APPROACH TO ABNORMAL LFT

Dr.Navas Shareef .P .P

LIVER FUNCTION TEST•Albumin •Bilirubin:• Total Bilirubin • Direct Bilirubin (conjugated bilirubin)

•Serum aminotransferases • Aspartate aminotransferase (AST)• Alanine aminotransferase (ALT)

•Alkaline Phosphatase•Prothrombin time

THE APPROACH

Important questions to address:•Acute vs. chronic (6 months, ?cirrhosis)•Asymptomatic vs. symptomatic

?impaired function•Recent insults to the liver?

EtOH, medications, pregnancy, hepatitis, herbs, gallstones, hypotension, toxins

THE APPROACH

•Hepatic vs cholestatic

•Magnitude of enzyme alteration (ALT >10x vs minor abnormalities)

•Rate of change

•Nature of the course of the abnormality (mild fluctuation vs progressive increase)

ALBUMIN

•Synthesized in the liver•Production is controlled by multiple factors including nutritional status, serum oncotic pressure, cytokines, and hormones •A serum albumin may be reflection of the synthetic function of the liver.

ALBUMIN

•most important plasma protein made by the liver• accounts for 65% of protein in serum• half-life ~17-21 days

•useful indicator of liver function

•Other causes of decrease:• sepsis or multiple organ failure• acute liver failure• dietary

BILIRUBIN

•Used to determine liver’s ability to clear endogenous/exogenous substances from the circulation

•derived mainly from hemoglobin (95%)• continuous production (300 mg daily)•normal values of “total” bilirubin = 0.1-1.0 mg/dL• Jaundice usually develops with a bilirubin ≥ 3 mg/dL

Direct Bilirubin• conjugated

• water soluble• polar• seen in urine

• elevated with biliary obstruction and hepatocellular disease.

Indirect Bilirubin•unconjugated• lipid soluble•non-polar•not in urine• Elevated with hemolysis, hepatic disease

UNCONJUGATED HYPERBILIRUBINEMIA

• Indirect bilirubin fraction >85% of total bilirubin occurs with increased bilirubin production or in defects of hepatic uptake or conjugation, which in turn may be inherited or acquired•Gilbert’s syndrome( 3-7% population ):benign disorder characterized by mild unconjugated hyperbilirubinaemia,which is often exacerbated by fasting & infections. It does not require any specific treatment and the patient should be reassured.

CONJUGATED HYPERBILIRUBINEMIA

•Direct bilirubin >15% of total bilirubin• inherited or acquired defects in hepatic excretion. •Bilirubin levels have prognostic significance in alcoholic hepatitis, primary biliary cirrhosis, and in acute liver failure. •As conjugated bilirubin is excreted in urine, bilirubin levels rarely exceed 6mg/dl in the absence of renal failure or haemolysis.

Bilirubin production and metabolism

UDPGlucoronosyltransferase

1g Hb=34mg Br

HEPATIC CLEARANCE REFLECTS:

1. delivery to hepatocyte hemolysis

2. uptake by hepatocyte shunts, drugs (i.e., sulfa)

3. transport within hepatocyte drugs, genetics

4. molecular alterations within hepatocyte genetics

5. secretion into bile cell damage, genetics

6. passage down bile ducts obstruction

AMINOTRANSFERASES

•Hepatic enzymes that are usually intracellular, but are released from hepatocytes with hepatocellular injury.•Catalyze -amino group transfers

aspartate or alanine ketoglutarate

•AST/ALT ratioNormal is 0.8In alcoholic hepatitis, is usually > 2

AMINOTRANSFERASES

aspartate aminotransferase (AST)• in cytosol and mitochondria• liver > heart > skeletal muscle > kidneys > brain > pancreas > lungs > WBCs > RBCs•half-life 17hrs

alanine aminotransferase (ALT)• in cytosol•predominantly liver•more sensitive and specific than AST•Half-life 47hrs

AMINOTRANSFERASES

• elevated in nearly all liver diseases (ALT > AST)•marked is usually hepatocellular disease• levels may/may not reflect extent of damage• do not correlate with eventual outcome• usually <500 in obstructive jaundice

Exception: acute phase of biliary obstruction by the passage of a gallstone into the common bile duct. In this, the aminotransferases can briefly be in the 1000–2000 IU/L range. However, levels decrease quickly, and the LFT rapidly evolve into typical of cholestasis

• usually parallel each other• AST > ALT with EtOH, fulminant, and pregnancy

AMINOTRANSFERASES

• acute hepatocellular disordersALT is higher than or equal to the AST.

