Ran Oren, MD Inst. Gastroenterology & Liver Diseases, Hadassah University Hospital, Jerusalem...

Ran Oren, MD Inst. Gastroenterology & Liver Diseases,Hadassah University Hospital, Jerusalem

Liver Function Tests (& Jaundice)

- בגוף ביותר הגדול 1500האיברגרם

עליונה ימנית בבטן נמצא

הכבד :תפקידי

, ופקטורי קרישה פקטורי לגוף החיוניים חלבונים יצירתגדילה

מהגוף חומרים ולהפרשת לעיכול החשובה מרה יצירת

) , , שומנים ) חלבונים סוכרים המזון אבות ויסות

רעלים סילוק

לפעילות תרופות הפיכת

רגנרציה ויכולת עצומה רזרבהמדהימה

Liver cells• Hepatocyte

• Bile duct epithelial cell

• Stellate cell

• Kupffer cell

• Endothelial cell

Liver diseases

• Acute

• Fulminant

• Chronic

• Cirrhosis

Etiology for liver diseases

• Inflammation• Infectious• Non-infectious

• Metabolic/Genetic

• Neoplasm

• Alcohol/drug induced/NAFLD

• Vascular

• Traumatic

Elevated liver enzymes (1)

• Hepato cellular damage• Alanine aminotransferase (ALT)

• Aspartate aminotransferase (AST)

• Cholestasis• Alkaline posphatase (AP)• Gamma glutamyltrasferase (gamma GT)

• TransportTransport• Bilirubin

• Synthetic functionSynthetic function• Albumin, INR

• Fibro-markerFibro-marker• Stage of fibrosis• Fibrodynamics

Liver Function Liver Function TestsTests

• Misnomer (elavated liver enzymes)

• The upper limit of normal range

• The significance of normal serum levels in various diseases (HCV,

HBV, NAFLD)

Questions ?Questions ?• What is “healthy”?

• What is a healthy population?

Total Total PopulationPopulation

50.150.1

“New normal”

37.437.4

Excluding all abnormal Tests

Excluding Abnormal Tests except diabetes and dislipidemia

40.040.0

ALT- 95 ALT- 95 percentilepercentile

ALT- healthy upper limitALT- healthy upper limit

* <0.00001

Maccabi

N=272,273 N=87,020 N=17,929

Importance of true Importance of true healthy range for ALThealthy range for ALT

Pro’s:

1.Valid indicator for liver disease

2. Early detection of liver disease

Con’s:

1. Economical burden

2. Patient’s anxiety

3. Decrease in blood donors pool

Reevaluation of ALT “normal” Reevaluation of ALT “normal” range => ALT range => ALT healthy healthy range range

• Piton et al, Hepatology, May, 1998-

ALT adjustment by sex and BMI

• Prati et al, Ann. Int. Med., July 2002

Prati et al, Ann. Int. Med., July 2002

• 6835 healthy Italian blood donors.

• Factors associated with ALT Age, BMI, serum cholesterol, triglycerides, glucose, physical exercise

• Healthy ranges of ALT - Low risk for liver disease (HCV) and NAFLD

• New upper limits (95 percentile): Men- 30U/l Women-19U/l

Hepato cellular damage

Elevated liver enzymes

• Acute elevation of transaminasesAcute elevation of transaminases• Chronic elevation of transaminasesChronic elevation of transaminases

in:in:• A patient taking a drug

• Obese patient / Suspected alcoholism

• Celiac disease

• Metabolic diseases

• Bilirubin Transport

• Cholestasis

• Acute elevation of transaminasesAcute elevation of transaminases• Chronic elevation of transaminasesChronic elevation of transaminases in:in:

• A patient taking a drug• Obese patient / Suspected alcoholism• Celiac disease• Skin lesions

• Metabolic diseases• Bilirubin Transport• Cholestasis

Causes of chronic elevated

Aminotransferases levelsHepatic:

• Viral hepatitis• NAFLD • Autoimmune• Drug induced• Alcohol• Metabolic

o Hemochromatosiso Wilson’s diseaseo Alpha 1 antitrypsin

Non Hepatic:• Celiac sprue• Muscle diseases• Strenous exercise

• Acute elevation of transaminasesAcute elevation of transaminases

• Chronic elevation of transaminasesChronic elevation of transaminases in:in:

