and the concentration of immunoglobulins. At the same time, some authors find a correlation between the TNFα level and the degree of insulin resistance and fibrosis [16, 17].TNFα in hepatocytes, on the one hand, can act as an inducer of apoptosis, realizing signal transmission to the caspase cascade, and, on the other hand, can suppress this process by activating the NF-κB signaling pathway . Perhaps that is why, with an increased level of TNFα in patients with SP and other forms of NAFLD, we registered a lower mRNA level of the caspase-3, -6, and -8 genes compared to the control. In NASH, compared to SP, along with an increase in liver cell damage (ALT, AST, ALP) and dyslipidemia (an increase in LDL levels), changes in the cytokine profile are observed - the level of IL-10 increases significantly.This cytokine has anti-inflammatory, immunomodulatory and immunosuppressive properties. Some researchers note a decrease in the level of IL-10 in NAFLD, explaining this by a protective immune response to fibrogenesis . However, the role of IL-10 in the regulation of fibrogenesis is not unambiguous . It should be noted that in patients with NASH-VA we determined a higher level of γ-globulins compared to that in SP and NASH-SA and NASH-UA, and this indicates the activation of specific humoral immunity.Thus, the observed increase in the level of IL-10 during the progression from SP to NASH-VA may reflect the activation of the body's immune response to the inflammatory process, as a result of which the secretion of IL-10 as an anti-inflammatory agent by producing cells (T-helpers, B-lymphocytes, monocytes, macrophages, mast cells). This assumption is indirectly confirmed by the presence of a positive correlation between the level of IL-10 and the concentration of proinflammatory cytokines in patients with NASH.Thus, in patients with NASH-SA, a strong correlation was found between the levels of IL-10 and IL-1β in the blood; in patients with NASH-VA, the level of IL-10 is positively correlated with the content of IL-6 and IL-1β in the blood. The levels of proinflammatory cytokines TNFα and IL-6 in NASH are higher than in controls, while the level of IL-6 tends to increase with increasing NASH activity. Thus, the content of IL-6 in NASH-VA is significantly higher than in S.P. An increase in the intensity of the inflammatory process during the progression of NASH is also confirmed by an increase in the content of CRP and γ-globulins.It should be noted a decrease in the mRNA levels of the studied caspase genes in patients with NASH of different degrees of activity relative to control, and only in the PBL of patients with weak NASH activity, this decrease is significant. However, as NASH progresses, there is an increase in the concentration of the cytokeratin-18 (TPN) fragment cleaved by caspase-3. It is known that TPN is formed during apoptosis of hepatocytes and is a serum marker of this phenomenon in NASH . Our data are consistent with the literature data on the intensification of apoptosis processes in NAFLD , at the same time, the results of this work may indicate the absence of apoptosis induction in PBL in patients with NASH.These facts suggest that the induction and regulation of degradation of PBL and hepatocytes can be carried out by different mechanisms. For example, cytokines can act as both inducers and suppressors of programmed cell death, and their effect on this process depends on the type of tissue and the stage of cell differentiation . The assumption that an increase in the level of proinflammatory cytokines during the development of NASH can mediate a decrease in the level of activity of the process of caspase-dependent apoptosis of PBL is confirmed by the presence of a negative correlation between the levels of proinflammatory cytokines (TNFα in patients with NASH-CA, IL-6 in patients with NASH-VA) and the level of mRNA of the gene effector caspase-3 in the LPK.It is possible that the preservation of the leukocyte population is necessary for effective cell-mediated lysis and phagocytosis of damaged hepatocytes. The results of a comparative analysis of biochemical parameters in patients with NAFLD at the LC stage indicate that in the process of fibrogenesis and loss of parenchymal cells, hyperbilirubinemia naturally increases and the levels of aminotransferases and prothrombin decrease. Regarding the cytokine profile in LC, we have shown that the levels of TNFα, IL-1β, and IL-10 do not significantly differ from the levels of these cytokines in NASH.At the same time, the concentration of IL-6 in patients with LC significantly exceeds that in patients with SP, NASH, and even more so in healthy individuals. IL-6 is an inducer of the synthesis of