2 Liver Function Test Albumin Bilirubin: Serum aminotransferases Total BilirubinDirect Bilirubin (conjugated bilirubin)Serum aminotransferasesAspartate aminotransferase (AST)Alanine aminotransferase (ALT)Alkaline PhosphataseProthrombin time
3 Albumin Synthesized in the liver Production is controlled by multiple factors including nutritional status, serum oncotic pressure, cytokines, and hormonesA serum albumin may be reflection of the synthetic function of the liver.
5 BilirubinUsed to determine liver’s ability to clear endogenous/exogenous substances from the circulationIndirect (unconjugated) bilirubinElevated with hemolysis, hepatic diseaseDirect (conjugated) bilirubinElevated with biliary obstruction and hepatocellular disease.Jaundice usually develops with a bilirubin ≥ 3 mg/dL
7 AminotransferasesHepatic enzymes that are usually intracellular, but are released from hepatocytes with hepatocellular injury.Includes aspartate aminotransferase (AST) and alanine aminotransferase (ALT)AST/ALT ratioNormal is 0.8In alcoholic hepatitis, is usually > 2
8 Alkaline PhosphataseA group of enzymes that catalyze the hydrolysis of a large number of organic phosphate esters.In liver, believed to play an active role in down-regulating the secretory activities of the intrahepatic biliary epitheliumFound in:LiverBoneintestineFirst trimester placentaKidneyGamma-glutamyl transpeptidase (GGT):Liver origin: Elevated GGTBone origin: Normal GGT
9 Prothrombin Time (PT)Liver is in charge of the synthesis of many clotting factors :Factor I (fibrinogen)Factor II (prothrombin)Factor VFactor VIIFactor IXFactor XFactors XII and XIIIElevated PT may be reflection of decreased synthetic activity of liver.
11 Assessing the patient with abnormal Liver Function Tests Most of the time, the cause of elevated LFTs can be illicited without invasive testing (biopsy)If no cause of abnormality is found, most frequently the cause is alcohol liver disease, steatosis, or steatohepatitisCertain patterns exist with LFTsHepatocellular Injury: Very high AST, ALT with mild/moderately elevated alkaline phosphatase.Cholestatis: mild/moderately elevated AST/ALT with very high alkaline phosphataseBilirubin can be elevated with both combinations.
12 Hepatocellular Injury Medications:History: Need to assess temporal relationship with drug, see if patient improves once medication removedNSAIDs, antibiotics, statins, anti-tuberculosis medications, anti-epileptic drugs, acetaminophenFrequently cause isolated elevated aminotransferasesAcetaminophen overdoseToxicity is likely to occur with single ingestions greater than 250 mg/kg or those greater than 12 g over a 24-hour periodAST/ALT elevations is first sign of liver damage (usually 24-hours after ingestion)Alcohol Use:Frequently have AST:ALT ratio ≥ 2:1History: Need accurate assessment of alcohol intake, including CAGE questions.
