- Email: [email protected]
How to investigate asymptomatic abnormal liver function tests
INVESTIGATIONS
How to investigate asymptomatic abnormal liver function tests
What’s new? C
C
Jane Collier
C
Abstract Asymptomatic abnormal liver function tests (LFTs) are common, affecting 8% of the population. The commonest causes are alcoholic and nonalcoholic fatty liver disease (NAFLD). They may be transient and should be repeated after weight reduction or cessation of alcohol or potentially hepatotoxic drugs. A careful history will help to exclude non-hepatic causes of abnormal liver blood tests as well as indicating a potential hepatic cause. Abnormal LFTs in patients taking statins are common and are more likely to be caused by co-existent NAFLD than by the treatment. Investigations are intended to identify patients with progressive liver disease, recognizing that cirrhosis can be clinically silent in the early stages. Concurrent clinical hepatomegaly, thrombocytopenia and splenomegaly all warrant further investigation to exclude cirrhosis. An ultrasound scan and a serological chronic liver disease screen remain the standard investigations. Liver biopsy still has an important role to play in diagnosis, but other non-invasive markers of liver fibrosis can differentiate mild fibrosis from cirrhosis. A new cause of acute hepatitis seen in the Western world is endemic hepatitis E and systemic IgG4 disease/autoimmune pancreatitis needs to be considered in the differential diagnosis of cholestatic biochemistry.
C
Systemic immunoglobulin G4 disease/autoimmune pancreatitis needs to be considered in differential diagnosis of cholestatic liver function tests The normal range for alanine aminotransferase (ALT) has been lowered as for example it has been shown that healthy hepatitis B carriers with a good prognosis usually have low normal ALT levels, i.e. <20 IU/litre Hepatitis E is endemic in the UK and is an important cause of acute viral hepatitis which mimics hepatitis A More widespread use/interest in non-invasive markers of liver fibrosis
should be just used to confirm that an elevated ALP level is of liver origin. Elevated GGT are not specific for alcohol misuse and also rise with simple fatty liver disease (non-alcoholic fatty liver (NAFL)). ALT/AST (aspartate aminotransferase): the upper limit of normal (ULN) for transaminases has been lowered over the last 5 years and some groups would consider 30 IU/litre to be the ULN for men and 19 IU/litre for women.3,4 For the purpose of this article the ULN is considered to be 40e45 IU/litre. Usually only ALT or AST is available but having both can be helpful in both alcoholic liver disease and cirrhosis where the AST/ALT ratio is more than 1.0. Both ALT and AST also rise with muscle injury, which is usually recognized because of an elevated serum creatine kinase.5 ALP: although there is some debate about the concentration of ALP requiring investigation, a threshold of 1.5 ULN is usually used.
Keywords alkaline phosphatase; hepatitis B; hepatitis C; liver function tests; non-alcoholic fatty liver disease
History and examination It is important when taking a history to remember that elevated LFTs may reflect underlying systemic disease rather than primary liver disease. An elevated ALP is commonly seen in active rheumatoid arthritis and also in the elderly with right heart failure due to hepatic congestion (Table 1). Elements of the history may also help to indicate specific liver diseases (Table 2). Pain does not occur in liver disease, so a history of episodes of right upper quadrant pain/epigastric pain in the presence of an elevated ALP is very suggestive of common bile duct stones that, if small, may pass spontaneously into the duodenum. The absence of stigmata of chronic liver disease does not exclude cirrhosis and clinical hepatomegaly is an indication for investigation whatever the degree of elevation of the LFTs.
Frequency Abnormal liver function tests (LFTs) are found in 8% of the general population.1 LFT abnormalities in asymptomatic individuals may be transient; if repeated within 3 weeks, 30% of elevated alanine aminotransferase (ALT) concentrations and 17% of elevated serum alkaline phosphatase (ALP) concentrations will have returned to normal.2 It is impractical to investigate everyone with elevated liver biochemistry and the aim of investigation is to identify cirrhosis, which in the early stages is usually asymptomatic, and liver disease that will progress if untreated.
Initial investigations
Definition
Repeat LFT The commonest causes of asymptomatic elevated LFTs are alcoholic or NAFLD and drugs. LFT should be repeated 4e6 weeks after abstinence from alcohol, weight reduction if body mass index is elevated and cessation of any recently started drugs, including herbal remedies and over-the-counter medication.
