Table 1: Pathology of liver abnormalities 50 (may be normal, or very high with complete biliary obstruction

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1 How to Treat PULL-OUT SECTION Complete How to Treat quizzes online /cpd to earn CPD or PDP points. INSIDE Non-hepatic causes Underestimated severity of liver disease Rare diagnoses Drug-induced liver damage Non-alcoholic fatty liver disease Minor abnormalities of LFTs Introduction the authors Professor Geoffrey C Farrell professor of hepatic medicine, Australian National University Medical School, and director, gastroenterology and hepatology unit, Canberra Hospital, Garran, ACT. ABNORMAL liver tests can be very useful when the pattern of changes corresponds to clinical suspicion about diagnoses, such as viral hepatitis or biliary obstruction. In recent community surveys, 3-10% of apparently healthy individuals have LFT abnormalities, particularly GGT and ALT elevation. These are nearly always relatively minor (that is, less than a threefold increase above the normal range) and not specific to the diagnostic patterns of the major conditions shown in table 1. There are several issues raised by these seemingly trivial LFT abnormalities. For example, the patient may not have liver disease and the apparent liver function abnormalities are caused by the involvement of another tissue and/or another disease, or they may suggest alcoholism. In addition, LFT abnormalities in an asymptomatic person can be confusing when hepatic imaging shows one or more lesions that, in the absence of LFT abnormalities, would usually suggest a benign condition, such as a haemangioma, simple cyst or focal nodular hyperplasia (FNH). Conversely, the unspectacular nature of the LFT abnormalities may underestimate the severity of important liver disease, particularly cirrhosis, and the presence Pattern (normal range) Serum bilirubin (< 20 μmol/l) Hyperbiliru binaemia and extent of LFT abnormalities is a poor guide to the treatment indications for hepatitis B and hepatitis C. On the other hand, minor LFT abnormalities may be the first clue to a less common but important form of liver disease that is yet to develop clinical manifestations. Table 1: Pathology of liver abnormalities Hepatitis (hepatocellular injury) (may be normal or very high, with jaundice) Cholestasis Cirrhosis Infiltration Minor, nonspecific 50 (may be normal, or very high with complete biliary obstruction 25 (often normal, high with decompensation) Most commonly, however, these minor non-specific test abnormalities reflect non-alcoholic fatty liver disease (NAFLD), the most prevalent form of liver disease in Australian adults and children. People with this common condition deserve optimal management in the community ALP (< U/L) ALT (<40 U/L) AST (<40 U/L) GGT (<35 U/L) Albumin (35-53 g/l) Comments and examples Gilbert s syndrome, haemolytic anaemia (order FBC) Acute hepatitis (A, B, C, E), drug-induced liver injury (isoniazid), chronic hepatitis (autoimmune albumin may be low) Biliary obstruction (order ultrasound), drug-induced liver injury, primary biliary cirrhosis etc Note AST higher than ALT also found in alcoholic hepatitis; globulins often increased; low platelets Metastatic malignancy, hepatocellular carcinoma (order CT scan), sarcoidosis (examine for lymph nodes; thoracic CT) Fatty liver, cirrhosis, chronic hepatitis, infiltration, drug effects setting because a fatty liver is the forerunner of diabetes, cardiovascular outcomes, common cancers, cirrhosis and liver cancer. This article discusses the issues raised by minor, non-specific liver test abnormalities and their management. cont d next page Dr Shivakumar Chitturi senior staff specialist, gastroenterology and hepatology unit, Canberra Hospital, Garran, ACT. Professor Narci Teoh professor of medicine, Australian National University Medical School, and senior staff specialist, gastroenterology and hepatology unit, Canberra Hospital, Garran, ACT. Copyright 2013 Australian Doctor All rights reserved. No part of this publication may be reproduced, distributed, or transmitted in any form or by any means without the prior written permission of the publisher. For permission requests, howtotreat@cirrusmedia.com.au 11 October 2013 Australian Doctor 25

2 Non-hepatic causes ABNORMALITIES of one or more of the clinical chemistry tests conventionally misnamed as LFTs might not be the result of liver disease. Some of the non-hepatic causes of minor LFT abnormalities are listed in table 2. Table 2: LFT abnormalities caused by conditions other than hepatobiliary disorders Abnormality Examples Comments Raised serum bilirubin; all else normal Raised ALP; normal GGT, ALT, serum bilirubin and albumin Haemolytic anaemia, massive haematoma Check for bilirubinuria, splenomegaly, FBC, blood film, reticulocyte count Consider the full clinical picture examine bones, breasts, prostate etc; rare manifestation of cirrhosis, hepatic malignancy Revisit the history and talk to significant others; exclude macrocytosis and ; establish any relationship with medication use Cause usually obvious (urinalysis, history); may be more perplexing with raised globulins exclude myeloma, lymphoma, haematological malignancy Figure 1: Raised liver enzymes can occur in patients with extrahepatic disorders, such as thyrotoxicosis in this man with proptosis. Hyperbilirubinaemia Hyperbilirubinaemia in which there is a minor increase in serum unconjugated bilirubin and no bilirubinuria on a dipstick, and where other LFTs are normal may point to Gilbert s syndrome or haemolysis. Gilbert s syndrome is common (occurring in at least 3% of the population), and so are NAFLD and hepatitis C. About one in 30 patients with NAFLD or hepatitis C also have Gilbert s syndrome. In such cases, GGT and ALT may be raised in addition to the hyperbilirubinaemia. This is potentially confusing because even minor elevation of serum bilirubin in the context of any chronic liver disease often indicates cirrhosis (table 3). Hence, patients with a raised bilirubin, GGT and ALT should be carefully assessed and considered for referral to a gastroenterologist or hepatologist. There is a genetic test for Gilbert s syndrome based on a polymorphism of the promoter sequence for bilirubin UDP-glucuronosyltransferase 1A1. While not widely available, it can be performed in some molecular diagnostic laboratories