• A patient taking a drugA patient taking a drug• Obese patient / Suspected alcoholism• Celiac disease• Skin lesions

• Cholestasis

• Acute elevation of transaminasesAcute elevation of transaminases

• Chronic elevation of transaminasesChronic elevation of transaminases in:in:• A patient taking a drug

• Obese patient / Suspected alcoholismObese patient / Suspected alcoholism• Celiac disease

• Cholestasis

Non Alcoholic Fatty Liver Disease?Disease?NAFLDNAFLD

• Is the most common form of liver disease

• Is no longer considered benign• May progress to end-stage liver

disease

• Celiac disease

• Cholestasis

Celiac Disease

• Prevalence 1:300

• Should be suspected in cases of idiopathic hypertransaminasemia

• Celiac disease

• Cholestasis

Wilson’s disease

Elevated ferritin Elevated ferritin levelslevels

• Liver dysfunction, either acute or chronic, of whatever origin (but particularly alcoholic) can lead to an increase in ferritin level.

• Other etiologies of increased ferritin levels include• Genetic hemochromatosis • Secondary iron-overload conditions (hemolysis,

transfusions) • Some cases of steatosis (Moirand et al., 1997) • Hepatocellular carcinoma • Infection • Leukemia, lymphoma, breast or lung cancer • Hyperthyroidism • Still's disease • Gaucher's disease

Hepatic iron index

Skin disorder and elevated liver enzymes

elevated

Do you know diseases leading to both elevated aminotransferases

and skin disorders?

• Hemochromatosis

• Cirrhosis

• Acute viral hepatitis

• Primary biliary cirrhosis (PBC)

• Other diseases

Do you know diseases leading to both elevated aminotransferases

and skin disorders?

• Hemochromatosis

• Cirrhosis

• Acute viral hepatitis

• Primary biliary cirrhosis (PBC)

• Other diseases

Differential diagnosis of abnormal liver Differential diagnosis of abnormal liver tests and skintests and skin

• Viral hepatitis A, B and C• vasculitis-like lesions can occur due to deposition in the skin of immune

complexes

• Viral hepatitis A• a transient maculo-papular or urticarial rash can occur

• Chronic hepatitis B• Polyarteritis nodosa with vasculitis, and in younger children in papular

acrodermatitis (Gianotti-Crosti syndrome) with papular eruptions on the face and extremities

• Chronic hepatitis C• Mixed cryoglobulinemia, polyarteritis nodosa, erythema nodosum and

lichen planus

• Porphyria cutanea tarda (elicited by or combined) with HCV • Alcohol abuse

• Psoriasis and can lead to nummular eczema (discoid plaques on the lower limbs)

• Sarcoidosis (rare)

Elevated liver enzymes• Acute elevation of transaminasesAcute elevation of transaminases• Chronic elevation of transaminasesChronic elevation of transaminases

in:in:• A patient taking a drug• Obese patient / Suspected alcoholism• Celiac disease

• CholestasisCholestasis• Bilirubin Transport

Anicteric cholestasis can be a manifestation of several diseasesAnicteric cholestasis can be a manifestation of several diseases

Which of the following diseases do Which of the following diseases do not cause not cause

anicteric cholestasis?anicteric cholestasis?

A. AIDSB. Primary biliary cirrhosis (PBC) and primary

sclerosing cholangitis (PSC)C. Arteritis temporalisD. Complete obstruction of the common bile ductE. EndocarditisF. Gilbert's syndromeG. AmyloidosisH. Renal tumor without liver metastasis

Alkaline phosphatase can be elevated in several

diseasesA. Osteomalacia B. Late pregnancy C. Liver abscess D. Celiac diseaseE. Hyperthyroidism F. Crigler-Najjar syndromeG. Milk-alkali syndrome (Burnett's) H. Scurvy I. Lung cancer without liver metastasis

Which cause for a near-normal gammaGT can be excluded when aminotransferases are elevated

•Alcohol abuse

•Cholestasis

•Drug hepatitis

Which cause for a near-normal gammaGT can be excluded when aminotransferases are elevated