GGT (g glutamyltranspeptidase): an isolated raised GGT in the absence of a symptom does not require further investigations and
Jane Collier MD FRCP is a Consultant Hepatologist at John Radcliffe Hospital, Oxford, UK. Conflicts of interest: none declared.
MEDICINE 39:9
529
Ó 2011 Elsevier Ltd. All rights reserved.
INVESTIGATIONS
Systemic causes of abnormal LFTs
Investigation of elevated ALT levels (hepatitic LFTs)
Elevated ALP
ALT <100 IU/litre Ultrasound Chronic liver disease screen Hepatitis B sAg Hepatitis C Ab Ferritin þ transferrin saturation Liver autoantibodies (antinuclear factor, smooth muscle antibody) Immunoglobulins a-1 antitrypsin Endomyseal antibody Copper/caeruloplasmin (if age <40 years) ALT >100 IU/litre As above þ consider a liver biopsy if diagnosis not clear ALT >500 IU/litre Also consider acute viral hepatitis Hepatitis A IgM Monospot for EpsteineBarr virus infection Cytomegalovirus IgM Hepatitis E IgM
Elevated ALT/AST
Polymyalgia rheumatica Hyper/hypothyroidism Active rheumatoid arthritis Systemic vasculitis Right heart failure Liver infiltration, i.e. lymphoma, sarcoid (granuloma) Coeliac disease Thyroid disease
ALP, serum alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate transaminase; LFTs, liver function tests.
Table 1
Most hepatotoxic drug reactions occur within 1e2 months of starting a drug. There are some exceptions, such as tetracyclines given for acne, which can occur up to 2 years later and may induce an autoimmune liver disease.6 In hepatitic drug reactions LFT usually normalize over weeks in contrast to cholestatic reactions where this can take months. It is important to ensure that LFT return completely to normal after drug withdrawal to exclude underlying co-existent chronic liver disease.
Ab, antibody; ALT, alanine aminotransferase; Ig, immunoglobulin; LFTs, liver function tests; sAg, surface antigen.
Table 3
Further investigations Further investigation depends on whether the LFT pattern is cholestatic or hepatitic. Advanced liver disease is likely in the presence of a low platelet count or a prolonged prothrombin time, with or without a low serum albumin, and warrants investigation with an ultrasound scan and chronic liver disease screen, even in the presence of mild elevations in ALP or ALT.
Hepatitic LFT (see Table 3) An ultrasound scan will identify abnormal liver texture and signs of portal hypertension such as splenomegaly. The presence of fat is common and does not always indicate liver injury. Persistently minor elevation in ALT (<100 IU/litre) is common in chronic hepatitis C and B, haemochromatosis and NAFLD. Haemochromatosis should be excluded by measuring serum ferritin, which can be elevated as an acute phase protein, and transferrin saturation, which is usually over 55%.7 The diagnosis is confirmed by genetic testing for the HFE gene; liver biopsy is indicated only if serum ferritin is higher than 1000 IU/ml. NAFLD is the commonest cause of abnormal LFT in the presence of a negative chronic liver disease screen and it is important to differentiate simple fatty liver disease (steatosis or NAFL), which is non-progressive, from non-alcoholic steatohepatitis (NASH), which can progress to cirrhosis.8 NAFL is more likely if ALT is less than 2 ULN in the absence of diabetes, hypertension and elevated triglycerides, and a liver biopsy can be avoided. In alcoholic liver disease there is often an elevated ALP and ALT with ALT rarely over 250 IU/litre. A higher concentration suggests co-existent liver injury such as inadvertent paracetamol toxicity. An ALT higher than 1000 IU/litre suggests either autoimmune liver disease, acute viral hepatitis or drug injury. Hepatitis E is now recognized as a cause of endemic acute viral hepatitis.9 In autoimmune liver disease, serum IgG is often more than 30 g/litre and a liver biopsy is required to confirm the diagnosis.10
Hints from the history in investigating abnormal LFTs History
Abnormal LFT
Possible diagnosis
Inflammatory bowel disease Ethnicity/country of birth IVDU/unscreened blood transfusions Alcohol Metabolic syndromea (increased BMI diabetes/ hypertension) Recent new drugs Family history knee/MCP joint pain emphysema difficulty writing/concentration
ALP ALT/AST ALT/AST
PSC Hepatitis B/C Hepatitis C
ALT/mixed ALT
Alcoholic disease NAFLD
ALP or ALT Drug induced Haemochromatosis a 1 antitrypsin Wilson’s
ALP, serum alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate transaminase; BMI, body mass index; IVDU, intravenous drug use; LFTs, liver function tests; MCP, metacarpophalangeal; NAFLD, non-alcoholic fatty liver disease; PSC, primary sclerosing cholangitis. a 30% of NAFLD will have a raised ALP.