and is useful in confusing situations. Serum alkaline phosphatase Serum alkaline phosphatase (abbreviated as ALP or SAP) is often raised without other biochemical abnormalities. This can rarely occur with liver or biliary tract disorders, for example with a stone in the common bile duct or hepatic malignancy, but more commonly it has a non-hepatic aetiology. Bone disease, such as Paget s disease, a fracture (including fragility fractures) or metastatic malignancy is most often the cause of a raised ALP. This is usually simple to confirm by the history, physical examination, radiology or a bone scan. It is possible to estimate the heat-stable isoform of ALP, which indicates origin from liver rather than bone, although this investigation is not widely Strikingly increased GGT, other tests normal or (eg, AST) minimally altered Low serum albumin, other tests normal Raised AST, ALT normal Minor, nonspecific (raised ALT, GGT, ALP various combinations) Bone disease, eg, Paget s, fractures, metastases; also found in cardiac failure (bilirubin may be raised) Alcoholism, other medications especially anticonvulsants Nephrotic syndrome; inflammatory bowel disease; proteinlosing enteropathy; malnutrition such as from eating disorder; burns Myositis, rhabdomyolysis Extrahepatic malignancy (renal); chronic infections or other inflammatory conditions Perform muscle enzyme tests; may be more confusing if ALP also elevated possible hepatic involvement with polymyalgia rheumatica, vasculitis (check CRP, etc) Need to distinguish from much more common NAFLD (with hepatic ultrasound), and from cirrhosis; consider referral to physician Table 3: Clues to cirrhosis in patients without liver failure Clue Findings that suggest cirrhosis Comments Physical examination Hard liver edge Spider naevi Highly specific (exclude malignancy) Spider naevi are the most sensitive and specific sign for cirrhosis Platelet count Thrombocytopenia Usually low in cirrhosis; progressive decline in patients with hepatitis C or NAFLD indicates advancing hepatic fibrosis; note alcohol may suppress platelets (reversible) Alphafetoprotein (AFP) Serum bilirubin AST and ALT Serum albumin Serum total globulin Often high with cirrhosis Any increase AST: ALT ratio >0.80 Borderline low Raised Very useful in general practice. Any new increase in AFP, or elevated absolute values >10-fold should arouse suspicion for hepatocellular carcinoma (order liver ultrasound) A diagnostic and prognostic marker for cirrhosis Low sensitivity but reasonable specificity for cirrhosis, but also occurs with alcohol (with or without cirrhosis) In cirrhosis, progressive decline of serum albumin over months or years often precedes presentation with ascites Common with cirrhosis but lacks both sensitivity and specificity available and may be expensive for the patient. A simpler approach is to exclude a concomitant increase in GGT that together would suggest liver disease. A practice point worth remembering is that in a hospital setting and in patients with other major medical illnesses, increases in ALP are often associated with cardiac failure or with systemic inflammation, not liver disease. Gamma-glutamyl transpeptidase GGT arises uniquely from liver, but increases occur in response to chronic excessive alcohol intake and to treatment with microsomal enzyme-inducing agents such as anticonvulsants. This phenomenon reflects increased synthesis and release of GGT and is often termed enzyme induction. In some instances, there may also be minor increases in serum ALT (or AST with alcohol) and/or ALP, thereby posing a greater challenge for discerning the difference between a drug effect vs drug-induced or other form of liver and hepatobiliary disease. In some community surveys, minor elevation of GGT alone is a risk factor for subsequent onset of type 2 diabetes. A family history of diabetes should be sought and the patient assessed for overweight and central obesity. Serum aspartate transaminase AST arises from muscle, lung, brain and other tissues as well as liver, whereas ALT is liver-specific. If the clinical chemistry laboratory routinely performs AST in its LFT panel (most do not), an isolated AST increase should alert the clinician to possible muscle disease. Other muscle-related enzymes such as creatine kinase should then be estimated. Serum albumin Serum albumin concentration is determined by the rate of albumin synthesis in the liver, but also by its distribution, haemodilution (eg, explaining the fall during the second trimester of pregnancy) and rate of degradation or loss of the protein. Low values can therefore reflect impaired hepatic synthetic function in cirrhosis, but are also found in nephrotic syndrome, protein-losing enteropathy, inflammatory bowel disease, under-nutrition and tissue cachexia associated with conditions such as starvation and eating disorders, burns, coeliac disease, Crohn s disease, myeloma and other malignancy. Thus, the significance of low serum albumin depends on the clinical context of these disorders (they are usually but not always obvious), as well as clinical or other laboratory evidence of chronic liver disease (table 3). LFTs in systemic disease As intimated for ALP, LFT abnormalities can occur in several extrahepatic diseases that may or may not be associated with significant liver pathology. Important ones include thyrotoxicosis (figure 1), coeliac disease, extrahepatic malignancy (particularly renal), vasculitis and other systemic inflammatory disorders. Consideration therefore needs to be given to a full history, screening of thyroid function, CRP, testing for urinary infection and haematuria, and hepatic imaging by CT scan. Referral to a hepatologist is particularly indicated if this is clearly a new condition and/or the patient appears to be unwell. Underestimated severity of liver disease MINOR LFT abnormalities can underestimate the severity of liver disease or the need for treatment, particularly cirrhosis, chronic hepatitis B and hepatitis C or haemochromatosis. Cirrhosis It is very important to make the diagnosis of cirrhosis when patients are well. This is because the significant complications of bleeding oesophageal varices, hepatic decompensation (ascites, muscle wasting, hepatic encephalopathy), hepatocellular carcinoma (HCC) and metabolic bone disease can all be ameliorated (prevented, delayed or better