• Alcohol abuse• Chronic alcohol abuse leads to greatly enhanced

serum gammaGT

• Cholestasis • Cholestasis leads to greatly enhanced serum

gammaGT. Serum alkaline phosphatases are also enhanced in cholestasis

• Drug hepatitis• Hepatitis (viral or toxic) leads to a moderate elevation

of gammaGT, but estrogens (oral contraceptives or pregnancy) hamper the synthesis of gammaGT

• Synthetic functionSynthetic function• Albumin, INR, cholesterol, glucose

Jaundice

CASE 1

The yellow patient

Case 1

• 6 year old girl

• 2 weeks fatigue

• Jaundice

• ALT 1200iu (n=30)

• AST 850 iu (n=30)

• Bilirubin 72 mmol/L (n=18)

What does “elevated bilirubin levels” mean?

Bilirubin: A breakdown of the porphyrin ring of heme containing proteins

Found in blood in 2 fractions:

• Conjugated = direct bilirubin• Unconjugated = indirect bilirubin

•Total bilirubin = direct + indirect

Formation of bilirubin

• The formation of bilirubin occurs in reticuloedothelial cells in the liver and spleen.

• To be transported in blood bilirubin must be solubilized.

• Unconjugated bilirubin bound to albumin is transported to the liver.

• It is taken by hepatocytes via a carrier mediated membrane transport.

When do we see jaundice?

• Bilirubin above 3 mg/dl is seen as scleral icterus

How much?

• 80% of 300 mg of bilirubin produced every day is derived from breakdown of hemoglobin in old red blood cells.

• The reminder comes from prematurely destroyed erythroid cells in the bone marrow and from turnover of hemoproteins such as myoglobin and cytochromes in body tissues.

In the hepatocyte

• Bilirubin enters the endoplasmic reticulum and is conjugated to glucoronic acid.

• Conjugated bilirubin diffuse from the ER to the canalicular membrane where it is actively trasnported into canalicular bile by an energy dependent mechanism involveing MDR protein 2.

In the intestine

• Conjugated bilirubin is not taken by the intestine cells.

• In the distal ileum it is hydrolyzed to unconjugated bilirubin by bacteria.

• Unconjugated bilirubin is reduced by the normal gut flora to form a group of colorless tetrahdyroles called urobilinogens.

• 90% of the urobilinogen is secreted in the feces.• 10% of the urobilinogen is passively absorbed to the

protal blood and re-excreted by the liver.• A small fraction of uroblinogen escapes hepatic uptake

and filters across renal glomeruli to urine.

CASE 2

The yellow patient

Conjugated = directWater soluble & excreted by the kidneyNormal in serum: 30% direct

Unconjugated = indirectInsoluble in water & bound to albumin in blood

Van Den Bergh assay: measure conjugated bilirubinAfter addition of alcohol, total amount is measuredThe indirect is the difference

Elevation of unconjugated bilirubin (<15%)

• Rarely due to liver disease• Hemolysis• Congenital: Crigler Najjar syndrome; Gilbert syndrome

Elevation of conjugated bilirubin (>15%)

• Liver or biliary tract disease

• Intrahepatic: hepatitis, acute and chronic liver disease, toxins

• Obstruction: intrahepatic, extrahepatic

• Inherited: Dubin Johnson, Rotor

Urine bilirubin

Unconjugated bilirubin always binds to albumin & is not filtered in the kidney All bilirubin in the urine is conjugated Presence of bilirubinuria implies liver disease Normal: no bilirubin in urine During prolonged cholestasis a small fraction of bilirubin from plasma is filtered by glomeruli

Differential diagnosis of jaundice

• Pure hypebilirubinemia

• Hepatocellular

• Cholestatic • Intrahepatic cholestasis

• Extrahepatic cholestasis

Only bilirubin elevated

DIRECT INDIRECT

Dubin-Johnson Rotor

Hemolysis evaluation

GILBERT HEMOLYSIS

Causes of isolated hyperbilirubinemia

Direct hyperbilirubinemia

• Inherited conditions• Dubin-Johnson syndrome• Rotor's syndrome

Causes of isolated hyperbilirubinemia

Indirect hyperbilirubinemiaA.Hemolytic disordersInherited: Spherocytosis; elliptocytosis; Glucose-6-

phosphate dehydrogenase and pyruvate kinase; sickle cell anemia

Acquired: Microangiopathic hemolytic anemias; Paroxysmal nocturnal hemoglobinuria; Spur cell anemia; Immune hemolysis