13 Hepatocellular Injury Hepatitis A:Acute infectionHistory: travel, recent outbreak, MSM; nausea, vomiting, jaundiceLabs: Hepatitis A IgM, frequent elevated bilirubinHepatitis B:Can be acute or chronicHistory: See if patient from Asia, Subsaharan Africa; Sexual history, Drug useLabs: Hepatitis B surface antigen, surface antibody, core antibodyHepatitis C:History: IV drug abuse, blood transfusion prior to 1992, Sexual history, TattoosLabs: Hepatitis C antibody (Hepatitis C viral load if HIV positive or immunocompromised)HIV:Often causes isolated elevated aminotransferasesHistory: Sexual History, IV drug useLabs: HIV Antibody test (ELISA with reflex Western Blot)
14 Hepatocellular Injury Hereditary HemochromatosisHistory: Family history of liver disease? Diabetes? Heart Failure? Bronze skin?Labs:Serum iron, TIBCCalculate iron saturation = serum iron/TIBCIf iron saturation > 45%, check ferritinFerritinIf > 400 ng/mL in men, or > 300 ng/mL in women, then need to check liver biopsy or genetic testingLiver biopsyHomozygous hereditary hemochromatosis if iron index > 1.9If under age 40, and positive genetic testing, no biopsy needed.Genetic Testing
15 Hepatocellular Injury Hepatic steatosis/Non-alcoholic steatohepatitis (NASH)Increase in AST/ALT are usually less than 4-fold.Ratio of AST/ALT is usually < 1History: Female, obesity, diabetesLabs:Labs to rule out other causes of hepatitisAbdominal Ultrasound: look for fatty infiltration of liver
16 Hepatocellular Injury Autoimmune HepatitisHistory: Young to middle-aged femaleLabs:Serum protein electrophoresis (SPEP) – if polyclonal increase in gamma globulinAnti-nucleur antibody: PositiveAnti-smooth-muscle antibody (SMA)Liver biopsy: should be performed if the above are negative, but autoimmune hepatitis still suspected.
17 Hepatocellular Injury Alpha-1-antitrypsin deficiencyHistory: Family history, emphysema, young ageLabs:Alpha-1-antitrypsin level/phenotypeTreatment:Intravenous alpha-1 antiprotease helps with lung disease, but liver transplant is ultimately only treatment for liver disease.
18 Hepatocellular Injury Wilson’s DiseaseA genetic disorder of biliary copper excretionHistory: Age (usually age 5 – 25, but up to age 40), family history of liver disease; neuropsychiatric diseaseEvaluation:Serum ceruloplasmin: LowOpthalmologist: Exam for Kayser-Fleisher rings24-hour urine copperLiver biopsy: Evaluate liver copper levelsTreatment:Copper chelating agentsZincIn some cases, ultimately liver transplant
20 Hepatocellular Injury Shock Liver (ischemic hepatitis)Etiology: Shock, severe hypotensionSeverely elevated AST/ALT (50 times normal)Treatment: Re-establish good blood pressure/perfusion.Prognosis: Usually patients recover, but can progress to fulminant liver failure requiring transplant.
21 Hepatocellular Injury Non-Hepatic CausesUsually only mild increase in AST/ALTMuscle disordersHypothyroidism/HyperthyroidismCeliac DiseaseAdrenal InsufficiencyAnorexia nervosa
22 Hepatocellular Injury What if work-up is negative and AST/ALT remain elevated?Observe:Patients with two-fold or less increase in AST/ALT and no hyperbilirubinemiaLiver BiopsyPatients with > two-fold increase in AST/ALT, or abnormalities of other liver function tests.
23 Cholestatic Pattern Predominantly elevated alkaline phosphatase Need to check GGT to see if bone or liver in originBlood types O and B: can have elevated serum alkaline phosphatase after eating a fatty meal due to an influx of intestinal alkaline phosphataseNeed to determine if the cholestasis is intrahepatic or extrahepatic in origin.
