Liver Function Tests

Earn CME/CE in your profession:


Continuing Education Activity

The liver has a significant role in metabolism, digestion, detoxification, and elimination of substances from the body. The liver function tests typically include alanine transaminase (ALT) and aspartate transaminase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), serum bilirubin, prothrombin time (PT), the international normalized ratio (INR), total protein and albumin. These tests can be helpful in determining an area of the liver where damage may be taking place and, depending on the pattern of elevation, can help organize a differential diagnosis. Elevations in ALT and AST in disproportion to elevations in alkaline phosphatase and bilirubin denote hepatocellular disease. Whereas an elevation in alkaline phosphatase 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.

Objectives:

  • Identify the most common cause of abnormal liver function test results.
  • Describe the pattern of liver function abnormality seen in alcoholic liver disease.
  • Outline the pattern of liver function test results in patients with cholestatic disease.
  • Summarize the significance of individual tests obtained in a liver function testing panel.

Introduction

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.[1]The liver also has a significant role in metabolism, regulation of red blood cells (RBCs), and glucose synthesis and storage. Typically when reviewing liver function tests, the discussion includes alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT),5'nucleotidase, total bilirubin, conjugated (direct) bilirubin, unconjugated (indirect)bilirubin, prothrombin time (PT), the international normalized ratio (INR), lactate dehydrogenase, total protein, globulins, and albumin. These tests can be helpful in determining the area of hepatic injury, and the elevation pattern can help organize a differential diagnosis.[2]

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. An elevation in  ALP and bilirubin in disproportion to ALT and AST would characterize a cholestatic pattern. A mixed injury pattern is defined as an elevation of alkaline phosphatase and AST/ALT levels. Isolated hyperbilirubinemia is defined as an elevation of bilirubin with normal alkaline phosphatase and AST/ALT levels.[3]The R ratio has been used to assess whether the pattern of liver injury is hepatocellular, cholestatic, or mixed. The R ratio is calculated by the formula R =(ALT value÷ALT ULN)÷(alkaline phosphatase value÷alkaline phosphatase ULN). An R ratio of >5 is defined as hepatocellular, <2 is cholestatic, and 2–5 is a mixed pattern.[4] 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 liver function tests are found in approximately 8% of the general population. These elevations may be transient in patients without symptoms, with up to 30% of elevations resolving after 3 weeks. Thus, care should be taken when interpreting these results to avoid unnecessary testing.[5] A borderline AST and/or ALT elevation is defined as <2X ULN, a mild AST and/or ALT elevation as 2–5X ULN, moderate AST and/or ALT elevation 5–15X ULN, severe AST and/or ALT elevation >15X ULN, and massive AST and/or ALT >10,000 IU/l.The magnitude of AST and ALT elevation varies depending on the cause of hepatocellular injury.[6]

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 +gamma glutamyl transferase + 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: Bone disease, pregnancy, chronic renal failure, lymphoma or other malignancies, congestive heart failure, childhood growth, infection, or inflammation.

Pathophysiology

Components of Liver Function Test

Hepatocellular Labs

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 as 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 as ALT, and elevation in AST may be seen as secondary to nonhepatic causes as well. AST activity in neonates and infants is approximately twice that in adults, but these decline to adult levels by approximately 6 months of age.[7]ALT is a cytosolic enzyme that is found in high concentrations in the liver. The half-life of ALT is approximately 47 ± 10 hours. ALT is usually higher than AST in most types of liver disease in which the activity of both enzymes is predominantly from the hepatocyte cytosol. Hepatocellular injury and not necessarily cell death is the trigger for the release of these enzymes into circulation. Both AST and ALT values are higher in normal males than females.[8]They also correlate with obesity with a normal reference range higher in those with higher body mass index.[9]

