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Interpreting Abnormal Liver Function Tests Author: Dr Martin Prince What are LFTs? Liver function tests (LFTs) are a panel of laboratory results that can be helpful in diagnosing and assessing the extent of liver disease. Although they are amongst the most frequently requested biochemical panels, abnormal results are often incompletely investigated. Doctors are often poor at estimating the most common causes of the abnormalities. 2 Despite the name, most of the components of the LFTs do not directly measure liver function. Four of the components of LFTs (ALT, AST, ALP, GGT) are enzymes that are normally found inside the cells of the liver (hepatocytes or biliary cells) but can “leak” into the blood after liver or biliary injury. Measuring the level of these enzymes in the serum will not determine the degree of liver dysfunction but can reflect the extent and mode of liver injury. The remaining two components of the LFTs (albumin and bilirubin) are substances that are produced or processed/excreted by the liver. These latter components are therefore a better measure of the level of liver function. Abnormal LFT results are not specific to liver disease (see below) and liver disease does not always manifest with abnormal LFTs (for example 20% of patients with 3 hepatitis C have persistently normal LFTs). Furthermore, as many as one in six of the asymptomatic general population now have abnormal LFT results due to increasing obesity and fatty liver. Despite their problems with sensitivity and specificity, LFTs when interpreted within the clinical context. What are the indications for LFTs? LFTs are useful in diagnosing and monitoring the progression of liver disease. Although often performed as part of the routine initial assessment of acutely presenting patients, they are most useful when patients present with signs or symptoms of liver disease (for example jaundice, right upper quadrant pain, ascites,fatigue or variceal bleeding). They may also be useful where apparently well patients have risk factors for liver disease (for example hazardous alcohol consumption) although their sensitivity for picking up cirrhosis may be low. LFTs are also a routine part of recommended monitoring for several forms of medication. In some cases, this is because the medication can be associated with serious liver problems (for example Methotrexate which can cause liver fibrosis). What are the components of the LFTs? The enzyme components of the LFTs are two aminotransferases, γ-glutamyltransferase and alkaline phosphatase. The two aminotransferases are Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST). These respond similarly to liver insults and many laboratories routinely only perform one or other of these tests (most often ALT). ALT and AST are found in hepatocytes and released in large amounts when there is hepatic parenchymal damage (i.e. hepatitis). They are also expressed in significant amounts in the heart, skeletal muscles and red blood cells and may increase after myocardial infarction, rhabdomyolysis and haemolysis. Their ratio may help to assess whether there is any liver fibrosis Alkaline phosphatase (ALP) is found in large amounts in the liver (where it is contained in biliary cells), bone and placenta. Raised blood levels may reflect biliary obstruction or bony disease such Paget’s disease, fractures or metastatic disease. Osteoporosis and myeloma typically do not raise ALP levels unless they are associated with fractures. It is usually possible to distinguish bony and biliary causes of ALP elevation on clinical grounds. In other cases it can be useful to examine GGT levels (see below) which rise with biliary but not bony disease. It may occasionally be necessary to request analysis of the individual sub-types of ALP (known as isoenzymes) to identify the source tissue type. ALP levels rise physiologically in periods of growth (e.g. adolescence) and pregnancy.γ-glutamyltransferase (GGT) is present in the liver, renal tubules, pancreas and intestine. However, it is largely the liver that is responsible for the presence of GGT in the blood. It is increased by biliary disease and thus can be a good marker for whether ALP rises are due to bony or biliary causes. It is also raised by “enzyme induction”, for example prolonged exposure to hazardous alcohol and to some drugs (such as Rifampicin, Phenobarbitone and Griseofulvin). Albumin is the predominant blood protein and is largely made by the liver. Low levels in the medically stable out patient may indicate poor underlying liver synthetic function. However albumin levels are extremely variable in acute illness and fall (often precipitously) in many acute illnesses, particularly if associated with sepsis. They can also be low in extreme malnutrition or where there is protein loss from the kidneys (nephrotic syndrome) or bowels (protein losing enteropathy). Bilirubin is a waste product produced by the catabolism of haemoglobin. The liver is responsible for much of this breakdown process and for conjugating bilirubin to make it water soluble to allow excretion in the bile. Raised bilirubin levels may reflect increased red cell breakdown (pre-hepatic jaundice), reduced liver function (hepatic jaundice) or biliary obstruction (post-hepatic jaundice). 