Cholestatic LFT If ALP is persistently 1.5 ULN then an ultrasound should be performed to differentiate extrahepatic from intrahepatic biliary disease and to exclude hepatic infiltration (i.e. liver metastases).
Table 2
MEDICINE 39:9
530
Ó 2011 Elsevier Ltd. All rights reserved.
INVESTIGATIONS
2 Lazo M, Selvin E, Clark JM. Brief communication: clinical implication of short-term variability in liver function test results. Ann Intern Med 2008; 148: 348e52. 3 Prati D, Taioli E, Zanella A. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med 2002; 137: 1e10. 4 Yuen N-F, Yuan H-J, Wong DK-H, et al. Prognostic determinants for chronic hepatitis B in Asians: therapeutic implications. Gut 2005; 54: 1610e4. 5 Nathwani RA, Pais S, Reynolds TB, Kaplowitz N. Serum alanine aminotransferase in skeletal muscle diseases. Hepatology 2005; 41: 380e2. 6 Bjornsson E, Talwalker J, Treeprasertsuk S, et al. Drug induced autoimmune hepatitis: clinical characteristics and prognosis. Hepatology 2010; 51: 2040e8. 7 European Association for the Study of the Liver. EASL Clinical Practice Guidelines for HFE haemochromatosis. J Hepatol 2010; 53: 3e22. 8 Angulo P, Hui J, Marchesini E, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 2007; 45: 846e54. 9 Purcell RH, Emerson SU. Hepatitis E: an emerging awareness of an old disease. J Hepatol 2008; 48: 494e503. 10 Hennes EM, Zeniya M, Czaja AJ, et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology 2008; 48: 169e76. 11 European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 2009; 51: 237e67. 12 Webster GM, Pereira SM, Chapman RWC. Autoimmune pancreatitis/IgG4 associated cholangitis and primary sclerosing cholangitis. Overlapping or separate diseases? J Hepatol 2009; 51: 398e402. 13 Rockey DC, Caldwell SH, Goodman ZD, Nelson RC, Smith AD. American association for the study of the liver. Liver biopsy. Hepatology 2009; 49: 1017e44. 14 Martinez SM, Crespo G, Navasa M, Forns X. Non-invasive assessment of liver fibrosis. Hepatology 2010; 53: 325e35.
Although bile duct stones are usually associated with pain they can occur without symptoms, particularly if the duct is very dilated. If no cause for bile duct dilatation is identified by ultrasound, magnetic resonance cholangiopancreatography (MRCP) should be performed. Endoscopic retrograde cholangiopancreatography (ERCP) is indicated in the presence of jaundice, as therapeutic intervention is likely to be needed. In the absence of extrahepatic biliary obstruction, antimitochondrial antibodies (AMA) should be checked to exclude primary biliary cirrhosis (PBC). These are positive in 90% of cases of PBC, who are usually female. In AMA-negative individuals an MRCP should be carried out to exclude intrahepatic biliary disease, such as primary sclerosing cholangitis (PSC), followed by a liver biopsy if the diagnosis remains unclear.11 Systemic immunoglobulin G4 (IgG4) disease is a recently recognized, steroid-responsive condition that can cause intrahepatic cholestasis and can occasionally mimic a hilar cholangiocarcinoma or inflammation of the pancreas (autoimmune pancreatitis) leading to a distal bile duct stricture12; its MRCP appearance is similar to that of sclerosing cholangitis. The diagnosis is confirmed by the presence of IgG4 plasma cells on histology and/or an elevated serum IgG4. Liver biopsy A liver biopsy is used to establish the cause of abnormal LFT and/or the degree of liver fibrosis. A liver biopsy should be undertaken to exclude cirrhosis in patients with clinical hepatomegaly, thrombocytopenia, splenomegaly on ultrasound or stigmata of chronic liver disease, whatever the degree of elevation of the LFTs. Identification of cirrhosis is important as it also leads to targeted screening for varices and hepatocellular carcinoma. Liver fibrosis is often patchy in biliary disease and a liver biopsy is not indicated where there is a clear diagnosis. Liver biopsy can usually be performed percutaneously with a bleeding risk of 0.1%. A transjugular liver biopsy is indicated in the presence of ascites, platelets fewer than 80 109/litre and a prothrombin time prolonged by more than 4 seconds.13
Practice points
