XII Liver1 with answers

XII Liver1 with answers - XII LABORATORY DIAGNOSIS...

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Unformatted text preview: XII LABORATORY DIAGNOSIS LABORATORY OF LIVER DISEASE OF Stephen M. Baird, M.D. Professor of Pathology, Emeritus <[email protected]> 858­534­2743 Wiki : ucsdlabmed.wikidot.com Laboratory Medicine (SPPS 216) OBJECTIVE OBJECTIVE S Describe the basic functions of the liver Describe how to use the laboratory to Describe determine if liver disease is present determine Describe how to use the laboratory to Describe determine what type of liver damage is present (cellular vs. biliary tract) vs. List the various tests used to diagnose hepatitis S.M. Baird, M.D. UCSD SPPS 216 KEY TERMS Alkaline Phosphatase AST ALT Bilirubin Cholestasis Cirrhosis Direct Bilirubin GGT Hepatitis Indirect Bilirubin S.M. Baird, M.D. UCSD SPPS 216 BACKGROUND SIGNIFICANCE Synthetic, catabolic, and detoxifying functions Synthetic, Complete loss of the liver or its functions Complete results in death within hours or days results Hepatic parenchymal cells are involved in Hepatic carbohydrate metabolism, protein synthesis (most clotting factors,) lipid metabolism, storage functions, excretion, and detoxification storage Disease may be a process confined to the Disease organ itself, or consequence of systemic disease disease S.M. Baird, M.D. UCSD SPPS 216 BACKGROUND SIGNIFICANCE Drug clearance by hepatic mechanisms Drug interactions at hepatic level Several drugs cause hepatic damage, essential Several for pharmacists to: for Assess state of biochemical functions Differentiate primary pathologic processes from Differentiate drug-induced effects drug-induced Diagnose etiology of primary processes S.M. Baird, M.D. UCSD SPPS 216 TESTS OF HEPATIC PARENCHYMAL DAMAGE Tests of Hepatocellular Damage (ref. ranges) AST 10-30 U/L ALT 11-45 U/L Bilirubin: Conjugated < 0.2, Total < 1.2 mg/dL Tests of Biliary Tract Disease Alkaline phosphatase (ALP) 30-130 U/L Gamma glutamyl transferase (GGT) female <24, male <38 U/L Bilirubin: conjugated < 0.2, total < 1.2 mg/dL S.M. Baird, M.D. UCSD SPPS 216 TESTS OF ETIOLOGY Hepatitis virus antigens; HBsAg, HCV by PCR Hepatitis virus antibodies (e.g., HAV-IgG, HAVIgM, HBcAb, HBeAb, HBsAb, HCAb) α-fetoprotein (neoplasms) Immunoglobulins (autoimmune and Immunoglobulins inflammation) inflammation) Autoantibodies (anti mitochondrial, anti smooth Autoantibodies muscle, anti nuclear) muscle, Iron, transferrin, ferritin (hemochromatosis) Copper, ceruloplasmin (Wilson’s disease) S.M. Baird, M.D. UCSD SPPS 216 DESCRIPTION OF TESTS Bilirubin Reference range: conjugated < 0.2, total < 1.2 mg/ dL End product of heme catabolism (daily) Transported to the liver to be conjugated and Transported excreted via the bile excreted Most of bilirubin in blood is in transit from tissues Most to liver, in unconjugated form, bound to albumin to Only small amounts of conjugated bilirubin are Only normally found in blood unless there is biliary obstruction obstruction S.M. Baird, M.D. UCSD SPPS 216 DESCRIPTION OF TESTS Bilirubin “Conjugated” refers to bilirubin glucuronide “Total” refers to conjugated plus unconjugated Unconjugated is neither measured nor reported as Unconjugated such, but is inferred by the clinician from the difference between total and conjugated difference Hemolysis causes erroneous lowering of results Hemolysis Light sensitive; analyze samples within 1-2 hours analyze Stable for months when serum is frozen Fasting increases bilirubin in blood slightly Fasting S.M. Baird, M.D. Slightly lower in women than in men UCSD