Mild diffuse LFT abnormalities History and physical examination (especially drugs, alcohol) Obesity, diabetes, hyperlipidemia Autoimmune features Serum globulins, ANA, SMA Miscellaneous considerations Consider USG, CT, MRCP, ERCP Liver biopsy as dictated by findings and subsequent course Lab Test Report 14 year old female with purpura, no liver, spleen or lymphadenopathy. Her CBC report is as follows: CBC by prick WBC 6400 Neutrophils 30 % Lymphocytes 65 % Eosinophils 03 % RBC count 4.93 million Hb 13.4 g/dl HCT 40 % MCV 81.1 Fl MCH 27.2 pg MCHC 33.5 % Platelet 0.15 lakhs Exciting Prizes Test for hemochromatosis Wilson’s disease Alpha-1 antitrypsin deficiency Celiac disease KNOWLEDGE TERMINUS “I don't wish to confess that I learnt a lot from the issue on lymphadenopathy. The tabular format and the simplicity with which you have condensed such a vast topic in 4 pages is highly commendable. Also how doctors will definitely think twice before treating”. Telephonic conversation with a senior teacher who did not wish to be named. SMS your diagnosis with your name to 9820559573 or call on 24173232 3 winners will be chosen by lucky draw from the correct entries To discuss the above report call Dr. Swati Kanakia on 9820229302 SPOT JUNCTION nopathy e d a h p m y L ctions and format is very e f n I n o r es The issu good. The tabula text books. It o y were ver need not refer t e have a copy e w useful. W r students. May o f is useful pital. os for out h te Vora t e d u a l C Dr. ian Pediatric Hospitals it Holy Spir ...................... the joy of learning! Winners of n4 Spot Junctio Correct Answer Acute Pancreatitis 1. Dr. Fayyaz Sattar 2. Dr. Kirit Lalan 3. Dr. Heril Nandu Mennorhagia - Think beyond Gynecology 8-10-05 & 22-10-05 Functional GI Disorders (NUD/IBS) 19-11-05 & 26-11-05 ITP 10-12-05 & 24-12-05 REGISTRATION IS FREE BUT COMPULSORY, PLEASE REGISTER WITH MS BINDU/VINOD ON 24101133/24173232 GrafFitI JUNCTION Published by Dr. Raju R. Kanakia for Kanakia Health Care, 2, Neelkanth Niwas, Purandare Park, Dr. B. Ambedkar Road, Dadar Circle, Mumbai 400 014 and printed by Medivision Infomedia Pvt. Ltd., Mumbai - 400 037. Tel.: 2410 3737 / 2410 3838 Fax:2410 3939 E-mail: [email protected] Rs. 1 4 MH/MR/EAST/18/2004-05 Consider nonalcoholic fatty liver disease (NASH) Serologic tests for viral hepatitis Risk factors for viral hepatitis Train or Strain your Brain Vol: 2 No: 2 OCTOBER 2005 RNI. MAHENG 09523/13/1/2004-TC Dear Friends, Dr. Raju Kanakia MD, DNB (Gastroenterology) l Gastroenterologist l Hepatologist I am sure all of you must have enjoyed Navratri, thanks to the Supreme Court relaxation of the deadline from 10 p.m. to midnight. But did you give a thought to the harmful effects of noise pollution? Festivals have now become a legitimate reason to indulge in noise pollution. Now Diwali is just round the corner and it too will lead to noise pollution by enthusiasts bursting crackers past midnight. We seem to have forgotten that Diwali or Deepawali is a festival of lights and not noise. At KHC, we remember and strive to light the “deep” of knowledge by providing you with practical information useful in day today practice. “Interpretation of Liver Function Tests” is yet another effort in that direction. Drs Swati and Raju Kanakia EDITOR’S PLATFORM l Interventional G.I. Endoscopist Mobile: 9820229301 l Digestive Health Centre, Dadar l Lilavati Hospital, Bandra l S L Raheja Hospital, Mahim l Lion Tarachand Bapa Hospital, Sion l Rushabh Nursing Home, Chembur Dr. Swati Kanakia MD, DCH, PhD l Pediatric Hematologist Oncologist Mobile: 9820229302 l Advanced Blood & Cancer Disorders Centre, Dadar l Lilavati Hospital, Bandra l Asian Institute of Oncology, S L Raheja Hospital, Mahim. l Sir H N Hospital, Prarthna Samaj l Lion Tarachand Bapa Hospital, Sion Liver Function Tests: Liver function tests represent a broad range of normal functions performed by the liver. The diagnosis of