5% of the population have low levels of conjugating enzymes (Gilbert’s syndrome) which causes raised unconjugated bilirubin levels in the presence of otherwise normal LFTs. Chronic liver disease, especially cirrhosis, where the causative agents have been treated (for example abstinent alcoholic cirrhosis or treated viral hepatitis) is often characterized by only minimal abnormalities of LFTs. Many patients with cirrhosis will have completely normal LFTs. In these patients serial measurement of bilirubin and albumin over prolonged periods provide a good marker of the progression of hepatic synthetic dysfunction and thus the severity of the liver disease. How to interpret abnormal LFTs 1. Consider the clinical context: The patient’s history, signs, symptoms and risk factors are invaluable in interpreting abnormal LFTs. Risk factors for viral hepatitis include travel / residence in developing countries, intravenous drug use, tattoos and blood transfusions. Careful drug histories (including both prescription and herbal / other-the-counter remedies) are necessary to look for drug induced liver disease. Asystematic alcohol history should be taken to indentify hazardous alcohol consumption. 2. Identify the predominant type / pattern of injury: ALT is typically raised in conditions that damage hepatocytes i.e. hepatitis (inflammation of the liver). In contrast, ALP and GGT tend to be elevated due to conditions that cause cholestasis (blockage of biliary excretion) or biliary inflammation (cholangitis). However, most insults to the liver can result in a “mixed pattern” of both. Here it is important to identify which enzymes are the most markedly raised compared to their upper limit of normal (ULN) to decide if the pattern is hepatocellular dominant or cholestatic dominant. Table 1 lists common problems associated with various patterns of LFT abnormality. It is good practice to repeat LFTs if they are found to be abnormal, especially in patients who are clinically unwell for other reasons. LFTs may rise transiently as a 2 non-specific response to serious systemic illness. 3. Identify the likely causes of LFT abnormalities: The clinical picture combined with abnormal LFT pattern will hopefully provide an insight into a patient’s likely condition. To confirm the underlying diagnosis it is usually necessary to perform a “liver screen” for the most common causes of liver disease, although this can be delayed until the LFTs are rechecked after 24 hours if the patient is systemically unwell and the LFT abnormalities are mild and appear secondary to systemic effects of non-hepatic illness. Table 2 lists the components of a liver screen. A liver screen should not be omitted for hazardous drinkers on the basis that alcoholic liver disease is the likely diagnosis. Many patients with liver disease in the context of excessive alcohol will also have a second cause of liver injury. 4. Consider a liver biopsy. Liver biopsy may be indicated in acute illness where the cause of LFT abnormalities is not clear (for example where the liver screen is normal) or where there is the need to confirm the severity of the liver disease (especially to stage the degree of hepatic fibrosis in chronic disease). This is an invasive test and carries a small risk of serious complications (a 1% risk of bleeding and 0.1% risk of life threatening complications) and should only be considered after discussion with senior team members. Clinical ExamplesPerhaps the best way to understand LFT interpretation is to work through clinical scenarios. Four examples are given below. Case 1. A 74yr old man is admitted to hospital with a one-week history of abdominal pain and jaundice. Urine and electrolytes: ‘mild dehydration’ Bilirubin: 65 μmol/L (0-17) ALT: 84 IU/L (8-45) GGT: 235 IU/L (0-65) ALP: 667 IU/L (30-112) ALB: 30 g/L (35-55) Discuss these results and the likely differential diagnosis This man is jaundiced as shown by the raised bilirubin. His ALT is around twice and the ALP six times the ULN. Thus the ALP is the predominant abnormality, making this a mainly cholestatic pattern of abnormal LFTs. This is backed up by the raised GGT. The differential diagnoses include a common bile duct stone; pancreatic or bile duct cancer; sclerosing cholangitis or primary biliary cirrhosis. ALT levels tend to be higher with duct stones than malignant cholestasis due to associated cholangitis and hepatocyte damage. The next investigation