outcomes ensured) with early diagnosis and key interventions. A contemporary key issue in liver disease is for doctors to improve their skills in making an early diagnosis of cirrhosis. LFTs may be normal in patients with cirrhosis of any cause, including alcoholic liver disease if the patient has stopped drinking. However, minor LFT abnormalities are common, and some changes suggest cirrhosis as outlined in table 3. Often cardinal signs of cirrhosis are readily apparent on careful physical examination; the two most important and reliable findings that indicate high probability of cirrhosis are a hard liver edge (figure 2A) and spider naevi (figure 2B). Investigations Even more commonly, the platelet count is low because its regulatory peptide, thrombopoietin, is synthesised in the liver (platelet destruction by splenomegaly may also occur). Serial platelet count is a very useful indicator of the fibrotic progression of chronic liver disorders, particularly with chronic hepatitis C and B infections the platelet count is the hepatologist s most reliable liver function test. A slightly raised alpha-fetoprotein (AFP) level is another common finding with cirrhosis. However, possibly because of reimbursement issues, AFP is under-utilised as a cirrhosis screen in general practice. In more advanced cirrhosis, impaired synthesis of clotting factors can result in prolonged prothrombin time or INR. Imaging Contemporary high-quality imaging may also provide diagnostic information in cirrhosis, such as a dilated portal vein, splenomegaly, varices and thickening of the gall bladder wall (which often portends the development of ascites). In advanced cases, nodularity or unevenness of the surface of the liver may be evident on ultrasonography (ask for a surface view) or CT scan. The liver ultrasound may also show increased echogenicity; this is often confused with the similar change in fatty 26 Australian Doctor 11 October 2013

3 liver disease, but the latter also causes posterior attenuation of the ultrasound shadow and blurring of hepatic vessels (figure 3). When doctors suspect cirrhosis, referral to a hepatologist or liver clinic is recommended so that more detailed clinical assessment and investigations can be expedited. The latter include transient elastography (figure 4), a convenient, non-invasive test of liver stiffness that has high diagnostic accuracy for detecting advanced hepatic fibrosis or for excluding significant fibrosis. Chronic hepatitis C virus infection A normal ALT and/or variable elevations of ALT and GGT often occur in chronic hepatitis C virus (HCV)-infected individuals. Finding out the duration of infection (>20 years) and the pattern of LFTs during the past decade is important. Increased ALT levels may reflect active HCV infection but are also found with fatty liver, which may occur concomitantly in over 60% of patients with hepatitis C and/or with alcohol misuse. In turn, some elevation of ALT increases the risk of developing cirrhosis and its complications of liver failure and hepatocellular carcinoma. Conversely, some patients with severe forms of chronic hepatitis C, including cirrhosis, have completely normal LFTs, and the absolute values of ALT (which often fluctuate) are a poor guide to the severity of liver disease. AST:ALT ratio Regardless of aetiology, a clue to cirrhosis is a reversal in the ratio of serum AST:ALT. Normally the AST:ALT ratio should be less than 0.8. Most laboratories perform serum ALT when LFTs are ordered as this is the most sensitive and specific test for hepatocyte injury. However, it is also useful to ask for AST when one suspects cirrhosis or alcohol abuse. An AST:ALT ratio greater than 0.8 has a high specificity, albeit relatively poor sensitivity, for cirrhosis. These changes can occur with HCV infection, in which case cirrhosis is likely, but they can also be features of concomitant alcoholic liver disease. Investigations Complementary investigations in the workup and ongoing review of someone with chronic HCV include an FBC, with particular attention to platelets, serum albumin, prothrombin time or INR, HCV RNA PCR and HCV genotyping. If the patient is known or suspected to have cirrhosis, the plan should also include sixmonthly hepatic imaging (ultrasound or CT) and AFP and to screen for treatable hepatocellular carcinoma. Irrespective of investigations, a thorough physical examination and reliable alcohol history are warranted. A hard liver edge, spider naevi, splenomegaly and other signs of portal hypertension, ascites, muscle wasting, and subclinical hepatic encephalopathy are cardinal clinical features of cirrhosis. Together with the need to discuss possible treatment of HCV (which is about to undergo a Figure 3: Key features of fatty liver disease on hepatic ultrasound. Compared with the renal cortex or spleen, increased echogenicity is evident. Image also shows posterior attenuation of the ultrasound shadow and blurring of hepatic vessels. Increased echogenicity alone is non-specific and can occur with cirrhosis. Regardless of aetiology, a clue to cirrhosis is a reversal in the ratio of serum AST:ALT. A major change with potent new agents), concern about the severity of HCV-related liver disease is an indication for referral to a hepatologist. Chronic hepatitis B virus infection Despite possessing a normal physical examination and normal ALT level, people who have chronic hepatitis B virus (HBV) infection (often referred to as carriers) should not be presumed to be, nor told that they are, healthy. For instance, an ALT of 38 IU/L (normal <40), is no longer regarded as normal by hepatologists. More appropriate healthy (true normal) values are <20 IU/L for lean women and <30 for lean men. B Figure 2: A: The correct technique for examining the liver; a hard protuberant liver (and spleen in left upper quadrant) is evident in a man with Wilson s disease who is known to have cirrhosis. B: Spider naevi. Figure 4: Transient elastography unit used for testing liver stiffness in order to identify advanced liver fibrosis and cirrhosis. The value shown (11.4 kpa) indicates highly likely cirrhosis in a patient with non-alcoholic fatty liver disease. Thus ALT (and AST) values in persons who are HBsAg positive require close scrutiny and reflection: several surveys have noted that values between one- and twofold increased above the upper