Intern Tutorial

MARCH 13, 2009

CLINICAL & LABORATORY APPROACH TO BLEEDING PATIENT

Sinus rhythm

Sinus rhythm= rhythm produced by electrical impulses formed within the SA node

P wave is always upright in leads I, II, aVF

Normal sinus rhythm rate 60-100/min

Sinus Rhythm

4 Questions to identify an ectopic rhythm

1. Are normal P waves present?

2. Are the QRS complexes narrow?

3. What is the relationship between the P wave and the QRS complexes?

4. The rhythm regular or irregular?

Ectopic impulse: premature beats

PAC

•Premature P wave

•Change morphology of P wave

•Usually narrow QRS


PJC Premature QRS

complex (usually narrow QRS)

Absent P wavePJC


PVCs

•Premature QRS complex

•No premature P wave

•Usually wide QRS complex with opposite T wave deflection

Ectopic impulse: Rapid ectopic rhythm Tachycardia group (rate~150-250/min)

Supraventricular tachycardia (SVT)Ventricular tachycardia (VT)

Flutter group (rate~250-350/min)Atrial flutterVentricular flutter

Fibrillation group (rate~350-450/min)Atrial fibrillation (AF)Ventricular fibrillation (VF)

Paroxysmal Supraventricular Tachycardia (PSVT)

Rate ~150-250/min, Regular rhythm

Abrupt onset & termination

Not seen sinus P wave (usually not seen P wave or retrograde P wave)

Usually narrow QRS complex

Paroxysmal Supraventricular Tachycardia (PSVT)

•Rate ~150-250/min, Regular rhythm

•Usually narrow QRS complex

•Abrupt onset & termination

•Not seen sinus P wave (usually not seen P wave or retrograde P wave)

Paroxysmal atrial tachycardia (PAT)

Regular Rate 150-250/min Warm up period Visible P wave (but

not sinus P wave)

Paroxysmal atrial tachycardia (PAT)

•Regular rhythm, rate ~150-250/min

•Narrow QRS complex

•Warm up period

•Visible P wave (but not sinus P wave)

PAT with block

Regular or irregular (if varying block) 2:1, 3:1, …

(2 P wave same morphology:1 QRS,

3 P wave same morphology:1 QRS)

PAT with 3:1 block

Multifocal Atrial Tachycardia (MAT)

Irregular rhythm ≥3 different P wave morphologies Rate >100/min (if rate

<100/min=Wandering pacemaker)

Ventricular Tachycardia (VT)

•Regular rhythm (may be slightly irregular)

•Rate ~150-250/min

•Wide QRS complex

Polymorphic VT

Like VT but QRS complexes different in morphology

Typical: QRS complexes spiral around the baseline, changing their axis and amplitude.

Polymorphic VT + prolong QT interval = Torsades de pointes

Atrial Flutter Regular or irregular

rhythm Atrial rate 250-

350/min Ventricular rate 1/2,

1/3, … of atrial rate “Saw tooth”

appearance AV block 2:1, 3:1,…

Atrial Flutter

•Regular or irregular rhythm

•Atrial rate 250-350/min

•Ventricular rate 1/2, 1/3, … of atrial rate

•“Saw tooth” appearance

•AV block 2:1, 3:1,…

Atrial Fibrillation (AF) Irregular rhythm Not seen P wave

(fibrillate baseline) Atrial rate ~350-

500/min Ventricular rate

variable

Atrial Fibrillation (AF)

•Irregular rhythm

•Not seen P wave (fibrillate baseline)

•Atrial rate ~350-500/min

•Ventricular rate variable

Ventricular Fibrillation

Multiple ventricular foci rapidly discharge producing a totally erratic ventricular rhythm without identifiable waves