liver disease depends upon a complete history, complete physical examination, and evaluation of liver function tests and further invasive and noninvasive Abnormal LFTs often, but not always, indicate that something is wrong with the liver, and they can provide clues to the nature of the problem. However, normal LFTs do not always mean that the liver is normal. Patients with cirrhosis and bleeding esophageal varices can have normal LFTs. Of the routine LFTs, only serum albumin, bilirubin and prothrombin time (PT) provide useful information on how well the liver is functioning. The commonly used liver function tests (LFTs) primarily assess liver injury rather than hepatic function. Indeed, these blood tests may reflect problems arising outside the liver, such as hemolysis (elevated bilirubin level) or bone disease (elevated alkaline phosphatase [ALP] level). An isolated elevation of just one test result should raise suspicion that a source other than the liver is the cause. When several liver tests are simultaneously out of the normal range, consideration of nonhepatic sources becomes irrelevant. Most clinical laboratories offer bundled blood tests, which often contain all or most of the following: TABLE 1- Basic Blood Tests in Hepatobiliary Disease Test Alanine transaminase (ALT/SGPT) Aspartate transaminase (AST/SGOT) Normal Range (adults) Significance 5-40 U/L Liver cell damage Monitor disease progress Liver cell damage Confirm hepatic cause of AST elevation 5-40 U/L Monitor disease progress Alkaline phosphatase (ALP) 45-130 U/L Hepatic infiltrative disease, cholestasis Total bilirubin 1-1.5 mg/dL Elevated in jaundice, hemolysis Biliary obstruction, hepatitis, drugs Conjugated (direct) 0.3 mg/dL Unconjugated (indirect) 1.0 mg/dL Gilbert’s disease, pernicious anemia, hemolysis 3.5-5.0 g/dL Lower with decreased liver function Albumin Gamma glutamyl transpeptidase (GGT) 4-40 U/L Prothrombin time (PT) 10-16 seconds Screening for alcohol abuse Monitor liver disease Cholestasis Monitor hepatic carcinoma progression Increases with decreased liver function KNOWLEDGE TERMINUS 1 Elevated alkaline phosphatase Bilirubin: Table 2. Nonhepatic causes of abnormal liver function test results Bilirubin, an endogenous organic anion, binds reversibly to albumin and is transported to the liver, where it is conjugated to glucuronic acid and excreted in the bile. It is derived primarily from catabolism of red blood cell heme and to a lesser extent from degradation of myoglobin, cytochromes, catalase, and peroxidase. Healthy people have a small amount of unconjugated (indirect) bilirubin but no conjugated (direct) bilirubin in their blood. However, commonly used laboratory tests often incorrectly identify some serum bilirubin as being conjugated in healthy people, so most testing centers report a range of normal for conjugated bilirubin. Test result Nonhepatic causes Decreased serum albumin level Protein-losing enteropathy Serum globulins, alpha1-antitrypsin clearance Nephrotic syndrome Urinalysis, 24-hr urinary collection for protein Congestive heart failure Cardiac examination, two-dimensional echocardiogram Myocardial infarction CK-MB, troponin, ECG Muscle disorders CK, ESR Bone disease GGT, serum leucine aminopeptidase, 59-nucleotidase Pregnancy GGT, 59-nucleotidase, hCG in serum and urine Hepatobiliary disease is indicated when the conjugated fraction of total bilirubin exceeds Elevated ALP level Elevated bilirubin level Elevated PT Alkaline phosphatase electrophoresis Hemolysis Reticulocyte count, peripheral smear, LDH, haptoglobin Sepsis Clinical setting, blood cultures Ineffective erythropoiesis Peripheral smear, urine bilirubin, hemoglobin electrophoresis, bone marrow aspiration and biopsy Shunt hyperbilirubinemia Clinical setting Antibiotic use, anticoagulant use, steatorrhea, dietary deficiency Response to vitamin K Extrahepatic source FIGURE 1. Typical serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) values for various diseases. Toxic or ischemic injury Acute viral hepatitis Alcoholic hepatitis Chronic hepatitis Cirrhosis Normal 10 30 100 300 Normal AMA, ACE level, serologic tests for hepatitis, alpha fetoprotein Gallstones Cholecystectomy and bile duct exploration, if indicated Focal lesion(s) CT/MRI, biopsy Billiary tract abnormalities Cholangiography (MRCP, ERCP, THC) Primary sclerosing cholangitis Above negative; elevation persists Liver biopsy (including electron microscopy) ALP, alkaline phosphatase; AST, aspartate aminotransferase; CK, creatine kinase; ECG, electrocardiogram; ESR, erythrocyte sedimentation rate; GGT, gamma-glutamyltranspeptidase; hCG, human chorionic gonadotropin; LDH, lactate dehydrogenase; PT, prothrombin time. ALT is the enzyme produced within the cells of the liver. The level of ALT abnormality is increased in conditions where cells of the liver have been inflamed or undergone cell death. As the cells are damaged, the ALT leaks into the bloodstream leading to a rise in the serum levels. Any form of hepatic cell damage can result in an elevation in the ALT. The ALT level may or may not correlate with the degree of cell death or inflammation. ALT is the most sensitive marker for liver cell damage. 1,000 3,000 10,000 U per L Colonoscopy GGT elevations of about twice normal. A mildly elevated GGT level is a typical finding in patients taking anticonvulsants and by itself does not necessarily indicate liver disease. Alkaline Phosphatase (ALP): Alkaline phosphatase is an enzyme, which is associated with the biliary tract. It is not specific to the biliary tract. It is also found in bone and the placenta. Renal or intestinal damage can also cause the alkaline phosphatase to rise. If the alkaline phosphatase is elevated, biliary tract damage and inflammation should be considered. However, considering the above, other etiologies must also be entertained. One way to assess the etiology of the alkaline phosphatase is to perform a serologic evaluation called isoenzymes. Another more common method to asses the etiology of the elevated alkaline phosphatase is to determine whether the GGT is elevated or whether other liver function tests are abnormal (such as bilirubin) Serum proteins - Albumin / Globulin: Most circulating proteins in plasma are synthesized in the liver, and levels indicate synthetic capability of the liver. Hypoalbuminemia is often associated with ascites and expansion of the extravascular albumin pool at the expense of intravascular albumin levels. In general, albumin is a good marker of severity of chronic liver disease, but levels may be affected by chronic renal insufficiency, urinary protein losses, or gastrointestinal losses. Markedly elevated levels of ALP suggest the possibility of such disorders as extrahepatic biliary obstruction, primary biliary cirrhosis, drug-induced cholestasis, primary sclerosing cholangitis, and infiltrative processes (e.g. tuberculosis, amyloid, granulomatous hepatitis, neoplasm). Increases in serum globulin levels are common in chronic liver disease but are nonspecific. However, the pattern of elevation may give a clue to the underlying cause. For example, in autoimmune hepatitis, the serum IgG level is elevated, whereas in primary biliary cirrhosis, the serum IgM level is elevated. Gamma Glutamic Transpeptidase (GGT): This enzyme is also produced by the bile ducts. However, it is not very specific to the liver or bile ducts. It is used often to confirm that the alkaline phosphatase is of the hepatic etiology. The GGT level is often elevated in persons who take three or more alcoholic drinks (45 g of ethanol or more) per day. Thus, GGT is a useful marker for alcohol intake. Phenobarbital, phenytoin and other drugs typically cause Prothrombin time (PT): Severity and prognosis of liver disease can be assessed using PT, which reflects deficiency of one or more of