SPPS 216 DESCRIPTION OF TESTS Bilirubin Elevations of unconjugated bilirubin without Elevations significant elevations of conjugated are seen in: significant Hemolytic disorders (increased load) Gilbert’s syndrome (transport and conjugation defect, Gilbert’s bilirubin 2-3 mg/dL) bilirubin Arias syndrome (partial conjugation defect, bilirubin Arias more than 6 mg/dL) more Crigler-Naijar syndrome (glucuronyl transferase Crigler-Naijar deficiency; 2 types) deficiency; Immaturity of the liver in the newborn (very common) Cirrhosis (but often no elevations) S.M. Baird, M.D. UCSD SPPS 216 DESCRIPTION OF TESTS Bilirubin Elevations of conjugated bilirubin with lesser Elevations increase of unconjugated are seen mostly in early phases of cholestasis and are transient phases Elevations of the conjugated plus unconjugated Elevations bilirubin are seen in: bilirubin Hepatitis Cirrhosis Posthepatic obstruction Dubin-Johnson syndrome Rotor’s syndrome Some forms of drug-induced cholestasis S.M. Baird, M.D. UCSD SPPS 216 DESCRIPTION OF TESTS Bilirubin Delta-bilirubin (bound to albumin) Not detected to any significant extent in normal adults, or Not with unconjugated hyperbilirubinemia with Increased levels are observed with prolonged conjugated Increased hyperbilirubinemia Concentration varies over a wide range, but may account Concentration for 30-50%, and in some instances as much as 90%, of the total serum bilirubin total Responsible for persistence of conjugated Responsible hyperbilirubinemia following clinical disappearance of bilirubinuria bilirubinuria Delta-bilirubin not cleared into urine since bound to Delta-bilirubin S.M. Baird, M.D. UCSD SPPS 216 albumin albumin DESCRIPTION OF TESTS Bilirubin Bilirubinuria Only conjugated, water-soluble form is excreted into Only urine urine Detectable bilirubinuria is always abnormal and for its Detectable demonstration qualitative or semi-quantitative tests suffice suffice Bilirubinuria is seen in: biliary obstruction, Bilirubinuria hepatocellular damage, Dubin-Johnson syndrome, and Rotor’s syndrome Rotor’s With an elevation of only unconjugated bilirubin, With unconjugated bilirubinuria is not present because unconjugated is normally bound to albumin and not filtered out normally S.M. Baird, M.D. UCSD SPPS 216 DESCRIPTION OF TESTS Plasma Proteins Plasma Plasma total protein concentrations in liver disease Plasma often are near normal but tend to be low often Albumin/Globulin reference range: 1.5:1 to 3.0:1 Most useful are albumin measurements in the Most albumin assessment of the severity of impairment because Ig is made by plasma cells, not hepatocytes Ig Cirrhosis & chronic hepatitis lead to polyclonal Cirrhosis hypergammaglobulinemia Albumin is also important in the evaluation of Albumin renal disease because it may be lost in urine renal S.M. Baird, M.D. UCSD SPPS 216 DESCRIPTION OF TESTS Blood Coagulation Prolongation of the PT is an indicator of hepatic Prolongation dysfunction, often serious. Not an early sign dysfunction, Impaired absorption in the gut, particularly of fat Impaired soluble substances, accompanies liver disease, reducing vitamin K (II, VII, IX, X) reducing In more severe conditions, PTT also prolonged Dysfibrinogenemias also in severe liver disease Primary fibrinolysis is increased in hepatic disease S.M. Baird, M.D. UCSD SPPS 216 DESCRIPTION OF TESTS Amino Acids Amino In SEVERE cirrhosis or hepatitis, higher blood In levels and increased aminoaciduria levels In severe liver necrosis, aminoaciduria reaches In such proportions that the solubility of certain amino acids is exceeded and crystals