B. Ineffective erythropoiesis: Cobalamin, folate, thalassemia, and severe iron deficiencies

C. Drugs: Rifampicin, probenecid, ribavirin

D. Inherited conditions: Crigler-Najjar types I and II; Gilbert's syndrome

• Hepatocellular

Hepatocellular conditions that may produce Jaundice

• Viral hepatitisHepatitis A, B, C, D and EEpstein-Barr virusCytomegalovirusHerpes simplex

• Alcohol• Drug Toxicity• Enviromental toxins

Vinyl chlorideWild mushrooms – Amanita phalloides or A. verna

• Wilson's disease• Autoimmune hepatitis

CASE 3

The yellow old patient

Case 3:• 78 years old male• Jaundice for 6 weeks• Lost 7 kg last month

GGT 1000 iu (normal up to 80)ALP 2000 iu (normal up to 130)Bilirubin 85 mmol/liter (normal up to 17)AST 75 (normal up to 40)ALT 65 (normal up to 40)INR 1.0

Cholestatic pattern

• Hepatocellular

Extrahepatic cholestatic conditions that may produce Jaundice

• Malignant• Cholangiocarcinoma• Pancreatic cancer• Gallbladder cancer• Ampullary cancer• Malignant involvement of the porta hepatic lymph

• Benign• Choledocholithiasis• Postoperative biliary structures• Primary sclerosing cholangitis• Chronic pancreatitis• AIDS Cholangiopathy• Mirizzi syndrome• Parasitic disease (ascariasis)

Intrahepatic cholestatic conditions that may produce Jaundice

Viral hepatitisFibrosing cholestatic hepatitis – hepatitis B and CHepatitis A, Epstein-Barr virus, cytomegalovirus

Alcoholic hepatitisDrug toxicityPrimary biliary cirrhosisPrimary sclerosing cholangitisVanishing bile duct syndrome: Chronic rejection; Sarcoidosis; DrugsInherited: Progressive familial intrahepatic cholestasis; Benign recurrent

cholestasisCholestasis of pregnancyTotal parenteral nutritionNonhepatobiliary sepsisBenign postoperative cholestasisParaneoplastic syndromeVenooclusive diseaseGraft-verus-host diaseaseInfiltrative disease: TB; Lymphoma; Amyloid

Cholestatic pattern

Review drugs

Ultrasound

Intrahepatic Extrahepatic

Non-dilated ducts Dilated ducts

ERCP / MRCP / CT/ EUS

AMA - AMA +

Liver biopsyERCP

Liver biopsy

Case 2:GGT 1000 iu (normal up to 80)ALP 2000 iu (normal up to 130)Bilirubin 85 mmol/liter AST 75 (normal up to 40)ALT 65 (normal up to 40)INR 1.0

Cholestatic pattern

Case 3:• 65 years old male• Jaundice for 6 weeks

GGT 1000 iu (normal up to 80)ALP 2000 iu (normal up to 130)AST 75 (normal up to 40)ALT 65 (normal up to 40)INR 1.0

Cholangiocarcinoma

Conjugated hyperbilirubinemia

DubinJohnson

Rotor’ssyndrome

Dark pigmentationof the liver

Normalpigmentation

Defect Impaired biliarycanalicilartransport of organicanions (conjugatedbilirubin) – effluxinto circulation

Defects in hepaticuptake and storageof bilirubin andrelated cholephylicorganic anions