limit of the stated normal range are actually more likely to be associated with established cirrhosis than are higher elevations. Cirrhosis/hepatocellular carcinoma People with chronic HBV infection, particularly after the age of 30, have a substantial risk of developing fibrosis, cirrhosis and/or hepatocellular carcinoma, particularly if HBV infection was acquired early in life (eg, via maternal transmission). The most important predictor of subsequent cirrhosis or hepatocellular carcinoma is a high level of HBV replication, determined by serum HBV DNA level (one test is reimbursable). If a liver test abnormality, no matter how minor, is due to chronic hepatitis B (with or without cirrhosis) and the individual s HBV DNA is >10,000 IU/mL, referral to a hepatologist is strongly recommended. In this situation, antiviral therapy may be indicated. Agents such as tenofovir and entecavir are highly effective, with minimal adverse effects or drug drug interactions. Fatty liver People with chronic HBV infection often also have NAFLD, and this is at least as common as chronic hepatitis as the cause for minor LFT abnormalities. Metabolic risk factors should be assessed, including weight gain, physical activity, waist circumference, BMI, and investigations for conditions associated with the metabolic syndrome (eg, diabetes, dyslipidaemia). Where raised ALT and GGT is suspected to be due to fatty liver rather than hepatitis B, HBV DNA levels and ultrasound may help elucidate the diagnosis. Indeterminate levels of HBV DNA (ie, ,000 IU/mL) and complex cases should be referred to a hepatologist. Annual reviews are recommended since values may fluctuate, which is associated with a higher risk of poor outcomes. Risk when immunosuppressed People who have chronic HBV infection without LFT abnormalities should also be advised to alert all their healthcare professionals of this infection to avoid the bombshell of a potentially fatal hepatitis B flare in someone who appeared not to have active disease. This is especially important if they are about to undergo immunosuppressive therapies, such as chemotherapy for solid or haematological malignancies, anti-tnf agents, or high-dose prednisone. Under such circumstances, the risk of HBV reactivation is very high, and this can lead to death from fulminant hepatic failure. All patients who are HBsAg positive should be referred to a hepatologist or specialist experienced in the management of chronic HBV infection prior to commencement of profound immunosuppressive therapy so that antiviral prophylaxis (lamivudine or entecavir) can be instituted. During and after chemotherapy, monthly monitoring of liver tests and three-monthly HBV DNA should be undertaken. Haemochromatosis LFTs are typically normal in haemochromatosis, even with cirrhosis. However, minor increases in ALT, AST and GGT may be important clues to concomitant alcohol dependence or obesity and diabetes-related steatosis, both of which increase the risk of cirrhosis in patients with haemochromatosis. Thus, LFT abnormalities in patients with iron storage disease are indications for assessment of alcohol intake, obesity and glucose tolerance, and referral to a hepatologist where appropriate. cont d next page 11 October 2013 Australian Doctor 27

4 Rare diagnoses LFT abnormalities may be a clue to rare but treatable liver disorders. The rare disorders are uncommon even in a hepatologist s practice and they include: primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis and rarer forms of autoimmune hepatobiliary disease, alpha-1 anti-trypsin deficiency, Wilson s disease and inherited metabolic and canalicular transporter deficiencies. Figure 5 shows a patient with primary biliary cirrhosis. Note, however, that not all patients with primary biliary cirrhosis look like this. The diagnosis should be suspected in a patient with unexplained LFT abnormalities (particularly but not exclusively ALP and GGT) and confirmed by a positive anti-mitochondrial antibody test. Because these conditions are uncommon, other doctors will rarely encounter them. On the other hand, since most of them are now very treatable there is an onus not to miss these liver diseases. This poses a challenge to diagnose them when minor abnormalities of LFTs are the only features at presentation. Clinical clues can include the family history, subtle features of cirrhosis, unexplained symptoms (fatigue, itch, cryptogenic neurological symptoms), the presence of other autoimmune disorders (personal and family history) and exclusion of the usual explanations for the LFT changes (alcohol, hepatitis C, NAFLD) and other more common causes (table 4). A standard battery of tests (known as a liver panel ) may also be useful for unexplained liver test abnormalities (table 5). Table 4: Uncommon liver diseases: what to look for, what to order, when to refer Disorder Clues to the diagnosis Specific diagnostic tests and comments Coeliac disease Abnormal LFTs in lean patient; coeliac disease may or may not be diagnosed previously Anti-TTG; consider referral to a gastroenterologist Primary biliary cirrhosis (PBC) Primary sclerosing cholangitis (PSC) Autoimmune hepatitis (AIH, formerly chronic active hepatitis ) Wilson s disease Alpha1-antitrypsin deficiency Canalicular transporter deficiency (progressive familial intrahepatic cholestasis) Middle-aged to older women of northern European ancestry; itch; fatigue; concomitant autoimmune thyroid disease or family history of same; LFTs more likely to reflect cholestasis (see table 1), but may not; xanthelasma and lipid disorders Men > women; 70% cases associated with inflammatory bowel disease; LFTs more likely to reflect cholestasis Young, middle-aged or older women > men; ALT >300 IU/L; personal or family history of other autoimmune disease; often but not always have fatigue and other symptoms of hepatitis; hard liver edge if have cirrhosis; spider naevi Family history (autosomal recessive); acute or subacute hepatitis in person <30 years of age or cirrhosis in young-middle age with neurological disorder and Kayser Fleischer corneal rings With or without emphysema; family history; any age present with cholestasis in children, with cirrhosis in adults Rare autosomal recessive disorders (several types based on which transport protein is defective); may or may not have had childhood liver disease or features of