Bradyarrhythmia

Sinus node dysfunction AV block

1st degree AV block

2nd degree AV block

3nd degree AV block

2nd degree AV block type I

2nd degree AV block 2:1

2nd degree AV block type II

Advanced 2nd degree AV block

Sinus arrest /pause

Sinus exit block

Sinus bradycardia

- Tachy brady syndrome

Sinus node dysfunction

Sinus bradycardia Sinus arrest /pause Sinus exit block Tachy-brady syndrome

tachyarrhythmia-atrial fibrillationbradyarrhythmia-sinus arrest

Sinus Bradycardia

Sinus bradycardia Sinus rhythm Rate<60/min

Sinus Arrest an d SA Exit Block

Tachy-brady syndrome

Escape Rhythms

Escape beats= rescuing beats originating outside the sinus node

AV Node (junctional rhythm): 40 to 60 beats/minute

Ventricles: 30 to 40 beats/minute

Junctional rhythm

Junctional rhythm

Rate 40-60/min Most often not seen P wave (Occasional

retrograde P wave) Narrow QRS complex

Idioventricular rhythm

Rate 30-40 /min Wide QRS complex

Accelerated Idioventricular rhythm

Rate 50-100/min Regular wide QRS complex

AV Block

First degree AV block Second degree AV block

Type I (Wenchkebach)Type II2:1 second degree AV blockAdvanced second degree AV block

Third degree AV block

1st DEGREE AV BLOCK

PR interval >0.2 sec All beats are conducted through to the ventricle

2nd DEGREE AV BLOCK: Mobitz type I (Wenckebach)

Progressive prolongation of the PR interval until a QRS is dropped

2nd DEGREE AV BLOCK: Mobitz type II

QRS complexes are dropped at regular intervals without prolongation of the PR interval

2nd DEGREE AV BLOCK 2:1

2 sinus P wave: 1 QRS complex Constant PR interval

(Impossible to tell whether it is Mobitz I or II)

High grade AV block (Advanced AV block)

≥ 3:1 AV blockConstant PR interval

Third degree AV block

No beats are conducted through to the ventricles.

AV dissociation: atrium and ventricles are driven by independent pacemakers

High grade AV block(constant PR interval)

3º degree AV block(AV dissociation)

Normal conduction

The Electrical Conduction System

Normal Bundle Branch Conduction

Ventricular depolarization Ventricular depolarization

V1 V6

Right Bundle Branch Block (RBBB)

Right Bundle Branch Block(RBBB)

Lead V1 M-shape QRS (RSR’)

Lead I, V6 Wide S wave

Left Bundle Branch Block (LBBB)

Left Bundle Branch Block (LBBB)

Lead V1 QS or rS

Lead I, V6 Monophasic R wave, no Q

RBBB, LBBB, IVCD

Secondary ST-T change

Left Anterior Fascicular Block

LAFB

1. Left axis deviation (usually>-60º)

2. Small Q in leads I & aVL, small R in II, III, aVF

3. Usually normal QRS duration

Left Posterior Fascicular Block

LPFB

1. Right axis deviation (usually> +120º)

2. Small R in leads I & aVL, small Q in II, III, aVF

3. Usually normal QRS duration

Axis change in fascicular block

Abnormal morphology

Abnormal P wave

LAE (P mitrale) RAE (P pulmonale) Abnormal P wave Axis

Abnormal P wave axis

Non-sinus P wave Arm lead reversal Dextrocardia

Abnormal P wave axis

Abnormal P axis : P wave is negative in I, II, aVF, positive in aVR

Origin of P wave is not SA node

In the same lead, there are two P wave morphology

This patient has atrial tachycardia

Arm lead reversal

Abnormal P wave axisQRS axis is also the same as P waveBoth P wave & QRS are normal in chest lead

Dextrocardia

Abnormal P wave axisQRS axis is also the same as P waveR wave regression in chest lead

Atrial enlargement

LAE RAE

PR interval

Short PR interval Prolongation of PR interval (AV block)

Preexcitation syndrome In the preexcitation

syndrome, there are accessory pathways by which the current can bypass the AV node and arrive at the ventricles ahead of time