was an ultrasound that confirmed the diagnosis. Case 2. A 28yr old man presents with a 5-day history of upper right abdominal pain and jaundice. Bilirubin: 69 μmol/L (0-17) ALT: 875 IU/L (8-45) GGT: 104 IU/L (0-65) ALP: 159 IU/L (30-112) ALB: 30 g/L (35-55)Discuss these results and the likely differential diagnosis Here the ALT is nearly 20 times the ULN and the predominant abnormality indicating a hepatitic pattern. The most likely diagnosis is viral hepatitis (possibly due to hepatitis A or B, Epstein-Barr virus or cytomegalovirus). Less likely differentials include drug-induced hepatitis (including paracetamol overdose), autoimmune hepatitis or vascular conditions such as Budd-Chiari syndrome. A liver screen showed high titres of hepatitis A IgM confirming that the LFT abnormalities were due to acute hepatitis A. Case 3. A 47yr old woman with a history of hazardous alcohol consumption (now abstinent for 8 years) attends a follow-up clinic. She had previously been informed that she has ‘cirrhosis’. Bilirubin: 28 μmol/L (0-17) ALT: 31 IU/L (8-45) GGT: 64 IU/L (0-65) ALP: 104 IU/L (30-112) ALB: 29 g/L (35-55) Are you able to reassure this lady and refute the diagnosis of cirrhosis? What else do these tests tell you? It is quite common in stable cirrhosis to have near normal LFTs and normal LFTs do not rule out cirrhosis. The albumin is below the normal range and the bilirubin elevated, indicating a degree of synthetic impairment and significant underlying liver disease. This suggests here cirrhosis may be quite severe. The normal GGT is compatible with her given history of abstinence. Case 4. A 79yr old man presents with a 10-month history of weight loss and irregular hepatomegaly. Bilirubin: 45 μmol/L (0-17) ALT: 95 IU/L (8-45) GGT: 352 IU/L (0-65) ALP: 3,876 IU/L (30-112) ALB: 26 g/L (35-55)Discuss these results and the likely differential diagnosis Weight loss combined with an irregular liver is suggestive of cancer, possibly with liver metastases. All the LFTs are abnormal but his ALP is disproportionately so. This suggests coexistent problems, possibly with bone pathology. Considering his age and gender this is suggestive of prostate cancer with both bone and liver metastases. Table 1: Common patterns of LFT abnormality Predominant LFT Common causes Less common causes abnormality ALT raised to less than 5 Alcoholic hepatitis, chronic HIV seroconversion, drug times ULN - “mild viral hepatitis (B & C), induced liver disease, hepatitic” Acute glandular fever (EBV Wilson’s disease, or CMV), autoimmune A1-antitrypsin deficiency hepatitis, fatty liver disease ALT 10 to 15 times ULN Acute viral hepatitis (A,B or Severe autoimmune - “severe hepatitic” E), ischaemic hepatitis, hepatitis, Budd-Chiari paracetamol overdose syndrome Raised bilirubin – all Gilbert’s syndrome Chronic haemolysis other LFTs normal Raised ALP and GGT Common bile duct stones, Sclerosing cholangitis, (+/- raised bilirubin) – cancer of the head of primary biliary cirrhosis, “cholestatic” pancreas, liver sarcoidosis cholangiocarcinoma, chronic pancreatitis Raised ALP alone Consider non-hepatic Bone metastases, causes: Physiological osteonecrosis (adolescence (due to rapid bone turnover) and pregnancy (from the placenta)), Paget’s disease, fractures Raised GGT alone – Chronic hazardous alcohol “enzyme induction” consumption, medications including some anticonvulsants, Rifampicin, Griseofulvin Table 2: Components of a liver screen for investigation of abnormal LFTs Test Condition screen for Notes Ultrasound abdomen Focal liver lesions (e.g. metastases), biliary obstruction, gall stones liver fibrosis / cirrhosis Ferritin Haemochromatosis Ferritin often raised as acute phase protein – may need repeating after acute illness improved Auto-antibodies (smooth Autoimmune hepatitis and Smooth muscle antibodies muscle, nuclear and primary biliary cirrhosis may also be raised in mitochrondrial) other causes of liver injury Hepatitis serology Hepatitis A, B and C CMV and EBV serology CMV, EBV Copper and Wilson’s disease Rarely needed in patients caeruloplasmin over age 50 A1-antitrypsin (A1AT) A1AT deficiency Rarely helpfulReferences 1. Sherwood P, Lyburn I, Brown S, Ryder S. How are abnormal results for liver function tests dealt with in primary care? Audit of yield and impact. BMJ 2001;322(7281):276-278 2. Whitehead M, Hawkes N, Hainsworth I, Kingham J. A prospective study of the causes of notably raised aspartate aminotransferase of liver origin. Gut 1999;45(1):129–133J 3. Healey CJ, Chapman RW, Fleming KA. Liver histology in hepatitis C infection: a comparison between patients with persistently normal or abnormal transaminases. Gut 1995;37:274-278 4. Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, Grundy SM, Hobbs HH. Prevalence of hepatic steatosis in an urban population in the United States: Impact of ethnicity. Hepatology 2004;40:1387–1395