cholestasis Anti-mitochondrial antibody (AMA; use a laboratory that gives specificity it should be anti-m2) Magnetic resonance cholangiopancreatography changes: beading, structuring, proximal dilatation; p-anca positive; must be referred to gastroenterologist owing to high risk of colorectal cancer and cholangiocarcinoma ANA >1:80; smooth muscle antibody (SMA) >1:40; liver-kidney microsomal antibody (LKM) rare type 2 AIH; high IgG; a dangerous disorder, can occasionally be hard to diagnose: referral is strongly indicated Urgent referral for acute or subacute cases when suggestive clinical picture; low serum ceruloplasmin (false negative 10% cases); high serum or urinary copper (many false positives); elective referral for well patients Low serum alpha1-antitrypsin level; Pi genotyping A cause of unexplained cirrhosis in young adults or older children and adolescents refer all such cases for specialist assessment, even if LFT abnormalities are minor Figure 5: Patient with primary biliary cirrhosis. Confirmation with a positive antimitochondrial antibody test is necessary. Table 5: A useful liver panel for general practice* Test What to do if positive, and when to refer Anti-HCV HCV RNA (PCR) genotype if detectable; AFP; liver ultrasound. Refer for full assessment if patient desires this, if duration of HCV infection >15 years, age >50 HBsAg HBV DNA, AFP, liver ultrasound if age >30 years. Refer for full assessment if patient desires this, if age >30 and HBV DNA >10,000 IU/L (any one value); important to indicate that treatment of HBV is highly effective at suppressing viral replication >5 logs and this normalises ALT, and prevents disease progression, greatly diminishing risk of hepatocellular carcinoma particularly before cirrhosis develops Fasting BSL; HbA 1c ; lipids Overweight patient with central obesity and family history of diabetes or fatty liver: suspect NAFLD and perform ultrasound. Refer for full assessment if patient desires, if age >50, diabetes and NAFLD, high serum ferritin, fatty liver for >10 years, BMI >30 kg/m 2 ANA, SMA, LKM; immunoglobulins (IgG level) Anti-mitochondrial antibody (M2 specificity) FBC Serum alpha1-antitrypsin Serum ceruloplasmin Coeliac serology Check titres significant (see table 4) but otherwise refer for full assessment of possible autoimmune hepatitis, particularly if patient unwell. Refer for treatment of primary biliary cirrhosis *Refer all patients with clinical findings suggestive of cirrhosis Macrocytosis may occur with otherwise undisclosed alcohol dependence (but also in cirrhosis), similarly for thrombocytopenia; likewise recheck values for AST and GGT and consider discussion of alcohol history with relative/partner of patient Refer if low and suspect alpha1-antitrypsin deficiency Refer if low and suspect Wilson s disease; values may be low in cirrhosis Often neglected in lean patient with abnormal LFTs: refer to gastroenterologist Drug-induced liver injury OVER 600 drugs have been associated with drug-induced liver injury. The leading causes include paracetamol, antimicrobials (eg, flucloxacillin, amoxycillin-clavulanic acid, cephalosporins, ketoconazole, terbinafine), NSAIDs (diclofenac), anticonvulsants (phenytoin, carbamazepine, sodium valproate), anti-tuberculosis agents (eg, isoniazid, pyrazinamide, rifampicin), platelet inhibitors (clopidogrel) and heparins. Minor elevations of serum ALT/ AST, usually less than three times the upper limit of normal, are noted in up to 3% of patients in clinical trials. Values usually settle without specific intervention and are not associated with signs or symptoms of liver injury. This pattern of liver tests is seen with many drugs (eg, all heparins, isoniazid) and is not the forerunner of acute liver injury. Conversely, a simultaneous increase of serum bilirubin (particularly with jaundice) can be associated with serious liver injury and death in up to 10%. This combination of results is used during drug development to flag agents with potential for serious liver toxicity. Any disturbance of liver synthetic function (albumin, platelet count, prothrombin time/inr) also necessitates immediate discontinuation of the suspect drug. Symptoms vs LFT abnormalities Another key point is that non-specific symptoms (nausea, malaise, facial swelling) may precede liverrelated features of serious druginduced liver injury. It follows that any new symptoms developing after commencement of a new drug (or dose alteration) should be evaluated carefully. Timely discontinuation of the drug is important; the single most reproducible characteristic of fatal cases of drug-induced liver injury is continued ingestion of the drug after liver injury has occurred. Patient education and supervision by prescribing doctors is critical. Identifying the culprit drug The newly added drug is the most likely offending agent. However, changes in drug dose, inter-current illness or co-prescription of other drugs can precipitate drug-induced liver injury in patients on previously well-tolerated drugs, and the track record of known forms of drug-induced liver injury (eg, amoxycillin/clavulanic acid) needs to be taken into account. cont d page Australian Doctor 11 October 2013

5 from page 28 Temporal relationships Response to stopping the suspect drug can be useful in making a diagnosis. Normalisation of ALT may be expected within three months in hepatocellular reactions, but improvements in LFTs can take several months with cholestatic reactions (eg, flucloxacillin or oral contraceptive-associated cholestasis). Abnormalities in liver tests may occur for the first time several weeks after stopping oxy-penicillins. A detailed drug history including overthe-counter medication and complementary and alternative medicines is therefore essential for someone with unexplained LFTs. For certain drugs, use for more than six months does not always guarantee safety. Examples include nitrofurantoin, which can cause chronic hepatitis, and minocycline, which has been linked to drug-induced autoimmune hepatitis. LFT pattern While LFT profile patterns (table 1) can be helpful in seeking culprit drugs in the setting of polypharmacy, signature patterns (eg, flucloxacillin and cholestasis, isoniazid and hepatitis) may not always be present in so-called mixed reactions, and more than one pattern can occur with a single drug. Specific drugs Paracetamol