Alternative non-invasive assessment of liver fibrosis In patients where serological markers have indicated a cause for abnormal LFT (i.e. hepatitis B and C), a liver biopsy is indicated only to establish the extent of fibrosis. Alternatives include Fibroscan and biomarkers of fibrosis, such as Fibrotest/Actitest and the European Liver Fibrosis (ELF) score.14 A Fibroscan delivers a pulse wave into the liver in order to quantify liver stiffness. Accurate readings are difficult to obtain in the presence of obesity, although different-sized probes have been developed in attempt to overcome this limitation. The current limitations of all these alternatives are that they clearly differentiate only between mild fibrosis and cirrhosis. A
C
C
C
C
C
C
REFERENCES 1 Clark JM, Brancati FL, Diehl AM. The prevalence and aetiology of elevated aminotransferase levels in the United States. Am J Gastroenterol 2003; 98: 960e7.
MEDICINE 39:9
531
An abnormal liver blood test may be caused by systemic disease Liver function tests (LFTs) should be repeated after a period of abstinence and weight reduction All new drugs are potentially hepatotoxic, but statins rarely are the cause of abnormal LFTs Non-alcoholic fatty liver disease (NAFLD) is a common cause of elevated alanine aminotransferase (ALT) in the presence of a negative chronic liver disease screen Simple non-progressive fatty liver disease (NAFL, simple steatosis) is more likely in the absence of diabetes with an ALT <2 upper limit of normal and ALT/aspartate transaminase (AST) ratio >1.0 Magnetic resonance cholangiopancreatography has replaced endoscopic retrograde cholangiopancreatography as the diagnostic test for identifying intrahepatic biliary disease (PSC) and cause of extrahepatic biliary obstruction
Ó 2011 Elsevier Ltd. All rights reserved.
How to investigate asymptomatic abnormal liver function tests
What’s new? C
C
Jane Collier
C
Abstract Asymptomatic abnormal liver function tests (LFTs) are common, affecting 8% of the population. The commonest causes are alcoholic and nonalcoholic fatty liver disease (NAFLD). They may be transient and should be repeated after weight reduction or cessation of alcohol or potentially hepatotoxic drugs. A careful history will help to exclude non-hepatic causes of abnormal liver blood tests as well as indicating a potential hepatic cause. Abnormal LFTs in patients taking statins are common and are more likely to be caused by co-existent NAFLD than by the treatment. Investigations are intended to identify patients with progressive liver disease, recognizing that cirrhosis can be clinically silent in the early stages. Concurrent clinical hepatomegaly, thrombocytopenia and splenomegaly all warrant further investigation to exclude cirrhosis. An ultrasound scan and a serological chronic liver disease screen remain the standard investigations. Liver biopsy still has an important role to play in diagnosis, but other non-invasive markers of liver fibrosis can differentiate mild fibrosis from cirrhosis. A new cause of acute hepatitis seen in the Western world is endemic hepatitis E and systemic IgG4 disease/autoimmune pancreatitis needs to be considered in the differential diagnosis of cholestatic biochemistry.
C
Systemic immunoglobulin G4 disease/autoimmune pancreatitis needs to be considered in differential diagnosis of cholestatic liver function tests The normal range for alanine aminotransferase (ALT) has been lowered as for example it has been shown that healthy hepatitis B carriers with a good prognosis usually have low normal ALT levels, i.e. <20 IU/litre Hepatitis E is endemic in the UK and is an important cause of acute viral hepatitis which mimics hepatitis A More widespread use/interest in non-invasive markers of liver fibrosis
should be just used to confirm that an elevated ALP level is of liver origin. Elevated GGT are not specific for alcohol misuse and also rise with simple fatty liver disease (non-alcoholic fatty liver (NAFL)). ALT/AST (aspartate aminotransferase): the upper limit of normal (ULN) for transaminases has been lowered over the last 5 years and some groups would consider 30 IU/litre to be the ULN for men and 19 IU/litre for women.3,4 For the purpose of this article the ULN is considered to be 40e45 IU/litre. Usually only ALT or AST is available but having both can be helpful in both alcoholic liver disease and cirrhosis where the AST/ALT ratio is more than 1.0. Both ALT and AST also rise with muscle injury, which is usually recognized because of an elevated serum creatine kinase.5 ALP: although there is some debate about the concentration of ALP requiring investigation, a threshold of 1.5 ULN is usually used.