Cholestasis Labs

Alkaline phosphatase is part of a family of zinc metalloenzymes that are highly concentrated in the microvilli of the bile canaliculus as well as several other tissues (e.g., bone, intestines, and placenta).[1]There are four isozymes: placental ALP or hPLALP (human placental ALP), germ cell ALP (GCALP or PLALP-like),  intestinal ALP (IALP), and tissue-nonspecific ALP (TNALP). Of these four, PLALP and GCALP are the most heat stable at 65°C, and the bone ALP component of TnALP is the least. In healthy non-smoking individuals, the PLALP and GCALP represent less than 1% of total ALP activity in the serum.[10]A condition that can result in significantly increased plasma ALP is benign transient hyperphosphatasemia. Originally described in infants, transient hyperphosphatasemia can also occur in adults and during pregnancy. There is a marked rise in ALP, often to several thousand IU/L, which would usually indicate significant pathology. It is, however, a benign condition with a return to normal of the ALP in 6–8 weeks. Transient hyperphosphatasaemia is associated with concurrent infections in over 60% of cases, particularly GIT infections. There is a characteristic pattern on polyacrylamide gel electrophoresis with the normal pattern of isoenzymes being accompanied by variant forms that react with neuraminidase. It is believed to be due to changes in carbohydrate side chains causing failure of recognition by receptors and reduced clearance, thus prolonging half-life.[11] 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, 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. Serum GGT shows electrophoretic mobility and lectin-affinity reaction identical to those of the liver enzyme but different from those of GGT from the kidney, urine, and pancreas.GGT levels are reported to be increased by an average of 12-fold in obstructive liver disease when compared to ALP, which increased only 3-fold, so GGT is slightly more sensitive than ALP in this regard.GGT activity level in children may be a reliable index of bile duct damage and it is a useful indicator in separating the two forms of idiopathic cholestasis, with or without a bile duct involvement. In infants diagnosed with biliary atresia and managed surgically, the GGT levels stay high in the blood if the infant is breastfed. This is due to the high level of GGT in human breast milk for at least 4 weeks postpartum.[12]There is a relationship between plasma GGT activity and weight, with values being 50% higher in individuals with a BMI >30. This is believed to be due to fat deposition in the liver (steatosis) in obese subjects. Steatosis with a raised plasma GGT also occurs in diabetes mellitus, non-alcoholic steatohepatitis, and non-alcoholic fatty liver disease. Any liver disease that results in fibrosis and/or cirrhosis, such as alcoholic cirrhosis, PBC, PSC, hemochromatosis, α1-antitrypsin deficiency, and Wilson’s disease will cause a raised plasma GGT. Space-occupying lesions, including malignancy (HCC or metastases secondary to malignancy elsewhere in the body), and granulomatous disease, for example, sarcoidosis and TB are also associated with a raised plasma GGT.5′-Nucleotidase (5′NT) is associated with the canalicular and sinusoidal plasma membranes. Its function is undefined. 5′NT is also found in the intestine, brain, heart, blood vessels, and endocrine pancreas. Serum levels of 5′NT are unaffected by sex or race, but age affects the level; values are lowest in children and increase gradually, reaching a plateau at approximately age 50 years. As with GGT, the primary role of the serum 5′NT level is to identify the organ source of an isolated serum alkaline phosphatase elevation. The 5′NT level is not increased in bone disease but primarily in hepatobiliary disease.LDH is commonly included in liver biochemical panels but has poor diagnostic specificity for liver disease. Markedly increased LDH levels are observed in hepatocellular necrosis, shock liver, lymphoma, or hemolysis associated with liver disease.[13]Bilirubin is the end result of heme catabolism, with 80% 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.[14]

Synthetic Function Tests

Albumin is synthesized by the hepatic parenchymal cells at a rate that is dependent on colloidal osmotic pressure and dietary protein intake. The rate of albumin synthesis is also subject to feedback regulation determined by the plasma albumin concentration. Maintenance of plasma albumin concentrations can be achieved with only 10% of normal hepatocyte mass. The half-life of albumin is 21 days. Traces of albumin can be found in almost all extracellular body fluids. Little is lost from the body by excretion.[15] It is catabolized in various tissues, which are taken up by cells by pinocytosis. Its constituent amino acids are released by intracellular proteolysis and returned to the body pool. 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 poor protein intake (malnutrition) or protein loss (nephrotic syndrome, malabsorption, or protein-losing enteropathy).[16]