Paracetamol is the safest simple analgesic for patients with cirrhosis. However, in cases where liver injury develops with therapeutic doses of paracetamol, drug levels may be misleading and can delay commencement of treatment. This is most likely after several days of relatively high dosing when fasting (eg, in sick children), or with excessive alcohol intake, or in patients who have multiple serious illnesses. Very high ALT levels (>50 times upper limit of normal) should always prompt consideration of paracetamol-related liver injury. Statins The use of statins in patients with NAFLD, a disorder with strong links to metabolic syndrome and its cardiovascular outcomes, should not be questioned. Deaths from cardiovascular disease are the leading cause of mortality in patients with fatty liver. However, initial concerns of hepatotoxicity Non-alcoholic fatty liver disease Up to 30% of Australians have NAFLD. The entire pathological spectrum of NAFLD, from simple steatosis through to hepatocellular carcinoma, may be present despite LFTs being normal. For example, in community-based studies using magnetic resonance spectroscopy, an accurate method of quantifying liver fat, about 70% of patients with NAFLD have normal LFTs. There has also been debate in the recent literature on the most appropriate reference ranges for serum transaminases. An ALT >30U/L (for men) and >19U/L (for women) is suggested as a more accurate indicator of liver injury than the upper limits of normal often stated in report forms (typically 40U/L, but up to 55U/L). Case studies Case study 1 BERYL, a 58-year-old obese woman with treated hypothyroidism, complains of itch at night. As part of a routine workup, the following LFTs come to light: serum bilirubin 25μmol/L (<20), ALT 48U/L (<40), aspartate AST 28U/L (<40), ALP 175U/L (<110), GGT 75U/L (<35), albumin 42g/L (35-53), globulins 40g/L (25-35). Hepatic ultrasonography shows diffusely increased echogenicity and gallstones in the gall bladder, but no features of cirrhosis or portal hypertension. Assuming she has NAFLD, would you send her to a dietitian and encourage gym membership, or perform additional investigations (and which ones)? Commentary Beryl complains of pruritus, which is not a symptom of NAFLD, and she has another autoimmune disease. So although the increased These revised cut-offs are based on community values for lean adults, and reflect levels of ALT usually attained after successful treatment of hepatitis C, autoimmune hepatitis and NAFLD. It is also salient to note that GGT and/or ALT values in the top quartile of the community range are a strong predictor for later onset of type 2 diabetes: the link is via NAFLD. The pathology of NAFLD mimics that of alcoholic liver disease. There is no diagnostic test that accurately differentiates the two conditions. Reliance on an accurate alcohol history (with all its caveats) is the only recourse. Interpretation of LFTs NAFLD (and NASH) cannot be and the use of vague meaningless terms such as hepatic dysfunction in product information sheets have led to underprescribing of these drugs. Baseline ALT abnormalities are common in patients with fatty liver, and statin use in patients with and without baseline abnormalities of liver tests has not been associated with more frequent or disproportionate increases in ALT or AST, while randomised trials have established the safety of statin use in patients with chronic hepatitis C and NAFLD. A rise in serum ALT or AST is commonly observed (occurring in 1-3% of cases) after initiation of statin treatment, but cases of statin-induced liver injury are rare (<1 in a million). As a result of accumulated evidence, the US Food and Drug Administration no longer mandates routine liver function tests in statin users. The most compelling case for statin use in patients with NAFLD is the likelihood of harm when patients are denied these drugs. In a post-hoc analysis of the Greek Atorvastatin and Coronary Heart Disease Evaluation study (GREACE), there was a 68% risk reduction in cardiovascular events among patients with excluded on the basis of normal LFTs (see box below). On the other hand, very high levels of serum ALT or AST (>250U/L) are unlikely to be due to NAFLD (or alcohol). Seek evidence of viral or autoimmune hepatitis, drugs (paracetamol) or herbal medication use. A high serum ferritin in the absence of increased transferrin iron saturation is a very common finding in patients with NAFLD. Patients with any abnormalities of liver synthetic function have a high likelihood of advanced hepatic fibrosis. Non-invasive assessment of liver fibrosis with transient elastography, or liver biopsy should be considered. Such presentations are uncommon. As mentioned already, an AST/ ALT ratio >0.8 is another feature of NAFLD (defined by raised ALT) and abnormal liver tests (10% vs 30% in untreated patients), which was significantly higher than the protection conferred in those without NAFLD. Methotrexate Methotrexate had a vexed history of causing cirrhosis when it was used in high daily dose as part of cancer chemotherapy and for psoriasis, particularly among patients who drank alcohol to excess. In the modern era, with methotrexate being given under strict dose guidelines as a once a week schedule, severe hepatic fibrosis, including cirrhosis and its outcomes, is now a rare complication. However, patients who have abnormal LFTs while taking methotrexate require clinical assessment. Many will have type 2 diabetes, obesity and resultant NAFLD, which appears to be a strong risk factor for methotrexate fibrosis. In this context, a liver biopsy used to be the only reliable means of establishing the safety of long-term methotrexate therapy. Today, use of transient elastography technology has virtually replaced the need for liver biopsy to establish presence or absence of significant hepatic fibrosis in these patients. advanced hepatic fibrosis in NAFLD and other liver diseases, but can also occur with alcoholic hepatitis. Increased mortality Patients with NAFLD have about 1.7-fold increased standardised mortality. The excess of deaths is from cardiovascular events, common cancers, cirrhosis and hepatocellular carcinoma. Traditionally, NAFLD patients with abnormal liver tests were asked to undergo lifestyle changes and everyone (including the treating physician) was satisfied if the serum ALT