Accessory

Pathway

WPW pattern

•Short PR interval

•Wide QRS complex with delta wave

•WPW syndrome= history of PSVT + WPW pattern ECG

Abnormal QRS complex

Abnormal Q wave Abnormal R wave Abnormal S wave

Normal ECG

Abnormal Q wave

Significant Q wave is 1 mm wide (0.04 sec in duration) or Q wave ≥1/3 of the QRS complex

Exclude lead aVR Significant Q wave = Infarction

Leads that may normally dis -play moderate to large size

d Q waves Lead III

Lead aVF

Lead aVL

Lead V1 (and sometimes also lead V2)

Lead aVR

Tall R in V1 Posterior wall MI Pre excitation Dextrocardia Duchene Muscular Dystrophy Right Bundle Branch Block Right Ventricular Hypertrophy Rotation of heart

Normal ECG

RVH

Dextrocardia

Abnormal P wave axisQRS axis is also the same as P waveR wave regression in chest lead

Isolated posterior wall MI

Pre excitation

Normal R wave progression

Causes of poor R progression LVH (left ventricular hypertrophy) RVH (right ventricular hypertrophy) Pulmonary disease (i.e., COPD, asthma) Anterior or anteroseptal infarction Conduction defects (I.e., LBBB, LAHB, IVCD) Cardiomyopathy Chest wall deformity Normal variant Lead misplacement

Poor R progression

ECG in COPD: Deep S in lead I, V5-6

ST segment deviations

J point elevation

Common causes of ST segment depression

1. Ischemia2. “Strain”3. Digitalis effect4. Hypokalemia / Hypomagnesem

ia5. Rate-related changes6. Any combination of the above

Various type of ST segment depression

ST elevation Acute myocardial injury Myocardial aneurysm Pericarditis Early repolarization pattern Myocarditis Repolarization abnormality

chanellopathy : Brugada syndromeelectrolyte abnormalitydrugs

Severe chest pain in a 45 yoman

Acute IWMI with ST depression V

1-V3

Myocardial injury

Early repolarization

LBBB with STT changes

Acute pericarditis

Evolution of acute pericarditis

ST segment elevations

Convex=MIConcave=pericarditis

T wave morphology

Inverted T abnormality Cardiac ischemia /injury Cardiomyopathy Brain pathology Repolarization abnormality

secondary repolarizationchanellopathy : LQTSelectrolyte abnormalitydrugs

Leads that may normally dis play

T wave inversion Lead III

Lead aVF

Lead aVL

Lead V1 (and sometimes also lead V2)

Lead aVR

- Causes of nonspecific ST T changes

Ischemia LVH Cardiomyopathy Mitral valve prolapse Drug effect (digitalis, antiarr

hythmic agents) Electrolyte disorder (i.e.,hyp

okalemia, hypomagnesemia)

CNS disorder (stroke, intracerebral bleed,etc.)

Hyperventilation Severe medical illness Severe emotional stress Exercise Hypoxemia Acidosis Temporature extremes (h

ypothermia,hyperthermia) Many others...

Hyperkalemia

Tall peak T: HyperK

Hyper K

Hyper K: Tall T, wide QRS, bradycardia

QT prolongation

Common causes of QT prolongation1. Drugs

○ Type I A & Type III antiarrhythmic agents ○ Tricyclic antidepressants○ Phenothiazines

2. “Lytes”○ Hypokalemia○ Hypomagnesemia○ Hypocalcemia

3. CNS○ Stroke○ Intracerebral or brainstem bleeding○ Seizure○ Coma

Hypokalemia

ECG in ischemic heart disease Q wave= infarction ST elevation= acute injury (transmural) ST depression= acute injury

(subendocardial) Inverted T wave =Ischemia

Consider for other Differential diagnosis

AMIAcute Myocardial Infarction (AMI)

ST elevated MI

ECG:ST elevation

Non ST elevated MI

ECG:ST depression or

Inverted T or

Normal ECG

Q wave MI Non Q MI

Q wave MI Non Q MI

Basic Lead Groups

Inferior leads - II, III, aVF

Septal leads - V1, V2

Anterior leads - V1 to V4

Lateral leads:

Lateral precordial leads - V4 toV6

high lateral leads - I, aVL

Basic Lead Groups

Coronary anatomy

ECG in AMI

Dating infarctionAcute infarction - onset within hours up to

a day ST segment elevation is hyperacute or c

oved, and often marked Q waves are small or absent T wave inversion is minimal or absent Reiprocal ST segment depression is ofte

n present, and may be marked.