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. Suppose the synthetic function of the liver is normal and prothrombin time is delayed. In that case, this may indicate treatment with warfarin, consumptive coagulopathy (e.g., disseminated intravascular coagulopathy), or deficiency of vitamin K.[17]

Serological Tests

Liver-related autoantibodies are crucial for the correct diagnosis and classification of autoimmune liver diseases, namely autoimmune hepatitis types 1 and 2 (AIH-1 and 2), primary biliary cirrhosis (PBC), and the sclerosing cholangitis variants in adults and children.AIH-1 is specified by anti-nuclear antibody (ANA) and smooth muscle antibody (SMA). AIH-2 is specified by antibody to liver kidney microsomal antigen type-1 (anti-LKM1) and anti-liver cytosol type 1 (anti-LC1). SMA, ANA, and anti-LKM antibodies can be present in de-novo AIH following liver transplantation.[18]PBC is specified by antimitochondrial antibodies (AMA) reacting with enzymes of the 2-oxo-acid dehydrogenase complexes (chiefly pyruvate dehydrogenase complex E2 subunit) and disease-specific ANA mainly reacting with nuclear pore gp210 and nuclear body sp100. Sclerosing cholangitis presents in at least two variants, first, the classical primary sclerosing cholangitis (PSC) mostly affects adult men wherein the only (and non-specific) reactivity is an atypical perinuclear antineutrophil cytoplasmic antibody (p-ANCA), also termed perinuclear anti-neutrophil nuclear antibodies (p-ANNA) and second the childhood disease called autoimmune sclerosing cholangitis (ASC) with serological features resembling those of type 1 AIH.[19]

Secondary Biochemical Liver Tests

Alpha-fetoprotein (AFP) measurements are used as a tumor marker for the detection and monitoring of primary hepatocellular malignancies, such as hepatoblastoma and HCC. Alpha-fetoprotein is produced by hepatoblasts and that's why it is raised in the regenerating liver, particularly in chronic viral hepatitis.[20]Carbohydrate deficient transferrin is a test that has high specificity for the detection of excess alcohol intake as a cause of liver damage. The carbohydrate antigen CA19-9 is useful in monitoring the activity of the autoimmune disease PSC, which often progresses to a tumor of the bile ducts or cholangiocarcinoma.[21] Measurement of serum ferritin can be useful in identifying hemochromatosis, but ferritin is a positive acute phase reactant so is raised in many illnesses as well as being released from damaged hepatocytes in acute hepatic failure.[22]

Specimen Requirements and Procedure

The serum is the specimen of choice. Consider all plasma or serum specimens potentially positive for infectious agents including HIV and the hepatitis B virus. All specimens should be handled with standard precautions and sent to the lab immediately for processing. Separated serum or plasma should not remain at +15°C to +30°C longer than 8 hours. If assays are not completed within 8 hours, serum or plasma should be stored at +2°C to +8°C. If assays are not completed within 48 hours, or the separated sample is to be stored beyond 48 hours, samples should be frozen at –15°C to –20°C. Frozen samples should be thawed only once. Analyte deterioration may occur in samples that are repeatedly frozen and thawed.[23]

Testing Procedures

Liver function tests are performed on semi-automatic or fully automated analyzers which are based on the principle of photometry. Photometry is the measurement of light absorbed in the ultraviolet (UV) to visible (VIS) to infrared (IR) range. This measurement is used to determine the amount of an analyte in a solution or liquid. Photometers utilize a specific light source and detectors that convert light passed through a sample solution into a proportional electrical signal. These detectors may be photodiodes, photoresistors, or photomultipliers. Photometry uses Beer–Lambert’s law to calculate coefficients obtained from the transmittance measurement. A correlation between absorbance and analyte concentration is then established by a test-specific calibration function to achieve highly accurate measurements.[24]