normalised. However, larger clinical studies indicate that serum GGT, ALT and AST are not a robust end point for therapeutic intervention. echogenicity on ultrasound suggests steatosis, it could equally well reflect significant hepatic fibrosis or cirrhosis. There is a minor increase in serum bilirubin that could also indicate cirrhosis (table 3). Otherwise, LFTs do not help much here as the findings are non-specific, although the slightly higher ALP (in relation to other test results) could be due to cholestasis. Primary biliary cirrhosis should be excluded as a cause of pruritus; it is much more common in women than men and is associated with autoimmune thyroiditis. In the case of Beryl, a strongly positive anti-mitochondrial antibody test (1:2560, with M2 specificity) confirmed the diagnosis of primary biliary cirrhosis, and a transient elastography study suggested cirrhosis was unlikely. She was started on ursodeoxycholic acid (15mg/kg) and six months later her LFTs were completely normal, indicont d page 32 References 1. Schneider AL, et al. Liver enzymes race, gender and diabetes risk: the Atherosclerosis Risk in Communities (ARIC) study. Diabetic Medicine 2013; 30: Björnsson E. Review article: drug-induced liver injury in clinical practice. Alimentary Pharmacology and Therapeutics 2010;32: Chalasani N, et al. Patients with elevated liver enzymes are not at higher risk for statin hepatotoxicity. Gastroenterology 2004;126: Athyros VG, et al. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. Lancet 2010; 376: Further reading Cyproterone and cirrhosis Cirrhosis in a child with hypothalamic syndrome and central precocious puberty treated with cyproterone acetate. European Journal of Pediatrics 1999; 158: MTX Visser K, et al. Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative. Annals of the Rheumatic Diseases 2009; 68: NAFLD Farrell GC, Larter CZ. Nonalcoholic fatty liver disease:from steatosis to cirrhosis. Hepatology 2006; 43:S Chitturi S, et al. Nonalcoholic fatty liver in Asia: Firmly entrenched and rapidly gaining ground. Journal of Gastroenterology and Hepatology 2011; 26: Kowdley KV, et al. Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease. Hepatology 2012; 55: Australian Doctor 11 October 2013

6 from page 30 cating an excellent prognosis. Case study 2 Richard is a 74-year-old man who has a history of prostate cancer that was treated with radiotherapy and cyproterone acetate 12 years ago. He now complains of non-specific abdominal pain. You find a hard liver edge during examination of the abdomen. He had developed prolonged jaundice while taking cyproterone acetate and it was discontinued. The following LFTs are obtained: serum bilirubin 15 μmol (<20), ALT 28U/L (<40), AST 18U/L (<40), ALP 275U/L (<110), GGT 25U/L (<35), albumin 42g/L (35-53) and globulins 30g/L (25-35). Which one or more of the following investigations is/are strongly indicated: bone scan, PSA, abdominal (liver) ultrasound, iron studies, and hepatitis serology? Commentary Richard has normal liver tests but a raised ALP. With his history of prostate cancer, PSA and a bone scan are strongly indicated as the alkaline phosphatase may be of bony origin, not liver. In addition, however, the finding of a hard liver Key issues about cirrhosis Making an early diagnosis of cirrhosis is essential This allows important complications like bleeding oesophageal varices, hepatocellular carcinoma, muscle wasting/malnutrition and fractures to be prevented or ameliorated LFTs may be normal in cirrhosis of any cause Two cardinal signs of cirrhosis are often present on physical examination: a hard liver edge and spider naevi The platelet count is the hepatologists most reliable liver function test (table 3) A slightly raised serum alpha-fetoprotein (AFP) is common: AFP is underutilized as a cirrhosis screen in general practice High quality CT or ultrasound may provide diagnostic information such as dilated portal vein, nodular liver outline, splenomegaly, varices, thickened gallbladder wall Increased echogenicity may be due to fibrosis and is often confused with fatty liver (which also often shows posterior attenuation of the ultrasound shadow and blurring of hepatic vessels) Any suspicion of cirrhosis is an indication for specialist referral to expedite definitive assessments, such as transient elastography or liver biopsy edge most likely indicates cirrhosis and an abdominal ultrasound or CT scan would be useful to establish if there is any other evidence of cirrhosis, and to completely exclude hepatic malignancy. Richard was found to have cirrhosis, in this case as a late complication of severe drug-induced liver damage caused by cyproterone acetate. He was then found to have portal hypertension with large oesophageal varices on CT scan and gastroscopy. These have now been banded endoscopically, thereby preventing any likelihood of variceal bleeding. Conclusion IN the present age of excellent diagnostic tests for the common forms of chronic viral hepatitis (hepatitis B and C), LFTs play a lesser role in diagnosis, although subtle changes, together with astute clinical assessment, platelet count and AFP allow doctors to diagnosis cirrhosis at an early stage. This is very important to prevent variceal bleeding, advanced (untreatable) cases of hepatocellular carcinoma and metabolic bone disease. In overweight patients and those with a family history of diabetes, even minor changes in GGT and ALT are an important pointer to future metabolic disease (including cardiovascular events and common obesity-related cancers). This is the ideal time to diagnosis NAFLD and institute the lifestyle changes (increased physical activity, modest weight reduction) needed to prevent premature mortality from these common problems. It is possible in the future that new biomarkers of liver injury, inflammation and fibrosis may be introduced for assessment of NAFLD cases, as liver biopsy is invasive and the logistics daunting for the size of the affected population. Meanwhile, transient elastography is proving useful for the detection of advanced fibrosis in this setting, as in hepatitis B and C. Very few cases of liver disease in a general practice setting will not be attributable to NAFLD, alcohol, HBV or HCV, and while autoantibodies and more specialised metabolic tests are widely available, it may be appropriate to refer such