Keywords alkaline phosphatase; hepatitis B; hepatitis C; liver function tests; non-alcoholic fatty liver disease
History and examination It is important when taking a history to remember that elevated LFTs may reflect underlying systemic disease rather than primary liver disease. An elevated ALP is commonly seen in active rheumatoid arthritis and also in the elderly with right heart failure due to hepatic congestion (Table 1). Elements of the history may also help to indicate specific liver diseases (Table 2). Pain does not occur in liver disease, so a history of episodes of right upper quadrant pain/epigastric pain in the presence of an elevated ALP is very suggestive of common bile duct stones that, if small, may pass spontaneously into the duodenum. The absence of stigmata of chronic liver disease does not exclude cirrhosis and clinical hepatomegaly is an indication for investigation whatever the degree of elevation of the LFTs.
Frequency Abnormal liver function tests (LFTs) are found in 8% of the general population.1 LFT abnormalities in asymptomatic individuals may be transient; if repeated within 3 weeks, 30% of elevated alanine aminotransferase (ALT) concentrations and 17% of elevated serum alkaline phosphatase (ALP) concentrations will have returned to normal.2 It is impractical to investigate everyone with elevated liver biochemistry and the aim of investigation is to identify cirrhosis, which in the early stages is usually asymptomatic, and liver disease that will progress if untreated.
Initial investigations
Definition
Repeat LFT The commonest causes of asymptomatic elevated LFTs are alcoholic or NAFLD and drugs. LFT should be repeated 4e6 weeks after abstinence from alcohol, weight reduction if body mass index is elevated and cessation of any recently started drugs, including herbal remedies and over-the-counter medication.
GGT (g glutamyltranspeptidase): an isolated raised GGT in the absence of a symptom does not require further investigations and
Jane Collier MD FRCP is a Consultant Hepatologist at John Radcliffe Hospital, Oxford, UK. Conflicts of interest: none declared.
MEDICINE 39:9
529
Ó 2011 Elsevier Ltd. All rights reserved.
INVESTIGATIONS
Systemic causes of abnormal LFTs
Investigation of elevated ALT levels (hepatitic LFTs)
Elevated ALP
ALT <100 IU/litre Ultrasound Chronic liver disease screen Hepatitis B sAg Hepatitis C Ab Ferritin þ transferrin saturation Liver autoantibodies (antinuclear factor, smooth muscle antibody) Immunoglobulins a-1 antitrypsin Endomyseal antibody Copper/caeruloplasmin (if age <40 years) ALT >100 IU/litre As above þ consider a liver biopsy if diagnosis not clear ALT >500 IU/litre Also consider acute viral hepatitis Hepatitis A IgM Monospot for EpsteineBarr virus infection Cytomegalovirus IgM Hepatitis E IgM
Elevated ALT/AST
Polymyalgia rheumatica Hyper/hypothyroidism Active rheumatoid arthritis Systemic vasculitis Right heart failure Liver infiltration, i.e. lymphoma, sarcoid (granuloma) Coeliac disease Thyroid disease
ALP, serum alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate transaminase; LFTs, liver function tests.
Table 1
Most hepatotoxic drug reactions occur within 1e2 months of starting a drug. There are some exceptions, such as tetracyclines given for acne, which can occur up to 2 years later and may induce an autoimmune liver disease.6 In hepatitic drug reactions LFT usually normalize over weeks in contrast to cholestatic reactions where this can take months. It is important to ensure that LFT return completely to normal after drug withdrawal to exclude underlying co-existent chronic liver disease.
Ab, antibody; ALT, alanine aminotransferase; Ig, immunoglobulin; LFTs, liver function tests; sAg, surface antigen.
Table 3
Further investigations Further investigation depends on whether the LFT pattern is cholestatic or hepatitic. Advanced liver disease is likely in the presence of a low platelet count or a prolonged prothrombin time, with or without a low serum albumin, and warrants investigation with an ultrasound scan and chronic liver disease screen, even in the presence of mild elevations in ALP or ALT.
