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.
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
Cholestatic pattern: elevated alkaline phosphatase + GGT + bilirubin out of proportion to AST and ALT
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.
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.
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.
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]
|||Ribeiro AJS,Yang X,Patel V,Madabushi R,Strauss DG, Liver Microphysiological Systems for Predicting and Evaluating Drug Effects. Clinical pharmacology and therapeutics. 2019 Apr 16; [PubMed PMID: 30993668]|
|||Vagvala SH,O'Connor SD, Imaging of abnormal liver function tests. Clinical liver disease. 2018 May; [PubMed PMID: 30992803]|
|||Wilkerson RG,Ogunbodede AC, Hypertensive Disorders of Pregnancy. Emergency medicine clinics of North America. 2019 May; [PubMed PMID: 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 journal of nuclear medicine : IJNM : the official journal of the Society of Nuclear Medicine, India. 2018 Oct-Dec; [PubMed PMID: 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 journal of gastroenterology. 2018 Aug 14; [PubMed PMID: 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. Annals of internal medicine. 2002 Jul 2 [PubMed PMID: 12093239]|
|||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]|
|||Cabrera-Abreu JC,Green A, Gamma-glutamyltransferase: value of its measurement in paediatrics. Annals of clinical biochemistry. 2002 Jan [PubMed PMID: 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. Digestive diseases and sciences. 1985 Mar [PubMed PMID: 2857631]|
|||Radovanović-Dinić B,Tešić-Rajković S,Zivkovic V,Grgov S, Clinical connection between rheumatoid arthritis and liver damage. Rheumatology international. 2018 May; [PubMed PMID: 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 journal of gastroenterology. 2019 Jan 21; [PubMed PMID: 30686905]|