Dating infarctionRecent (or “subacute”) infarction - onset within a day or

so, up to several days to a week. Q waves are often present; they may be small or large. ST segment elevation is minimal or absent. T wave inversion is often present and may be marked. Reciprocal ST segment depression is minimal or absent

.

Dating infarction

Old infarction - onset over a week ago Q waves are present and are often large. ST segment elevation is absent. T wave inversion is minimal or absent. There is no reciprocal ST segment depres

sion.

Acute MI (Anterior wall)

ST elevation:Acute inferior wall MI

Old inferior wall MI

Summary

Data gathering1. Rate

2. Rhythm

3. Axis

4. Interval

5. Chamber enlargement

6. Morphology

SummaryAbnormalities Rate & rhythm (Arrhythmia)

TachyarrhythmiaBradyarrhythmia

MorphologyP waveQRS complexST segmentT waveInterval: PR, QRS, QT

Further reading

The Only EKG Book you’ll ever need. Malcolm S. Thaler. Fourth edition.

Rapid Interpretation of EKG’s. Dale Dubin.

Marriott’s Practical electrocardiography Galen S. Wagner.

ECG ทางคลิ�นิ�ก : ยงย�ทธ สหั�สก�ลิ

Total circulating level of thyroid hormone

Total circulating level of free hormone

Dynamic test of thyroid functionTests of peripheral tissue functionTests of hypothalamic-pituitary

function

Serum TT4Serum TT3




function

- Direct methods: FT4, FT3

- Indirect methods: Calculated free thyroxine index




function

Thyroidal radioisotope uptakeT3 suppression test




function

Ankle tendon reflex durationSerum lipid levelsEKG




function

TSH (Thyrotropin)TRH (Thyrotropin releasing

hormone )test

4Thyroxine (T ) circulates ~999.7% bbbbb bb bbb bbbbbb bbbbbbbb

- - 6075TBG ( %);- - / (1 5 3 0 %)- ( 1 0 %);

[ Thyroxine Binding globulin (TBG), Transthyretin (TTR)/Prealbumin (TBPA)]

T 3riiodothyronine (T ) is ~ 99.7% bbbb d, pr i mar i l y t o TBG

TT4 and TT3 circulate at nanomola r concentrations,

bbb bbb bbbbbbbb bb bbb bbbbbbbb4 3b bbbbb

- The i nt er met hod var i abi l i t y f or tbbbb bbbbbbb bbbbbbbbbbbb

TT4 -1017% andTT3 -20 30%,

I t is believed that the minute free fraction o f hormone is responsible for the biologic ac

tivity of thyroid hormones at the cellular le vel

0024. %FT 02 3. % FT

( Robbins J. 1996. Thyroid hormone transport proteins and the p hysiology of hormone binding. In: Gray CH, James VHT, eds. Hor

-mones in Blood. London: Academic Press. 96 110.)

Sbbbbb bbbbbbbbbb bbb bbbbbb bbbbbbb (TBGexcess or defi ci ency)

Familial Dysalbuminemic Hyperthyro xinemia, FDH

T4 and T3 autoantibodies Ibbbbbbbbbb bbbbbbbbbb bbbb bb bbbb

matoid Factor and Heterophilic antibo dies(HAMA)

Salicylate, FurosemideHeparinAmiodarone, Iopanoic acid,

Propanolol > 160 mg/dAmphetamineHeroin, Methadone

Phenytoin, Phenobarbital, Carbamazepine

Dopamine (FT4 อาจปกติ�ก�ได้�)Lithium

GlucocorticoidDopamine

Hyperestrogenic stateDrugDiseaseGenetic

Hyperestrogenic state

PregnancyEstrogen therapyNew bornOral contraceptive pillsEstrogen producing tumor