proinflammatory proteins, against the background of their increasing secretion, reactive oxygen species contribute to the uncoupling of the process of oxidative phosphorylation, depletion of mitochondrial ATP, which leads to damage and necrosis of hepatocytes in CP . This is confirmed by the presence of positive correlations between the content of IL-6 and the activity of ALT and AST in CP.In patients with LC, we also revealed a slight increase in the level of IL-1β in comparison with the control and the S.P. group. It is known that IL-1β plays an important role in the induction of lipogenesis and SP in obesity . In contrast to NASH patients, in whom the mRNA level of some caspase genes is lower than in the control, the profile of these genes in LC is similar to that of the control group donors. At the same time, in patients with NASH, a relationship is found between the level of proinflammatory cytokines and the level of transcripts of caspase genes in PBL, while in patients with LC, it is not.It is likely that the level of transcription of caspase genes in PBL in NAFLD may depend on the level of induction of the inflammatory process. We assume that the generalized immune response arising in LC against the background of portal hypertension and systemic circulation of antigens may mediate the induction of PBL apoptosis. Conclusion The obtained data confirmed the leading role of TNFα and IL-6 in the progression of NAFLD. An increase in the concentration of these pro-inflammatory cytokines is observed already at the earliest stage of NAFLD - at C.P. At the same time, the level of TNFα does not differ depending on the form of NAFLD, while the content of IL-6 tends to increase as the intensity of the inflammatory process increases during the progression of NASH and significantly increases in CP, in which the hyperproduction of IL-6 is one of the inducers of damage and necrosis of hepatocytes. With the transition from steatosis to NASH, the level of IL-10 in the blood increases sharply, while the level of IL-10 is consistently higher than normal in NASH and CP. Probably, activation of the immune response during long-term chronic inflammation leads to a compensatory increase in the production of IL-10 as an anti-inflammatory agent.In this work, it was shown for the first time that the profile of mRNA expression levels of caspase genes in the duodenum differs depending on the form of NAFLD. In patients with SP and NASH, there is a decrease in mRNA levels of the gene for effector caspase-3, as well as other caspases-6, -8, and -9 relative to the control. It is important that a decrease in the transcriptional activity of the gene for the effector caspase-3 is observed with SP and NASH of all degrees of activity. We have obtained confirmation that an increase in the level of proinflammatory cytokines during the development of NASH can mediate a decrease in the level of activity of the process of caspase-dependent apoptosis of PBL.Moreover, as NASH progresses, the activity of hepatocyte apoptosis increases. This can be judged by the increase in the blood of a specific indicator of this process - the concentration of the cytokeratin-18 fragment. Thus, the processes of apoptosis of hepatocytes and LPK in NAFLD can be regulated by different mechanisms. At the same time, our results indicate that the level of transcription of caspase genes in the PBL of patients with NAFLD may depend on the level of activity of the inflammatory process. Under Ts.P. generalized immune response due to severe damage to liver cells and blood shunting in portal hypertension may possibly mediate the induction of apoptosis of PBL, as evidenced by an increase in the level of expression of caspase genes in patients with LC (to the control level) compared with patients with NASH. Thus, this study identified the features of the necrotic-inflammatory process in different forms of NAFLD, which have a potential prognostic value. Along with a change in the general clinical picture, the progression of NAFLD leads to a change in the cytokine profile and expression levels of the caspase genes in the vLPC.Financial support for research was carried out from the federal budget for the implementation of the state assignment (Topic No. 0221−2014−0034). The work was also supported by a scholarship of the President of the Russian Federation for young scientists and postgraduate students who carry out promising research and development in priority areas of modernization of the Russian economy for 2015–2017. The work was also carried out as part of the implementation of the Strategic Development Program of PetrSU for 2012—2016. There is no conflict of interest.
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