the liver-synthesized factors. In cholestatic liver disease, PT prolongation can result from vitamin K deficiency, but differential diagnosis includes malabsorption, disseminated intravascular coagulation, inherited deficiencies of coagulation factors, and medications that antagonize the prothrombin complex. To correct PT, vitamin K is often given at a dosage of 10 mg/day for 3 days. Correction by at least 30% within 24 hours suggests that hepatic function is intact and that vitamin K deficiency may be the source of the problem Aspartate Aminotransferase (AST/SGOT): This enzyme also reflects damage to the hepatic cell. It is less specific for liver disease. It may be elevated in other conditions such as a myocardial infarct (heart attack). Although AST is not a specific for liver as the ALT, ratios between ALT and AST are useful to physicians in assessing the etiology of liver enzyme abnormalities. Elevated ALT History and physical examination (especially drugs, alcohol, obesity, diabetes) IgM anti-HBc + Acute hepatitis HBsAg IgM anti-HBc + Chronic hepatitis + Normal GGTP or 5' nucleotidase Abdominal USG Malignant tumor Alanine Aminotransferase (ALT/SGPT): Anti-HCV History and physical examination (especially pruritus, cholestasis, drugs, pregnancy, renal disease, bone symptoms) Elevated: hepatobilliary disease Elevated AST level the upper limit of normal, even if the total serum bilirubin concentration is normal or near normal. The presence of conjugated, water-soluble bilirubin in the urine (bilirubinuria) always indicates hepatobiliary disease. Hemolysis and Gilbert syndrome are common conditions that cause benign elevation of unconjugated bilirubin. + Discriminating tests Hepatitis C Serum levels of AST and ALT are elevated to some extent in almost all liver diseases. Mild elevation is typically found in patients with fatty liver, nonalcoholic steatohepatitis, and chronic viral hepatitis. Highest elevation occurs in acute viral hepatitis, hepatic necrosis induced by drugs (e.g. acetaminophen) or toxins, and ischemic hepatitis related to circulatory shock. Although elevated aminotransferase levels may be the first clue to liver disease and screening has proved useful for detecting subclinical disease in asymptomatic persons, patients with normal levels may have significant liver damage. For instance, recent studies have demonstrated that patients with chronic HCV infection may have histologic evidence of chronic hepatitis despite repeatedly normal results on liver tests. Above negative: Consider Wilson’s disease (<age 40): Cu, ceruloplasmin Hemochromatosis: Fe, TIBC, ferritin Autoimmune hepatitis: ANA, SMA serum globulins Alpha-1 antitrypsin deticiency: AAT level Celiac disease: transglutaminase antibody AST:ALT ratio of more than 2:1 is characteristic in patients with alcoholic liver disease. Above negative: ?USG or CT for fatty liver Consider liver biopsy Elevated GGTP History and physical examination (especially alcohol, obesity, diabetes, drugs, myocardial infarction, COPD, renal disease, pancreatic disease) Abdominal USG Focal Lesion (s) Biliary tract disease Abnormal liver echotexture CT/MRI, biopsy Cholangiography (MRCP, ERCP, THC) Consider liver biopsy Above negative; persistent elevation after abstinence from alcohol for 2-3 months Consider liver biopsy 2 3 Summary Evaluating abnormal liver test results requires careful attention to the corresponding clinical data obtained during history taking and physical examination. Generally, it is helpful to separate liver tests into three categories: tests that assess synthetic function, tests that assess hepatocellular necrosis (hepatocellular enzymes), and tests that assess cholestasis. The clinical setting together with the specific pattern of liver function abnormalities can narrow differential diagnosis and provide a cost-effective approach to assessing patients and identifying those who need liver biopsy.