Hepatitic LFT (see Table 3) An ultrasound scan will identify abnormal liver texture and signs of portal hypertension such as splenomegaly. The presence of fat is common and does not always indicate liver injury. Persistently minor elevation in ALT (<100 IU/litre) is common in chronic hepatitis C and B, haemochromatosis and NAFLD. Haemochromatosis should be excluded by measuring serum ferritin, which can be elevated as an acute phase protein, and transferrin saturation, which is usually over 55%.7 The diagnosis is confirmed by genetic testing for the HFE gene; liver biopsy is indicated only if serum ferritin is higher than 1000 IU/ml. NAFLD is the commonest cause of abnormal LFT in the presence of a negative chronic liver disease screen and it is important to differentiate simple fatty liver disease (steatosis or NAFL), which is non-progressive, from non-alcoholic steatohepatitis (NASH), which can progress to cirrhosis.8 NAFL is more likely if ALT is less than 2 ULN in the absence of diabetes, hypertension and elevated triglycerides, and a liver biopsy can be avoided. In alcoholic liver disease there is often an elevated ALP and ALT with ALT rarely over 250 IU/litre. A higher concentration suggests co-existent liver injury such as inadvertent paracetamol toxicity. An ALT higher than 1000 IU/litre suggests either autoimmune liver disease, acute viral hepatitis or drug injury. Hepatitis E is now recognized as a cause of endemic acute viral hepatitis.9 In autoimmune liver disease, serum IgG is often more than 30 g/litre and a liver biopsy is required to confirm the diagnosis.10
Hints from the history in investigating abnormal LFTs History
Abnormal LFT
Possible diagnosis
Inflammatory bowel disease Ethnicity/country of birth IVDU/unscreened blood transfusions Alcohol Metabolic syndromea (increased BMI diabetes/ hypertension) Recent new drugs Family history knee/MCP joint pain emphysema difficulty writing/concentration
ALP ALT/AST ALT/AST
PSC Hepatitis B/C Hepatitis C
ALT/mixed ALT
Alcoholic disease NAFLD
ALP or ALT Drug induced Haemochromatosis a 1 antitrypsin Wilson’s
ALP, serum alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate transaminase; BMI, body mass index; IVDU, intravenous drug use; LFTs, liver function tests; MCP, metacarpophalangeal; NAFLD, non-alcoholic fatty liver disease; PSC, primary sclerosing cholangitis. a 30% of NAFLD will have a raised ALP.
Cholestatic LFT If ALP is persistently 1.5 ULN then an ultrasound should be performed to differentiate extrahepatic from intrahepatic biliary disease and to exclude hepatic infiltration (i.e. liver metastases).
Table 2
MEDICINE 39:9
530
Ó 2011 Elsevier Ltd. All rights reserved.
INVESTIGATIONS
2 Lazo M, Selvin E, Clark JM. Brief communication: clinical implication of short-term variability in liver function test results. Ann Intern Med 2008; 148: 348e52. 3 Prati D, Taioli E, Zanella A. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med 2002; 137: 1e10. 4 Yuen N-F, Yuan H-J, Wong DK-H, et al. Prognostic determinants for chronic hepatitis B in Asians: therapeutic implications. Gut 2005; 54: 1610e4. 5 Nathwani RA, Pais S, Reynolds TB, Kaplowitz N. Serum alanine aminotransferase in skeletal muscle diseases. Hepatology 2005; 41: 380e2. 6 Bjornsson E, Talwalker J, Treeprasertsuk S, et al. Drug induced autoimmune hepatitis: clinical characteristics and prognosis. Hepatology 2010; 51: 2040e8. 7 European Association for the Study of the Liver. EASL Clinical Practice Guidelines for HFE haemochromatosis. J Hepatol 2010; 53: 3e22. 8 Angulo P, Hui J, Marchesini E, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 2007; 45: 846e54. 9 Purcell RH, Emerson SU. Hepatitis E: an emerging awareness of an old disease. J Hepatol 2008; 48: 494e503. 10 Hennes EM, Zeniya M, Czaja AJ, et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology 2008; 48: 169e76. 11 European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 2009; 51: 237e67. 12 Webster GM, Pereira SM, Chapman RWC. Autoimmune pancreatitis/IgG4 associated cholangitis and primary sclerosing cholangitis. Overlapping or separate diseases? J Hepatol 2009; 51: 398e402. 13 Rockey DC, Caldwell SH, Goodman ZD, Nelson RC, Smith AD. American association for the study of the liver. Liver biopsy. Hepatology 2009; 49: 1017e44. 14 Martinez SM, Crespo G, Navasa M, Forns X. Non-invasive assessment of liver fibrosis. Hepatology 2010; 53: 325e35.