DrugHeroinMethadonePerphenazine

Disease

Acute intermittent porphyriaAcute viral hepatitisChronic active liver diseaseAIDSOat cell carcinoma

Genetic

X-linked familial increase in serum TBG

Exogenous androgensMajor illnessDrugDiseaseGenetic

Drug

CorticosteroidsDrugs displacing thyroxine binding sites

- Salicylate- Diphenylhydantoin- Furosemide

Disease

Cushing’s syndromeSevere (Cirrhotic) liver diseasesActive acromegalyNephrotic syndromeProtein-losing enteropathies

Genetic

Familial X-linked deficiency of TBG

SerumTgmeasur ement i s used as a t umor mabbbb bb bbb b bbbbbb bbb bb bbbbbbbb b

ith differentiated thyroid carcinomas (DTC)

bbbbbbb bb b bbbbbb bbb bbbbb bbbbbb on IMA or RIA techniques

- Ther e i s a t r end f or non i sot opi c Ibb bbbbbbb bb bbbbbbb bbb bbbbbbb

Ma ssofdifferentiatedt hyr oi d t i ssue pr esent (nor ma l tissue + tumor)

A ny inflammation of, or injury to thyr oid tissue, such as follows fine needle

aspiration biopsy, surgery, radioiodin e t her apy or t hyr oi di t i s

b egree of stimulation of TSH receptor s (by TSH, hCG or TSAb)

(DTC= differentiated thyroid carcinoma)

TSH

Tg

A- ntithyroidperoxidase(TPO), thyroglobulin(Tg) and TSHr ecept or s ar e use d i n t he di agnosi s of aut oi mmune t

bbbbbb bbbbbbbbb

Thyroid Autoantibody Prevalences and Associations with Hypothyroidism

A ntibody measurement techniques h - ave evolved from semi quantitative a

gglutination and complement fixation tests and whole animal bioassays to s

pecific ligand assays using recombina nt antigens and cell culture systems t

ransfected with the human TSH recepbbb

TRAb (TSAb & TBII)(TRAb= Thyrotropin receptor Ab; TSAb= Thyroid stimulating Ab; TBII = Thyrotropin binding inhibitory Ig)

Thyroglobulin autoantibody (TgAb) in terference with serum Tg measureme

nts remains the most serious problem limiting the clinical value of serum Tg

bbbbbbbbbbb. Serial TgAb measurements can be us

ed as an independent prognostic test - for the presence of Tg secreting thyro

bb bbbbbb

- - Comparisons of TgAb negative and TgAb Positive Subjects

TRAb tests are used in the differential diagnosis of hyperthyroidism, the pre

diction of fetal and neonatal thyroid d ysfunction due to transplacental pass

age of maternal TRAb and prediction the course of Graves' disease treated with antithyroid drugs

( Michelangeli V, Poon C, taft J, Newnham H, Topliss D, and Colm an P. 1 9 9 8 . The prognostic value of thyrotropin receptor an

tibody measurement in the early stages of treatment of Graves' -disease with antithyroid drugs. Thyroid. 8:119 24.)

TherelationshipbetweenserumTSHandfreeT4concentrationisshownfornormalsubjects(N) and i n t he t ypi cal abnor mal i t i es of t hyr oi d f unct i on: A, - primary hypothyroidism ; B, central or pituitary dependent hypothyroidis

m; C, thyrotoxicosis due to autonomy or abnormal stimulation of the glan - d; D, TSH dependent thyrotoxicosis or thyroid hormone resistance. Note t

hat linear changes in the concentration of T4 correspond to logarithmic c hanges in serum TSH.

An algorithm for the initial assessment of thyroid fun ction, based on initial assay of serum TSH. This

strategy also has some limitations.