Interfering Factors

Hemolysis, icterus, and lipemia are the most common specimen integrity issues that can interfere with laboratory tests and may lead to erroneous results and interpretations and ultimately to inappropriate medical decisions. Oxygenated and deoxygenated hemoglobin have slightly different absorbance spectra but show maximal absorbance around 415 nm, with significant absorbance between 320 and 450 nm and 540 and 580 nm. Colorimetric assays that use absorbance measurements in one or more of these ranges are therefore susceptible to interference. Examples include iron, lipase, albumin, and g-glutamyl transferase.

Alkaline phosphatase assays are susceptible to negative interference because alkali denaturation of hemoglobin may cause a negative offset in absorbance readings. Icterus exerts effects on chemistry tests primarily through spectrophotometric and chemical interferences. Bilirubin absorbs light between 400 and 540 nm, with a peak around 460 nm. Colorimetric assays taking primary or secondary absorbance measurements at these wavelengths may be affected. The unconjugated and conjugated forms of bilirubin may exert different effects on certain assays. Conjugated bilirubin has been found to cause a greater degree of interference with most assays. Lipemia causes light scattering, differential partitioning of analyte between the polar and aqueous phases of the sample, and interaction of the lipoprotein particles with assay reagents may all cause interference in results. Lipaemia causes light scattering across the visual spectrum (300 to 700 nm). Colorimetric assays taking absorbance readings at the shorter wavelengths of the visual spectrum are therefore most susceptible to interference. As a result, assays that utilize changes in NAD(P)H concentration, which is measured around 340 nm, are susceptible to lipaemia interference. ALT levels can increase due to certain drugs, which should be avoided before testing.

Drug hepatotoxicity can be nonidiosyncratic (predictable) or idiosyncratic (unpredictable). Also, drug-associated hepatotoxicity can classify as immune-mediated and non-immune-mediated. The incidence of drug-induced liver injury is 19 cases per 100,000 persons. The most common drug causing drug-induced liver injury is amoxicillin/clavulanate.[25][26][27]Diurnal variations in ALT have been observed in both healthy individuals and those with cirrhosis. Up to 45% variation has been seen, with higher values being observed in the afternoon.

Other factors which can affect ALT include African-American race (15% higher than Caucasians), body mass index (40 to 50% higher with high body mass index), and exercise (20% lower in those who exercise).[28] Metronidazole may interfere with ALT methods because of its relatively high concentration and absorbance near 340 nm.[29] Serum ALP activities are 10–15% higher in African-Americans. Following food ingestion, increases of up to 30 U/L may be seen. In patients with blood groups B and O; these increases can persist for up to 12 hours; attributable to the intestinal isoenzyme. Smoking causes elevated levels of PLALP, which return to the normal range after 1 to 2 months of smoking cessation. 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. An unexplained high serum ALP result should always be confirmed with a repeat fasting sample. Increases up to two- or three-fold are normal in the third trimester of pregnancy due to the presence of the placental isoenzyme.

Results, Reporting, Critical Findings

The results of liver function tests should correlate with the initial findings in a complete history and physical examination of the patient. A thorough review should include important questions regarding the patient’s age, past medical history (diabetes, obesity, hyperlipidemia, inflammatory bowel disease, celiac sprue, thyroid disorders, autoimmune hepatitis, acquired muscle disorders, alcohol use disorder, medication use, toxin exposure, and family history of genetic liver conditions (Wilson’s disease, alpha-1-antitrypsin deficiency, hereditary hemochromatosis).[30]A review of systems should also include signs and symptoms of chronic liver disease such as jaundice, ascites, peripheral edema, hepatosplenomegaly, gynecomastia, testicular hypotrophy, muscle wasting, encephalopathy, pruritus, and gastrointestinal bleeding. Other tests that help determine the cause of elevated transaminase levels found on a hepatitis panel include fasting lipid levels, hemoglobin A1C level, fasting glucose, complete blood count with platelets, a complete metabolic panel, iron studies, hepatitis C antibody, and hepatitis B surface antigen testing.

