Before examining liver function tests (LFTs), one first must recall the liver's job. The liver, located in the right upper quadrant of the body and below the diaphragm does a lot for the body. Its primary jobs are to detoxify various metabolites, synthesize proteins, and produce enzymes necessary for digestion. 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 an area of the liver where damage may be taking place and depending on 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 disproportion elevations in alkaline phosphatase and bilirubin denotes a 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.
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. 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.
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). 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) but is more specific for biliary disease when compared to alkaline phosphatase because it is not present in bone.
Bilirubin is formed from the lysis of red cells within the reticuloendothelial system. Unconjugated bilirubin is transported to the liver loosely bound to albumin. Bilirubin is water-insoluble and cannot be excreted in 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 intake of protein (malnutrition) or loss of protein (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. This requires factors II, V, VII, and X and, as these are made in the liver, the liver's function is important. 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.
History and physical exam remain priorities when it comes to the differentials of LFTs. One needs to know and look for the risk factors such as viral hepatitis, sexual history, tattoos, any blood transfusion, hospitalization in a developing country, medication or herbal remedies, and exposure to toxins.
Reference ranges for LFTs tend to vary depending on the laboratory.
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 strengthens with alcohol abuse. GGT cannot be used alone since it is not very specific for alcohol.
Medications are known to cause liver damage. Many of these are commonly used in daily practice such as NSAIDs, antibiotics, statins, anti-seizure drugs, and drugs for tuberculosis treatment. Heavy emphasis should be given in the history of the types of herbal remedies and ayurvedic or homeopathy used. Acetaminophen, a very common drug in the United States, causes very high LFTs and liver failure.
Any hepatitis virus in an acute setting can cause increased LFTs. Therefore, serum antibody for hepatitis A, B, C, D, and E should be checked. Many other viruses including 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. It is recommended to check anti-smooth muscle antibody, anti-liver/kidney microsomal antibodies, and antibodies to the liver antigen to help diagnose autoimmune hepatitis.
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 to ALT ratio is generally 1:1. All other labs are usually within normal limits.
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. Also, an examination of HFE mutations (C282Y, H63D) is pivotal for the diagnosis of hemochromatosis.
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. Also, check the 24-hour urinary copper excretion test. More than 100 micrograms of copper excretion in the urine indicate Wilson 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 white persons. Its primary manifestation is early-onset panacinar emphysema.
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