TSH Reference Ranges

Measurement of serum T4 , rather than serum TSH, is the more. r eliable single test of thyroid function when steady state condition

s do not apply, as in the early phase of treatment for thyrotoxicosi s or hypot hyr oi di sm.

This assay does not have a general diag nostic role, despite previous suggestion

s that it might be useful in distinguishin g true hypothyroidism from the hypothy

roxinemia of severe illness.

( Burmeister LA, Reverse T3 does not reliabl y differentiate hypothyroid sick syndrome f

rom euthyroid sick syndrome. Thyroid 199 -5 5 43541; : .)

- Grave's Disease- Toxic nodular Goiter- Toxic Thyroid Adenoma

- Acute viral thyroiditis- Silent thyroiditis- Struma ovarii- Excessive Levothyroxine ingestion

การส�งติรวจ Thyroid function tests จะส�งเมื่ !อมื่"ข้�อบ่�งชี้"&ทางคลิ�นิ�ก

การเลิ อกชี้นิ�ด้ข้องการติรวจใหั�เหัมื่าะสมื่ จะเป(นิประโยชี้นิ*แลิะประหัย�ด้ค�าใชี้�จ�าย

การติรวจ TSH เพี"ยงติ�วเด้"ยว สามื่ารถใชี้�เป(นิการติรวจค�ด้กรองข้�&นิแรกว�าผู้/�ป0วยมื่"ความื่ผู้�ด้ปกติ�ในิการท1างานิข้องติ�อมื่ธ�ยรอยด้*หัร อไมื่�

ในิผู้/�ท"!มื่"การเจ�บ่ป0วยร�นิแรงแลิะสงส�ยภาวะ Hypothyroidism ใหั�ติรวจ TFT ท�&ง FT4, FT3 แลิะ TSH

Approach to Patients with Abnormal LFTs

And Viral Markers

• Misnomer, not effectively assess the

actual function of liver• Liver chemistry tests = biochemical

tests for hepatic injury, cholestasis,

hepatic synthesis• Normal values do not mean “normal” eg. normal

ALT is Mean+ 2 SD and was set as early as 1950s

Advantages Non invasive method of

screening liver dysfunction

Pattern of laboratory test abnormalities to recognize the type of liver disorder

Assess the severity of liver dysfunction

Follow the cause of liver disease

Disadvantage Lack sensitivity: normal

results in serious liver disease

Not specific for liver dysfunction

Seldom lead to a specific diagnosis

Chemistry Implication

ALT/AST Hepatocellular damage

Bilirubin Cholestasis, impair conjugation, biliary

obstruction

ALP Cholestasis, infiltration, obstruction

GGT Cholestasis, obstruction

5’-nucleotidase Cholestasis, obstruction

Albumin Synthetic function

PT Synthetic function

Albumin Coagulation

factors

Aminotransferases• Bilirubin• Alkaline

phosphat-ase

• GGT

Test of the biosynthetic capacity of the liver

Liver synthesize factors I, II, V, VII, IX and X PT prolong : single or combination factors

deficiency Advantage of using PT more than INR Indicate severity and prognosis of liver disease

PT prolong not specific for liver disease Consumptive coagulopathy, vitamin K deficiency and

ingestion of drugs Factor V is synthesized by liver but not affected

by vitamin K deficiency Vitamin K deficiency : PT improve at least 30%

after vitamin K injection 10 mg within 24 hrs

Synthesized exclusively by the liver,Half life 19 - 21 days Serum level reflects the rate of synthesis,degradation and volume of distribution

HypoalbuminemiaDecreased synthesis:

-Severe liver damage or chronic liver disease-Chronic inflammation-Protein malnutrition

Losing albumin: -Protein losing enteropathy

-Nephrotic syndrome

Serum immunoglobulins are produced by stimulated B lymphocyte

Elevation of serum globulin level:• Chronic liver disease:

- Indicate impaired function of RE cells in hepatic sinusoids- Shunting of portal venous blood

• Chronic inflammatory and malignant diseases

*Triger DR,et al,Lancet,1973

Reverse A/G ratio Cronic liver disease or cirrhosis Chronic inflammation or infection