Although bile duct stones are usually associated with pain they can occur without symptoms, particularly if the duct is very dilated. If no cause for bile duct dilatation is identified by ultrasound, magnetic resonance cholangiopancreatography (MRCP) should be performed. Endoscopic retrograde cholangiopancreatography (ERCP) is indicated in the presence of jaundice, as therapeutic intervention is likely to be needed. In the absence of extrahepatic biliary obstruction, antimitochondrial antibodies (AMA) should be checked to exclude primary biliary cirrhosis (PBC). These are positive in 90% of cases of PBC, who are usually female. In AMA-negative individuals an MRCP should be carried out to exclude intrahepatic biliary disease, such as primary sclerosing cholangitis (PSC), followed by a liver biopsy if the diagnosis remains unclear.11 Systemic immunoglobulin G4 (IgG4) disease is a recently recognized, steroid-responsive condition that can cause intrahepatic cholestasis and can occasionally mimic a hilar cholangiocarcinoma or inflammation of the pancreas (autoimmune pancreatitis) leading to a distal bile duct stricture12; its MRCP appearance is similar to that of sclerosing cholangitis. The diagnosis is confirmed by the presence of IgG4 plasma cells on histology and/or an elevated serum IgG4. Liver biopsy A liver biopsy is used to establish the cause of abnormal LFT and/or the degree of liver fibrosis. A liver biopsy should be undertaken to exclude cirrhosis in patients with clinical hepatomegaly, thrombocytopenia, splenomegaly on ultrasound or stigmata of chronic liver disease, whatever the degree of elevation of the LFTs. Identification of cirrhosis is important as it also leads to targeted screening for varices and hepatocellular carcinoma. Liver fibrosis is often patchy in biliary disease and a liver biopsy is not indicated where there is a clear diagnosis. Liver biopsy can usually be performed percutaneously with a bleeding risk of 0.1%. A transjugular liver biopsy is indicated in the presence of ascites, platelets fewer than 80 109/litre and a prothrombin time prolonged by more than 4 seconds.13
Practice points
Alternative non-invasive assessment of liver fibrosis In patients where serological markers have indicated a cause for abnormal LFT (i.e. hepatitis B and C), a liver biopsy is indicated only to establish the extent of fibrosis. Alternatives include Fibroscan and biomarkers of fibrosis, such as Fibrotest/Actitest and the European Liver Fibrosis (ELF) score.14 A Fibroscan delivers a pulse wave into the liver in order to quantify liver stiffness. Accurate readings are difficult to obtain in the presence of obesity, although different-sized probes have been developed in attempt to overcome this limitation. The current limitations of all these alternatives are that they clearly differentiate only between mild fibrosis and cirrhosis. A
C
C
C
C
C
C
REFERENCES 1 Clark JM, Brancati FL, Diehl AM. The prevalence and aetiology of elevated aminotransferase levels in the United States. Am J Gastroenterol 2003; 98: 960e7.
MEDICINE 39:9
531
An abnormal liver blood test may be caused by systemic disease Liver function tests (LFTs) should be repeated after a period of abstinence and weight reduction All new drugs are potentially hepatotoxic, but statins rarely are the cause of abnormal LFTs Non-alcoholic fatty liver disease (NAFLD) is a common cause of elevated alanine aminotransferase (ALT) in the presence of a negative chronic liver disease screen Simple non-progressive fatty liver disease (NAFL, simple steatosis) is more likely in the absence of diabetes with an ALT <2 upper limit of normal and ALT/aspartate transaminase (AST) ratio >1.0 Magnetic resonance cholangiopancreatography has replaced endoscopic retrograde cholangiopancreatography as the diagnostic test for identifying intrahepatic biliary disease (PSC) and cause of extrahepatic biliary obstruction
Ó 2011 Elsevier Ltd. All rights reserved.