Signs Asymptomaticjaundice

Asymptomaticjaundice

Bilirubin 2-5 mg/dL – 60%conjugated

2-5 mg/dL – 60%conjugated

Non-conjugated hyperbilirubinemia

CriglerNaiiarType 1

CriglerNaiiarType 2

Gilbert’ssyndrome

BilirubinUGT-activityIn heaptic cell

Undectable Severlydecreased but

detectable

Reduced by30%

Uncojugatedbilirubin

10-40 mg/dL 7-15 mg/dL 1-5 mg/dL

Phenobarbitalaction

No effect Reducesbilirubin with

more 20 %

Jaundicedisappears

Prognosis Kericterusdeath

Rarelykernicterus

Excellent

• Synthetic functionSynthetic function• Albumin, INR, cholesterol, glucose

Features of an Ideal Marker of Liver FibrosisFeatures of an Ideal Marker of Liver Fibrosis

• Liver specificLiver specific

• Stage of fibrosisStage of fibrosis

• Activity of matrix depositionActivity of matrix deposition

• Easy to performEasy to perform

StudyStudy Serological Test Serological Test Disease Disease Correlation with Correlation with Fibrosis Fibrosis

SensitivitySensitivity Specificity

McCormick (146) ALT HCV 0.35

Assy (72) HCV 0.51Wong (74) HCV 76 48

Imperiale (61) AST/ALT ratio HCV 56 90

Giannini (64) HCV 77.8 96.9

Pohl (89) HCV 56 90Park (63) HCV 0.19 47 97Angulo (76) NAFLD 0.182

Sheth (62) 53 100 Giannini (64) Platelets HCV 91.1 88.3

Beaton (147) Hemochromatosis 79 82

Giannini (64) AST/ALT ratio + platelet count HCV 96.7 86.4

Pohl (89) HCV 41 99Bonacini (148) Discriminant* score Mixed 0.64 46 96

Saadeh (149) HCV 32 96

Croquet (65) Prothrombin index Mixed 0.70

Teare (69) PGA Mixed 91 81

Naveau (68) PGAA index Alcohol 79 89

Imbert-Bismut (71) Fibrotest HCV 75 85

Rossi (150) HCV 67 78

Forns (86) Forns fibrosis index HCV 94 51

Wai (88) APRI HCV 89 75

• Age (y)

• Male gender n, (%)

• AST (IU/L)

• ALT (IU/L)

• Gamma-GT (IU/L)

• Bilirubin (mg/dL)

• Glucose (mg/dL)

• Cholesterol (mg/dL)

• Albumin (g/L)

• Leucocytes (109/L)

• Platelets (109/L)

• Prothrombin time (%)

• Viral load (IU/mL X103)

• HCV Genotype 1

Identification of Chronic Hepatitis C Patients Identification of Chronic Hepatitis C Patients

Without Hepatic Fibrosis by a Without Hepatic Fibrosis by a Simple Simple Predictive ModelPredictive Model

Xavier Forns,et alXavier Forns,et al, , Hepatology. 2002 Oct;36(4 Pt 1):986-92Hepatology. 2002 Oct;36(4 Pt 1):986-92. .

• AST

• 2 macroglobulin

• ALT

• Haptoglobin (decrease)

• globulin

• GGT

• Total bilirubin

• Apo A1 (decrease)

• Albumin (decrease)

1 globulin

2 globulin (decrease)

• globulin

Biochemical markers of liver fibrosis in patients withBiochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective studyhepatitis C virus infection: a prospective study

Vlad Ratziu, Laurence Pieroni, Frederic Charlotte, Yves Benhamou, Thierry Poynard, for Vlad Ratziu, Laurence Pieroni, Frederic Charlotte, Yves Benhamou, Thierry Poynard, for thethe

MULTIVIRC group, MULTIVIRC group, THE LANCET • Vol 357 • April 7, 2001THE LANCET • Vol 357 • April 7, 2001

Markers of matrix depositionMarkers of matrix deposition Procollagen I C terminal

Procollagen III N terminal

Tenascin

Tissue inhibitor of metalloproteinase TIMP

Markers of matrix removalMarkers of matrix removal Procollagen IV C peptide

Procollagen IV N peptide (7-S collagen)

Collagen IV

Undulin

Metalloproteinase MMP

Urinary desmosine and hydroxylysylpyridinoline

UncertainUncertain Hyaluronan

Laminin

YKL-40 (Chondrex)