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 a higher body mass index.[24] A patient's blood test values should be interpreted based on the reference value of the laboratory in which the test is done and it is recommended that each laboratory establish its own reference interval based on its methodology.

  • Alanine transaminase: 4-36 IU/L
  • Aspartate transaminase:5-30 IU/L
  • Alkaline phosphatase:30 to 120 IU/L
  • Gamma-glutamyltransferase:6-50 IU/L
  • Bilirubin:2 to 17 µmol/L
  • Direct bilirubin:0-6 µmol/L
  • Prothrombin time: 10.9 to 12.5 seconds
  • Albumin: 35-50 g/L
  • Total protein: 60-80 g/L
  • Lactate dehydrogenase:50-150 IU/L

Clinical Significance

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.

Alcohol

In patients with alcohol use disorder, AST to ALT ratio is generally at least 2:1, showing a high level of AST activity in alcoholic liver disease.[31] Elevated GGT along with AST also suggests alcohol abuse. GGT should not be used alone since it is not very specific for alcohol.[32]

Medications

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, 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.[25] 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.[26] Methotrexate, the 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).[33] Herbal medications can also cause an elevation in LFTs.[34]

Viral Hepatitis

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.[35] Several other viruses, including HIV, Epstein-Barr (EBV), and Cytomegalovirus (CMV), can also cause hepatitis.[36]

Autoimmune 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.[37]These patients can have positive autoantibodies, including antinuclear antibodies, anti-smooth muscle antibodies, anti-liver/kidney microsomal antibodies, and antibodies to the liver antigen.[38]

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.[39]The AST and ALT are usually both elevated with a ratio of 1:1, with other liver function tests being normal.[40]

Hemochromatosis

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.[41] 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) are pivotal for the diagnosis of hereditary hemochromatosis. Secondary hemochromatosis can also be seen due to increased iron intake.[42]

Wilson Disease

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.[43]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.[44]

Alpha-1 Antitrypsin Deficiency

Alpha-1 antitrypsin deficiency (AATD) is a relatively common yet often undiagnosed genetic condition.[45]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.[46]

Celiac Disease

Celiac disease is a common disorder of gluten sensitivity that may be associated with modest elevations of liver transaminases; screening should be considered in patients with persistently elevated liver enzymes and consists of tissue transglutaminase IgA, and serum IgA level or tissue transglutaminase IgA and anti-deamidated gliadin peptide IgG.[47][48][47]

Thyroid Disorders

Both hypothyroidism and hyperthyroidism have been associated with abnormal liver enzymes, including both hepatocellular and cholestatic patterns of injury, particularly in more severe cases of myxedema and/or thyrotoxicosis. Screening should be considered in patients with a compatible medical history and consist initially of thyroid stimulating hormone, and selective testing of free T4 and free/total T3.[49]

Quality control and Lab Safety

For non-waived tests, laboratory regulations require, at the minimum, analysis of at least two levels of control materials once every 24 hours. Laboratories can assay QC samples more frequently if deemed necessary to ensure accurate results. Quality control samples should be assayed after calibration or maintenance of an analyzer to verify the correct method performance. To minimize QC when performing tests for which manufacturers’ recommendations are less than those required by the regulatory agency (such as once per month), the labs can develop an individualized quality control plan (IQCP) that involves performing a risk assessment of potential sources of error in all phases of testing and putting in place a QC plan to reduce the likelihood of errors.[23] Westgard multi rules are used to evaluate the quality control runs and in case of any violation of a rule, proper corrective and preventive action should be taken before patient testing is performed.