Hypoalbuminemia ,hypoglobulinemia, anemia and decrease cholesterol level Malnutrition

Hypoalbuminemia ,hypoglobulinemia and increase cholesterol level Protein losing enteropathy Nephrotic syndrome

Aminotransferases

• Bilirubin• Alkaline

phosphatase• GGT

Test to detect injury to hepatocytes

•Albumin•Coagulation factors

AST or SGOT• Cytoplasmic and

Mitochrondial form

• The half-life• Total AST ~ 17

hrs • Mitochondrial

AST ~87 hrs

ALT or SGPT• Cytoplasmic

forms• The half-life is

47+10 hrs

Hepatic EnzymesHepatic Enzymes

Ischemia

Immune reaction

(AIH,PBC,PSC)

Infection (virus, bacteria)

Medications

Toxin / Alcohol

Endogenous Exogenous

Hepatocyte

AminotransferaAminotransferasese

Copper/Iron overload

(Wilson’s disease/Hemochromatosis)

Most types of liver disease : ALT>AST activity

AST come from non hepatic tissue: heart ,skeletal tissue and red blood cell

ALT is low concentrations in tissue other than liver Specific for hepatocellular injury Non hepatic conditions etc myopathic disease1-2 and

kidney

1 Scola RH, et al. Arg Neurosiquiatr 20002 Lin YC, et al. Taiwan Erch Ko I Hsueh Hut Tsa Chili 1999

Test Normal Mild Moderate Marked

AST 11 – 40 <2 -3 2 - 3 to 20 >20

ALT 3 - 40 <2 -3 2 - 3 to 20 >20

ALP 35 – 105 <1.5 -2 1.5 - 2 to 5 >5

GGT 2 – 65 <2 -3 2 - 3 to 10 >10

Factor AST ALT

Time of day 45% variation during day; highest in afternoon, lowest at night

Day to day 5-10% variation from one day to next 10-30% variation from one day to next

Race/gender 15% higher in African-American men

Body mass index (BMI)

40-50% higher with high BMI 40-50% higher with high BMI

Meals No effect No effect

Exercise 3-fold increase with strenuous exercise 20% lower in those who exercise at usual levels than in those who do not exercise or exercise more strenuously than usual

Specimen storage

Stable at room temp for 3 d, in refrigerator for 3 wks (<10% decrease); stable for years frozen (10-15% decrease)

Stable at room temp for 3 d, in refrigerator for 3 wks (10-15% decrease). Marked decrease with freezing/thawing

Hemolysis, hemolytic anemia

Significant increase Moderate increase

Muscle injury Significant increase Moderate increase

Other Macroenzymes Macroenzymes

Useful in narrowing the DDX for cause of the liver injury1) Level of aminotransferase elevation

2) Predominant AST elevation

3) Rate of aminotransferase declination

1. Level of aminotransferase elevation Acute hepatic injury

Hepatocyte damage occurs abruptly and over a short period of time

Aminotransferase elevation : > 8 – 10 times UNL Chronic hepatic injury

Hepatocyte damage occurs chronicity more than 6 months

Aminotransferase elevation : < 5 times UNL

Acute viral hepatitis (rarely >2000-3000 IU/L)

Ischemic liver Toxic and drugs:

Paracetamol, halothane Acute Budd-Chiari Syndrome Hepatic infarct or artery ligation

Chronic Hepatitis B and C Alcohol Medication,Toxin Nonalcoholic Fatty liver Disease Autoimmune Hepatitis Wilson disease Hemochromatosis

Disease Peak ALT (x URL)

AST / ALT Ratio

Peak Bili (mg/dL)

PT Prolong (s)

Viral Hepatitis

10-40 <1 <15 <3

Alcoholic Hepatitis

2-8 >2 <5 1-3

Toxic injury

>40 > 1 early <5 >5(transient)

Ischemic injury

>40 >1 early <5 >5 (transient)