25 Cholestatic Pattern - Intrahepatic Primary Biliary CirrhosisAutoimmune diseasePredominately in women, usually ages 35-65May have history of other autoimmune diseaseSymptoms: Prurutis, fatigue, hyperpigmentation, musculoskeletal complaintsLabs:RUQ UltrasoundAnti-mitochondrial antibodyLiver biopsy to verify diagnosis
26 Cholestatic Pattern – Both Intrahepatic and Extrahepatic Primary Sclerosing Cholangitischronic progressive disorder of unknown etiology that is characterized by inflammation, fibrosis, and stricturing of medium size and large ducts in the intrahepatic and extrahepatic biliary tree~ 90% have inflammatory bowel disease, especially ulcerative colitisSymptoms: Pruritus, fatigue, RUQ painDiagnosis:UltrasoundCholangiogram: multifocal stricturing and dilation of intrahepatic and/or extrahepatic bile ductsPrognosis:Poor; average life expectancy after diagnosis is ~12 years10-15% risk of developing cholangiocarcinomaLiver transplant is ultimate only treatment
27 Cholangiogram of Primary Sclerosing Cholangitis
29 Cholestatic Pattern - Extrahepatic Chronic PancreatitisHistory: Recurrent pancreatitisSymptoms: Abdominal pain, frequently referred to backHIV CholangiopathyUsually seen in AIDS patients with CD4 count well below 100/mm3Usually caused by: Cryptosporidium. Microsporidium, CMVSymptoms: RUQ pain, Diarrhea, Occassional fever, Occassional jaundiceDiagnosis:ERCPCholangiography – shows multifocal strictures of extrahepatic biliary tree
30 Isolated Hyperbilirubinemia Unconjugated (indirect) hyperbilirubinemiaOverproduction of bilirubinHemolysisDubin-Johnson Syndrome and Rotor SyndromeDecrease in uptake, conjugation, or excretion of bilirubinIncreased unconjugated (indirect) bilirubinLiver Disease
31 Isolated Unconjugated Hyperbilirubinemia DrugsProbenecid, RifampicinGilbert’s DiseaseAutosomal recessive disorder3 to 7 % of populationMost common in white malesJaundice, increased unconjugated bilirubin (always < 6)Occurs when patient under stress/infectionCrigler-Najjar type IICaused by gene mutationReduced activity of Bilirubin UDP glucuronosyl
34 SUMMARY Isolated elevated indirect (unconjugated) bilirubin Hemolysis DrugsGilbert’s DiseaseCrigler-Najjar type II
35 Scenario # 1A 43-year old woman who has consumed a pint of 80-proof whiskey daily for 18 years presents with right upper quadrant pain. The pain began approximately a week ago and has been transiently relieved by her taking two extra-strength acetaminophen tablets every 4 hours for the past 4 days. She has had some nausea and vomiting but no fever. There is no history of jaundice or cholelithiasis. The patient used intravenous drugs and shared needles during her late teen years.
36 Scenario # 1 Physical Exam Labs: Bilirubin: 2 mg/dL AST: 3800 Enlarged tender liver that percusses to 17 cm in the right midclavicular line and a tattoo on the right buttockLabs:Bilirubin: 2 mg/dL AST: 3800Alk. Phos: 198PT: normal
37 Scenario #1 The most likely diagnosis is: (A) Alcoholic hepatitis (B) Acute cholecystitis(C) Acetaminophen hepatotoxicity(D) Acute viral hepatitis B(E) Acute viral hepatitis C
38 Scenario # 2A 54-year old asymptomatic man volunteers to donate blood and is found to have elevated aminotransferase levels. He has no known medical problems and no history of hepatitis. He drinks no alcohol, takes no medications, and has not seen a physician in more than 10 years. He is active, works as a truck driver, and has noted no change in his physical condition. He has no family history of liver disease.
40 Scenario # 2 The appropriate management of this patient would be: Interferon therapy for presumed chronic non-B, non-C hepatitisAlcohol rehabilitation and counselingWeight loss and therapy for hyperlipidemiaEndoscopic retrograde cholangiopancreatography (ERCP) to evaluate the biliary treeCorticosteroid therapy
41 Scenario # 3A 43-year old woman complains of itching that keeps her awake at night. Physical examination is normal except for the liver, which is felt 7 cm below the right costal margin.CBC is normalCreatinine: 0.8 mg/dL, Bilirubin: 0.6 mg/dLALT: 78 U/L, Albumin: 4.2 g/dLAlkaline Phosphatase: 450 U/LCholangiogram: normal
42 Scenario # 3Which test would be most accurate in diagnosing her underlying disorder?(A) Serum protein electrophoresis(B) Anti-Smooth Muscle Antibody(C) Antimitochondrial antibody(D) Technetium-99m liver-spleen scan(E) Endoscopic retrograde cholangiopancreatography (ERCP)
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