atypical cases for a specialist opinion. How to Treat Quiz Minor abnormalities of LFTs 11 October 2013 Instructions Complete this quiz online and fill in the GP evaluation form to earn 2 CPD or PDP points. We no longer accept quizzes by post or fax. The mark required to obtain points is 80%. Please note that some questions have more than one correct answer. GO ONLINE TO COMPLETE THE QUIZ /education/how-to-treat 1. Which TWO statements are correct regarding minor abnormalities of LFTs? a) Less than 1% of apparently healthy individuals have minor abnormalities of LFTs b) LFTs are considered to be relatively minor if the value is lower than a threefold increase above the normal range c) Most commonly, minor abnormalities in LFTs are associated with non-alcoholic fatty liver disease (NAFLD) d) The severity of abnormalities in the LFTs correlates with the degree of end-stage liver disease 2. Which TWO statements are correct regarding the interpretation of individual LFT indices? a) It is impossible to tell whether a raised ALP is coming from the liver or the bone b) Serum albumin concentration does not simply reflect hepatic synthetic function c) ALT arises from muscle, lung, brain and other tissues as well as liver, whereas AST is liverspecific d) GGT arises uniquely from the liver 3. Which THREE of the following patterns of abnormalities in LFTs may correspond to associated non-hepatic causes? a) Minor elevation of GGT alone is a risk factor for subsequent onset of type 2 diabetes b) An isolated rise in serum bilirubin may suggest the presence of a massive haematoma c) An isolated rise in ALP may suggest underlying cardiac failure d) Low serum albumin is a reflection of malnutrition only 4. Which THREE additional test abnormalities can help identify an unrecognised cirrhosis when LFT abnormalities are minor? a) Low INR reflecting impaired synthetic function b) Thrombocytopenia, reflecting reduced thrombopoeitin synthesis c) A progressive rise in alpha-fetoprotein (AFP) corresponding to the progression of cirrhosis to hepatocellular carcinoma d) Posterior attenuation of the ultrasound shadow and blurring of hepatic vessels on liver ultrasound 5. Which THREE statements are correct regarding minor abnormalities of LFTs in patients suspected to have uncommon liver conditions? a) Coeliac disease should be excluded in lean patients with minor abnormalities of LFTs b) A cholestatic picture in patients with inflammatory bowel disease may indicate primary sclerosing cholangitis c) Ceruloplasmin may be falsely negative in 10% of Wilson s disease d) A hepatocellular pattern in a suspected individual may prompt exclusion of primary biliary cirrhosis 6. Which TWO statements are correct regarding LFTs in drug-induced liver damage? a) A rise in transaminases after initiating statins occurs frequently in >35% of patients b) Very high ALT levels (>50 times upper limit of normal) should always prompt consideration of paracetamol-related liver injury c) A complete resolution of LFT abnormalities occurs within six weeks of stopping fluxcloxacillin in cases of flucloxacillininduced liver injury d) Despite safer prescribing guidelines, patients on methotrexate with abnormal LFTs require further assessment 7. Which TWO statements are correct regarding LFTs in NAFLD? a) An ALT >30U/L for men and >19U/L for women may be a more accurate indicator of liver injury than the current given ranges b) High normal GGT and/or ALT levels may reflect NAFLD that predicts the development of type 2 diabetes in the future c) Very high levels of serum ALT or AST (>250U/L) are most likely due to NAFLD d) An AST:ALT ratio of 1:3 suggests that the LFT abnormalities are due to NAFLD, not alcoholic liver disease 8. Agnes is a 57-year-old woman with chronic HBV infection. Which TWO statements are correct regarding her diagnosis and presentation? a) An assessment for cirrhosis is not necessary at her age b) She should inform all her doctors of her hepatitis B status c) A normal physical examination and normal ALT level precludes any further management d) An assessment of her metabolic risk factors should be made 9. Agnes has a BMI of 31 and has minor LFT abnormalities. Which TWO statements are correct regarding her assessment and investigations? a) An AST:ALT ratio >0.80 is both a sensitive and specific screening test for underlying cirrhosis b) Where LFT abnormalities may be either due to fatty liver or hepatitis B virus (HBV), HBV DNA levels and ultrasound may help elucidate the diagnosis c) Spider naevi are the most sensitive and specific sign of cirrhosis d) With minor abnormalities, HBV DNA levels are not required 10. Which TWO statements are correct regarding Agnes prognosis and ongoing management? a) If her HBV DNA level is >10,000 IU/mL, antiviral therapy may be indicated b) A >10-fold increase in AFP over the normal range should prompt further investigations c) The level of HBV replication is not a good predictor of subsequent cirrhosis or hepatocellular carcinoma d) Agnes should not be given a statin because her risk of hepatotoxicity is higher than her risk from metabolic syndrome CPD QUIZ UPDATE The RACGP requires that a brief GP evaluation form be completed with every quiz to obtain category 2 CPD or PDP points for the triennium. You can complete this online along with the quiz at. Because this is a requirement, we are no longer able to accept the quiz by post or fax. However, we have included the quiz questions here for those who like to prepare the answers before completing the quiz online. how to treat Editor: Dr Steve Liang steve.liang@cirrusmedia.com.au Next week Anosmia and parosmia are conditions that are commonly caused by sinonasal disease, primarily rhinitis and rhinosinusitis. Such olfactory disturbance is often associated with age and is usually classed as either a conductive (odorant delivery) or receptive (chemosensation) condition. The next How to Treat investigates the aetiology, assessment and treatment of these olfactory conditions. The authors are Associate Professor Richard Harvey, program head and conjoint associate professor, rhinology and skull base surgery, University of NSW and St Vincent s Hospital, Darlinghurst, and clinical associate professor, Macquarie University, North Ryde; and Dr Pascal Bou-Haider, neuroradiologist, St Vincent s Hospital, Darlinghurst, NSW. 32 Australian Doctor 11 October 2013