Enhancing Healthcare Team Outcomes

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 workups. 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 are 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.[50]


Article Details

Article Author

Vasimahmed Lala

Article Author

Muhammad Zubair

Article Editor:

David A. Minter

Updated:

9/24/2022 3:25:53 PM

PubMed Link:

Liver Function Tests

References

[1]

Iluz-Freundlich D,Zhang M,Uhanova J,Minuk GY, The relative expression of hepatocellular and cholestatic liver enzymes in adult patients with liver disease. Annals of hepatology. 2020 Mar - Apr     [PubMed PMID: 31628070]

[2]

Ribeiro AJS,Yang X,Patel V,Madabushi R,Strauss DG, Liver Microphysiological Systems for Predicting and Evaluating Drug Effects. Clinical pharmacology and therapeutics. 2019 Jul     [PubMed PMID: 30993668]

[3]

Vagvala SH,O'Connor SD, Imaging of abnormal liver function tests. Clinical liver disease. 2018 May     [PubMed PMID: 30992803]

[4]

Kwo PY,Cohen SM,Lim JK, ACG Clinical Guideline: Evaluation of Abnormal Liver Chemistries. The American journal of gastroenterology. 2017 Jan     [PubMed PMID: 27995906]

[5]

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 journal of nuclear medicine : IJNM : the official journal of the Society of Nuclear Medicine, India. 2018 Oct-Dec;     [PubMed PMID: 30386047]

[6]

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 journal of gastroenterology. 2018 Aug 14     [PubMed PMID: 30122876]

[7]

Oh RC,Hustead TR,Ali SM,Pantsari MW, Mildly Elevated Liver Transaminase Levels: Causes and Evaluation. American family physician. 2017 Dec 1     [PubMed PMID: 29431403]

[8]

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. Annals of internal medicine. 2002 Jul 2;     [PubMed PMID: 12093239]

[9]

Ruhl CE,Everhart JE, Trunk fat is associated with increased serum levels of alanine aminotransferase in the United States. Gastroenterology. 2010 Apr     [PubMed PMID: 20060831]

[10]

Sharma U,Pal D,Prasad R, Alkaline phosphatase: an overview. Indian journal of clinical biochemistry : IJCB. 2014 Jul;     [PubMed PMID: 24966474]

[11]

Verma J,Gorard DA, Persistently elevated alkaline phosphatase. BMJ case reports. 2012 Aug 24     [PubMed PMID: 22922932]

[12]

Koenig G,Seneff S, Gamma-Glutamyltransferase: A Predictive Biomarker of Cellular Antioxidant Inadequacy and Disease Risk. Disease markers. 2015     [PubMed PMID: 26543300]

[13]

Whitfield JB, Gamma glutamyl transferase. Critical reviews in clinical laboratory sciences. 2001 Aug     [PubMed PMID: 11563810]

[14]

Fevery J, Bilirubin in clinical practice: a review. Liver international : official journal of the International Association for the Study of the Liver. 2008 May     [PubMed PMID: 18433389]

[15]

Rozga J,Piątek T,Małkowski P, Human albumin: old, new, and emerging applications. Annals of transplantation. 2013 May 10;     [PubMed PMID: 23792522]

[16]

Chen CB,Hammo B,Barry J,Radhakrishnan K, Overview of Albumin Physiology and its Role in Pediatric Diseases. Current gastroenterology reports. 2021 Jul 2     [PubMed PMID: 34213692]

[17]

Buliarca A,Horhat A,Mocan T,Craciun R,Procopet B,Sparchez Z, Viscoelastic tests in liver disease: where do we stand now? World journal of gastroenterology. 2021 Jun 21;     [PubMed PMID: 34163112]

[18]

Sebode M,Weiler-Normann C,Liwinski T,Schramm C, Autoantibodies in Autoimmune Liver Disease-Clinical and Diagnostic Relevance. Frontiers in immunology. 2018     [PubMed PMID: 29636752]

[19]