are formed amino Characteristic leucine “spheres” Tyrosine “rosettes” in urine in “acute yellow liver acute atrophy.” atrophy S.M. Baird, M.D. UCSD SPPS 216 DESCRIPTION OF TESTS Blood Ammonia Blood Elevated blood ammonia is seen in: Severe liver disease Actual or impending hepatic coma Due to: Reduced removal of ammonia from the portal blood, Reduced and “shunting” of portal blood, bypassing the liver and Blood ammonia levels show some, but not close, Blood correlation with the presence and deepness of the coma correlation Some patients show abnormal behavior after eating a Some protein-rich meal protein-rich S.M. Baird, M.D. UCSD SPPS 216 DESCRIPTION OF TESTS AST (Aspartate Aminotransferase) and ALT AST (Alanine Aminotransferase) The most sensitive indicators of hepatic cell injury May be elevated without elevation of bilirubin or May other detectable impairment of liver function other Highest levels are seen in acute hepatic necrosis Their elevations usually parallel each other ALT elevations without those of AST are ALT occasionally seen in mild hepatic disease and in the recovery phase of hepatitis recovery ALT is generally a more sensitive indicator of acute ALT S.M. Baird, M.D. UCSD SPPS 216 liver cell damage than AST liver DESCRIPTION OF TESTS ALP (Alkaline Phosphatase) ALP Present in high concentration in biliary tract < 3 times normal generally means times hepatocellular damage hepatocellular > 3 times normal generally means post times hepatic obstruction (gall stone or cancer) hepatic Other sources include bone, GI, placenta, Other tumors (isoenzymes) tumors Bone burns, liver lives (isoenzymes) S.M. Baird, M.D. UCSD SPPS 216 DESCRIPTION OF TESTS GGT (Gamma Glutamyl Transferase) Enzyme found in liver and pancreas, larger Enzyme amounts in kidney amounts Elevations of hepatic alkaline phosphatase due to a Elevations bone disease or due to cholestasis bone GGT determinations help differentiate bone and GGT liver sources of alkaline phosphatase liver GGT is also a sensitive indicator of alcoholinduced liver disease and of recent alcohol induced ingestion (used in ATP to detect return to drinking). drinking). S.M. Baird, M.D. UCSD SPPS 216 VIII VIII LABORATORY LABORATORY DIAGNOSIS OF LIVER DISEASE: DISEASE: Case Studies Laboratory Medicine (SPPS 216) Case 1 (Ann. Pharmacother. 36(12):1887-1889, 2002) Case A 41-year-old white man had received a prescription for celecoxib 200 mg/d for 3 days for pain associated with right-knee trauma. Shortly after taking the second dose of the drug, he began to experience epigastric pain, nausea, anorexia, malaise, pruritus, cutaneous and scleral jaundice with dark urine, and pale stools. In spite of the symptoms, the man took the final dose (total dose: 600 mg). The symptoms persisted and, 48 hours after the third dose of celecoxib, he was seen by his family physician, who found: a total bilirubin 8.4 mg/dL, direct bilirubin 7.6 mg/dL, AST 97 IU/L, ALT 234 IU/L, and GGT 134 IU/L. 234 S.M. Baird, M.D. UCSD SPPS 216 Case 1 Case How do you interpret these lab values? ↑ bilirubin and ↑ GGT suggest cholestasis. Mild ↑ in AST and ALT suggest hepatocellular damage 1. 2. What is the significance of the pale stools? 2. Cholestasis. Gut microbes convert bilirubin into Cholestasis. brown pigments. brown S.M. Baird, M.D. UCSD SPPS 216 3. What other tests should be ordered? Hep A, B, C-all were negative as were Epstein-Barr and cytomegalovirus. Ultrasound showed heptatomegaly with gallstone of 2.2 cm. 4. Is this a common adverse drug reaction for this class of drugs? No. Idiosyncratic reaction. Naranjo scale = probable relationship 5. What percent of patients that present with cholestasis are drug-induced? 