?האם הביופסיה מייצגת? הומוגנית

Sampling Variability of Liver Biopsy in NAFLD

האם ביופסית הכבד חשובה ?לאבחנת המחלה

סמך על :האבחנה

ההפטיטיס לוירוס חיוביים בדם C נוגדניםAnti HCV Ab’s

עםהנגיף לנוכחות מולקולרית עדותHCVPCR positive

?מהם חסרונות הביופסיה

• במהלך פעמיים או פעם מבוצע ולכן חודרניהשנים

• Inter/intra-observer variability

• רק מהכבד 1:50000דוגם• 3:10000תמותה • 1:1000תחלואה

• אחוז 30כאב • " - ב וכי קרישה נגד התוויות קיימות

• 2000$מחיר-

האם קיימות אלטרנטיבות לביופסית הכבד? ?מה דרוש מהאלטרנטיבה

• - האלטרנטיבה סטטי מצב דוגמת ביופסיהדינמיקה לייצג אמורה

לכבד • ספציפית

ומינימליים • עדינים שנויים מייצגת

•Reproducible

Staging Systems• Ordinal categorical variables

• Categories are not evenly distributed

• Ordinal categorical variables

• Categories are not evenly distributed

0 1 2 3 4

Scheuer Fibros is Score

MildModerate

severe

• Blood tests

– Fibrotest

– APRI

– ELF

– Forn’s

– FIBROSpect

– Fibrometer

– Hepascore

– FIB-4 (coinfected patients)

• Blood tests

– Fibrotest

– APRI

– ELF

– Forn’s

– FIBROSpect

– Fibrometer

– Hepascore

– FIB-4 (coinfected patients)

Non-Invasive: Test of Fibrosis

• Liver Imaging

–Transient

elastrography

–MR spectoscopy

–Diffuse-

weighted MRISterling, Hepatology. 2006 43(6):1317-25Halfon Am J Gastro. 2006; 101: 547-55Wai Hepatol. 2003; 38: 518-26Forms, Hepatol. 2002; 36:986-92Patel, J Hepatol. 2004; 41: 935-42

Rosenberg, Gastro 2004 127:1704-13Zaman, Am J Gastro. 2007; 120: e9-12Lewin, Hepatol. 2007; 46: 658-65Adams, Clin Chem. 2005; 51:1867-167Cales, J Hepatol. 20054; 42: 1373-1383

Fibroscan-LimitationsFibroscan-Limitations

-Ascites-Ascites -Obese patients*-Obese patients*

-Narrow intercostal space*-Narrow intercostal space*

*need a special probe.*need a special probe.

FibroTestFibroTest ActiTest ActiTest• Serologic markers based algorithmSerologic markers based algorithm

• Assess the degree of fibrosis and Assess the degree of fibrosis and necroinflammatory histological activitynecroinflammatory histological activity

• Combined 5 componentsCombined 5 components

FibroTestFibroTest ActiTest ActiTest

F0 F1 F2 F3 F4

FibroFibroTest: Test: from blood donors to from blood donors to cirrhotics (n=1570) Clin Chem 2004, cirrhotics (n=1570) Clin Chem 2004,

Comp Hepatol 2004Comp Hepatol 2004

FibroTestFibroTest ActiTest ActiTest LimitationsLimitationsImpact of inflammation and therapyImpact of inflammation and therapy - inaccurate in patients receiving - inaccurate in patients receiving

anti-viral therapy .anti-viral therapy . - sensitive to haemolysis (Ribavirin). - sensitive to haemolysis (Ribavirin). Impact of co-morbidityImpact of co-morbidity - Gilbert Syndrome.- Gilbert Syndrome. -arthritis, connective tissue -arthritis, connective tissue

diseases-not proveddiseases-not proved.

לסכום

הכבד • ממחלות גדול חלק בין משותף מכנה קיים , המעבדה ובדיקות הבדיקה הקליניקה מבחינת

לתפקודי • הכבד אנזימי בין ההבדל את להבין ישהכבד

בדם • בילירובין רמת לעלית הסיבות את להבין יש

כתחליף • חודרניות הבלתי בבדיקות הינו העתידהכבד לביופסית

Ran Oren, MD Inst. Gastroenterology & Liver Diseases, Hadassah University Hospital, Jerusalem...

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