Bogdanos DP,Invernizzi P,Mackay IR,Vergani D, Autoimmune liver serology: current diagnostic and clinical challenges. World journal of gastroenterology. 2008 Jun 7     [PubMed PMID: 18528935]

[20]

Coates P, Liver function tests. Australian family physician. 2011 Mar;     [PubMed PMID: 21597511]

[21]

Scarà S,Bottoni P,Scatena R, CA 19-9: Biochemical and Clinical Aspects. Advances in experimental medicine and biology. 2015     [PubMed PMID: 26530370]

[22]

Kell DB,Pretorius E, Serum ferritin is an important inflammatory disease marker, as it is mainly a leakage product from damaged cells. Metallomics : integrated biometal science. 2014 Apr;     [PubMed PMID: 24549403]

[23]

Lippi G,von Meyer A,Cadamuro J,Simundic AM, Blood sample quality. Diagnosis (Berlin, Germany). 2019 Mar 26     [PubMed PMID: 29794250]

[24]

Gowda S,Desai PB,Hull VV,Math AA,Vernekar SN,Kulkarni SS, A review on laboratory liver function tests. The Pan African medical journal. 2009 Nov 22     [PubMed PMID: 21532726]

[25]

Andrade RJ,Lucena MI,Fernández MC,Pelaez G,Pachkoria K,García-Ruiz E,García-Muñoz B,González-Grande R,Pizarro A,Durán JA,Jiménez M,Rodrigo L,Romero-Gomez M,Navarro JM,Planas R,Costa J,Borras A,Soler A,Salmerón J,Martin-Vivaldi R,Spanish Group for the Study of Drug-Induced Liver Disease., Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology. 2005 Aug     [PubMed PMID: 16083708]

[26]

Sgro C,Clinard F,Ouazir K,Chanay H,Allard C,Guilleminet C,Lenoir C,Lemoine A,Hillon P, Incidence of drug-induced hepatic injuries: a French population-based study. Hepatology (Baltimore, Md.). 2002 Aug;     [PubMed PMID: 12143055]

[27]

Leise MD,Poterucha JJ,Talwalkar JA, Drug-induced liver injury. Mayo Clinic proceedings. 2014 Jan     [PubMed PMID: 24388027]

[28]

Hall P,Cash J, What is the real function of the liver 'function' tests? The Ulster medical journal. 2012 Jan     [PubMed PMID: 23536736]

[29]

Cheong HC,Jeong TG,Cho YB,Yang BJ,Kim TH,Kim HC,Cho EY, Metronidazole-induced encephalopathy in a patient with liver cirrhosis. The Korean journal of hepatology. 2011 Jun     [PubMed PMID: 21757988]

[30]

Malakouti M,Kataria A,Ali SK,Schenker S, Elevated Liver Enzymes in Asymptomatic Patients - What Should I Do? Journal of clinical and translational hepatology. 2017 Dec 28     [PubMed PMID: 29226106]

[31]

Nyblom H,Berggren U,Balldin J,Olsson R, High AST/ALT ratio may indicate advanced alcoholic liver disease rather than heavy drinking. Alcohol and alcoholism (Oxford, Oxfordshire). 2004 Jul-Aug;     [PubMed PMID: 15208167]

[32]

Kim E,Park SH, [Diagnosis and Severity Assessment of Alcohol-Related Liver Disease]. The Korean journal of gastroenterology = Taehan Sohwagi Hakhoe chi. 2020 Aug 25;     [PubMed PMID: 32839367]

[33]

Tagy AH,Saker ME,Moussa AA,Kolgah A, The effect of low-dose combined oral contraceptive pills versus injectable contraceptive (Depot Provera) on liver function tests of women with compensated bilharzial liver fibrosis. Contraception. 2001 Sep     [PubMed PMID: 11704097]

[34]

Yang JM,Sun Y,Wang M,Zhang XL,Zhang SJ,Gao YS,Chen L,Wu MY,Zhou L,Zhou YM,Wang Y,Zheng FJ,Li YH, Regulatory effect of a Chinese herbal medicine formula on non-alcoholic fatty liver disease. World journal of gastroenterology. 2019 Sep 14     [PubMed PMID: 31558860]