X- times, URL - upper reference limit

2. Predominant AST elevation Alcoholic liver disease Extrahepatic source of AST:

Hemolysis Skeletal muscle disease Cardiac muscle

Cirrhosis

AST > ALT activity Alcohol induces release of mitochondrial AST

from cells without visible cell damage 1

Pyridoxine deficiency decreases hepatic ALT activity 2

1 Zhov S-L, et al. Hepatology 19982 Luding S, et al. Gastroenterlogy 1980

3. Rate of aminotransferase declination Rapid declination of aminotransferase

Ischemic hepatic injury Drug induced hepatitis : short half life drug Acute biliary tract obstruction Fulminant hepatitis

Slow declination of aminotransferase Acute viral hepatitis Drug induced hepatitis : long half life drug Autoimmune disease,Metabolic disease

0

2000

4000

6000

8000

10000

1 2 3 4 5 6 7 8 9 10

AST

LDH

Days

U/L

Giltin N,et al ,Am J Gastroenterol,1992

The patients had a rapid striking elevation of AST and LDH, with rapid resolution

History of drugs, alcohol, co morbid conditions,family history and PE

HBsAg Anti-HCVconsider- -

NASH (DM, obese: ALT>AST)Wilson(neuro, family: ceruloplasmin)Autoimmune(female:ANA, SAM)Hemochromatosis(Fe, ferritin, TIBC)

elevated > 6 months without cause

Biopsy

HCV-RNAHBeAg, DNA

Albumin Blood-clothing

factors

Aminotransferases• Bilirubin• Alkaline

phosphatase

• GGT

Test of the capacity of the liver to transport organic anions and metabolize drugs

Heme

Biliverdin IX

Unconjugated bilirubin IX

Lipid-soluble,

Normally in plasma

Conjugated bilirubin Conjugated bilirubin IXIX

Water-solubleWater-soluble

Normally in bileNormally in bile

Heme Oxygenase

Biliverdin reductase

NADPH

Bilirubin UGT

Alkaline Phosphatase(ALP)

0

1

2

3

4

5

6

Age

Female

Male

Up

per

refe

ren

ce lim

it(r

ela

tive t

o 2

5-3

5 y

rs,

Male

s)

0 10 20 40 60 80

Age and Gender effects on URL for ALP:The URL for 25-35 year old male is set at 1.0.ALP is many fold higher in children and adolescents,reaching adult activities by about age 25.

Factor Change Comments

Day to day 5-10% Similar in liver disease and health, and in elderly and young

Food ingestion Increases as much as 30 U/L In blood groups B and O; remains elevated up to 12 hours; due to intestinal isoenzyme

Body mass index (BMI)

25% higher with increased BMI

Exercise No significant effect

Hemolysis Hemoglobin inhibits enzyme activity

Pregnancy Increases up to 2-3 fold in third trimester

Due to placental and bone isoenzymes

Smoking 10% higher

Oral contraceptives 20% lower

Specimen storage Stable for up to 7 d in refrigerator, months in freezer

A membrane bound enzyme Decreasing order : proximal renal tubule, liver,

pancreas and intestine GGT activity in serum comes primarily from liver The half-life :

7-10 days in humans 28 days in alcohol-associated liver injury

Increased GGT : diabetes, hyperthyroidism, rheumatoid arthritis, COPD,

acute myocardial infarction*

Age-and gender related differences

*Hedworth-Whitty RB,et al,Brit Heart J,1967

Mild elevation ALP

Repeat to confirmHistory and PE

Hepatic image

Normal Confirmcheck GGT

GGTcontinue

GGT normalbone

Drug or alcoholrepeat 2-8 wksafter withdrawal

Specific diseasework up accordingly

NASH

Dilated duct

ERCP

Normal

Parenchymal disease

Infiltrative lesion • TBc, fungal, other granulomatous, malignancy• PBC

Liver mass (s) Partial biliary tract obstruction (Stone, PSC) Drugs – Anti - convulsants, Warfarin

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Intern Tutorial