2-5% of jaundice cases caused by drug induced cholestasis. 6. How should this patient be treated? Immediately stop drug. Follow liver panel. This pt eventually recovered. Case 2 (Am. J. Med. Sci. 325(5):292-295, 2003) Case A previously healthy 65-year-old man developed scleral jaundice. Simultaneously, he experienced severe fatigue, and reported light-colored stools, dark urine, and generalized pruritus. The patient denied abdominal pain, fever, abnormal bleeding, or skin rashes. One month before the onset of symptoms, he was prescribed terbinafine (Lamisil; Novartis Pharmaceuticals Corp., New Jersey) for onychomycosis (fungal infection of the nails). (fungal Initial laboratory tests showed bilirubin 21 mg/dL, Initial (conjugated bilirubin, 18.8 mg/dL), aspartate aminotransferase 313 IU/L (reference range: 8-58 IU/L), alanine aminotransferase 179 IU/L (reference range: 8-52 IU/L), and alkaline phosphatase 1040 IU/L (reference range: 34-124 S.M. Baird, M.D. IU/L). IU/L). UCSD SPPS 216 Case 2 Case How do you interpret these lab values? Cholestatic hepatitis 1. 2. What other lab tests should be ordered? Hep A, B, C, CMV, Epstein Barr- all neg S.M. Baird, M.D. UCSD SPPS 216 3. Is this a common ADR for this drug? No-terbinafine generally well tolerated. Hepatic dysfunction incidence 1: 45,000. 4. How should this patient be treated? d/c terbinafine, put patient on cholestyramine and bile salts, liver fxn panel still elevated, added prednisone, 30 days later bilirubin returned to normal. Case 3 (Am. J. Med. Sci. 325(1):31-33, 2003) Case An 80-year-old man had been diagnosed with hypopharyngeal cancer and received radiation therapy. He had an episode of acute bronchitis, for which he was given 500 mg of oral amoxicillin/clavulanic acid (Augmentin). Because of persistent upper respiratory symptoms and fever over the subsequent 2 days, 500 mg of oral ciprofloxacin twice a day was added. Within 48 hours, the patient’s fevers began to subside, with an improvement in respiratory symptoms. Six days later, the patient developed a generalized maculopapular, intensely pruritic rash. Pertinent laboratory studies showed total bilirubin of 0.8 mg/dL, aspartate aminotransferase (AST) of 150 U/L, alanine aminotransferase (ALT) of 154 U/L, alkaline phosphatase of 120 U/L, serum albumin of 2.1 g/dL, and prothrombin time of 13.9 seconds. Four days later the liver profile showed an AST of 577 U/L, ALT of 972 U/L, ALP of 358 U/L, total bilirubin of 1.9 mg/dL, direct bilirubin of 1.1 S.M. Baird, M.D. mg/dL, and GGT of 638 U/L. UCSD SPPS 216 Case 3 Case What is the interpretation of these lab What values? values? Low albumin suggests ↓ synthetic fxn ↑ transaminases- hepatocellular damage transaminasesGGT and bilirubin-cholestasis 1. 2. Propose a mechanism for these observations. Acute hepatotoxic hypersensitivity rxn. Acute Mechanism of hepatoxicity unknown. Mechanism S.M. Baird, M.D. UCSD SPPS 216 3. What is the mechanism of action of Augmentin? Amox-beta lactam antibiotic Clavulanic acid- suicide inhibitor of betalactamase 4. Is this a common ADR for these compounds? No. Augmentin is associated moderate (asymptomatic) increase in transaminases (23% of patients) but rarely hepatic dysfunction 5. How should this patient be treated? d/c augmentin and ciprofloxacin ...
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This note was uploaded on 09/14/2011 for the course PHARM lm taught by Professor Staff during the Spring '11 term at UCSD.

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