[35]

Hardikar W, Viral hepatitis. Journal of paediatrics and child health. 2019 Sep     [PubMed PMID: 31317618]

[36]

Keerl C,Bernsmeier C, [Elevated liver function tests - as incidental finding in general practice]. Therapeutische Umschau. Revue therapeutique. 2020;     [PubMed PMID: 33054645]

[37]

Linzay CD,Sharma B,Pandit S, Autoimmune Hepatitis 2019 Jan;     [PubMed PMID: 29083819]

[38]

Terziroli Beretta-Piccoli B,Mieli-Vergani G,Vergani D, Autoimmmune hepatitis. Cellular & molecular immunology. 2022 Feb     [PubMed PMID: 34580437]

[39]

Manne V,Handa P,Kowdley KV, Pathophysiology of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis. Clinics in liver disease. 2018 Feb     [PubMed PMID: 29128059]

[40]

Sheka AC,Adeyi O,Thompson J,Hameed B,Crawford PA,Ikramuddin S, Nonalcoholic Steatohepatitis: A Review. JAMA. 2020 Mar 24     [PubMed PMID: 32207804]

[41]

Voloshinа NB,Osipenko MF,Litvinova NV,Voloshin AN, Hemochromatosis - modern condition of the problem. Terapevticheskii arkhiv. 2018 Apr 19;     [PubMed PMID: 30701865]

[42]

Adams P,Altes A,Brissot P,Butzeck B,Cabantchik I,Cançado R,Distante S,Evans P,Evans R,Ganz T,Girelli D,Hultcrantz R,McLaren G,Marris B,Milman N,Nemeth E,Nielsen P,Pineau B,Piperno A,Porto G,Prince D,Ryan J,Sanchez M,Santos P,Swinkels D,Teixeira E,Toska K,Vanclooster A,White D,Contributors and Hemochromatosis International Taskforce., Therapeutic recommendations in HFE hemochromatosis for p.Cys282Tyr (C282Y/C282Y) homozygous genotype. Hepatology international. 2018 Mar;     [PubMed PMID: 29589198]

[43]

Schilsky ML, Wilson Disease: Diagnosis, Treatment, and Follow-up. Clinics in liver disease. 2017 Nov     [PubMed PMID: 28987261]

[44]

Mulligan C,Bronstein JM, Wilson Disease: An Overview and Approach to Management. Neurologic clinics. 2020 May     [PubMed PMID: 32279718]

[45]

Strnad P,McElvaney NG,Lomas DA, Alpha{sub}1{/sub}-Antitrypsin Deficiency. The New England journal of medicine. 2020 Apr 9     [PubMed PMID: 32268028]

[46]

Patel D,Teckman JH, Alpha-1-Antitrypsin Deficiency Liver Disease. Clinics in liver disease. 2018 Nov     [PubMed PMID: 30266154]

[47]

Glissen Brown JR,Singh P, Coeliac disease. Paediatrics and international child health. 2019 Feb     [PubMed PMID: 30099930]

[48]

Lebwohl B,Sanders DS,Green PHR, Coeliac disease. Lancet (London, England). 2018 Jan 6     [PubMed PMID: 28760445]

[49]

Piantanida E,Ippolito S,Gallo D,Masiello E,Premoli P,Cusini C,Rosetti S,Sabatino J,Segato S,Trimarchi F,Bartalena L,Tanda ML, The interplay between thyroid and liver: implications for clinical practice. Journal of endocrinological investigation. 2020 Jul     [PubMed PMID: 32166702]

[50]

Gurses AP,Xiao Y, A systematic review of the literature on multidisciplinary rounds to design information technology. Journal of the American Medical Informatics Association : JAMIA. 2006 May-Jun     [PubMed PMID: 16501176]