• c/c viral hepatitis and NAFLDAST:ALT ratio is typically <1 (but as cirrhosis develops,

this ratio rises to >1)• alcoholic liver disease

AST:ALT ratio >2:1 . The AST in alcoholic liver disease is rarely >300 IU/L, and

the ALT is often normal. A low level of ALT in the serum is due to an alcohol-

induced deficiency of pyridoxal phosphate

ACUTE HEPATITIS (ALT>10XULN)

•Viral• Ischaemic•Toxins•Autoimmune•Acute Budd-Chiari•Early phase of acute obstruction•Metastatic liver-diffuse (extremely rare)

“HIT AND RUN” PATTERN OF LIVER ENZYMES(AST 17H, ALT 47H):

ISCHEMIC, TOXIC, CBD STONE

AST

ALT

Elevated AST & ALT, <4X normal

Hx & physical; stop hepatotoxic

meds

LFTs, PT, albumin, CBC, Hep A/B/C, Fe,

TIBC, Ferritin

Positive serology

Negative serology

Negative serology,

asymptomatic

Serologies:HAV IgMHBsAgHBcIgMHCV Ab or RNA

Stop EtOH & meds; wt loss; glucose

control

Repeat LFTs

ObservationUltrasound, ANA, smooth

muscle Ab, ceruloplasmin,

antitrypsin, gliadin & endomysial Ab

NEGATIVE SEROLOGY- ASYMPTOMATIC

Liver biopsy

Abnormal Normal

6 months

☺

Consider ultrasound, ANA, smooth muscle Ab, AMA,ceruloplasmin,

antitrypsin

Liver biopsy

NEGATIVE SEROLOGY- CLINICAL SIGNS/SYMPTOMS OF LIVER DISEASE

Abnormal

• ANA(antinuclear antibody)

sle, autoimmune hepatitis etc…

• ASMA (anti smooth muscle antibody)

autoimmune hepatitis….

• AMA (anti mitochondrial antibody)

primary biliary cirrhosis….

ALKALINE PHOSPHATASE• enzymes that catalyze hydrolysis of large number of organic phosphate esters.• ALP mainly comes from surface of bile duct epithelial cells. Cholestasis enhances synthesis and release of ALP • Since half life is 1week ; ALP rise late in bile obstruction and decrease slowly after resolution• Found in:

• Liver• Bone• intestine• 3rd trimester placenta• Kidney

ALKALINE PHOSPHATASE

• increases seen with cell injury or obstructionslight to moderate (1-2x) – usually hepatocellular

large increases (3-10x) – obstruction or cholestasis

ALKALINE PHOSPHATASE

GAMMA-GLUTAMYL TRANSPEPTIDASE (GGT)

•GGT – to confirm hepatic source of ALP• elevated ALP of Liver origin: Elevated GGT

elevated ALP of Bone origin: Normal GGT•Normal levels=0-45 IU/L•Non specific as Causes of elevations include

liver disease » pancreatic disease

alcohol » renal disease

cardiac disease » obesityradiotherapy » diabetesdrugs – GGT is “inducible”• phenobarbital anticoagulants• dilantin oral contraceptives• acetaminophen tricyclic antidepressants

•Usually normal in pregnancy

PROTHROMBIN TIME (PT)

•Liver is in charge of the synthesis of many clotting factors :

•Factor I (fibrinogen) , II (prothrombin) ,V ,VII , IX , X , XII and XIII

•PT measures the rate of conversion of prothrombin to thrombin (requiring factors II, V, VII, and X) and thus reflects a vital synthetic function of the liver•Elevated PT may be reflection of decreased synthetic activity of liver.

PROTHROMBIN TIME (PT)Other causes of prolongation:

congenital deficienciesconsumptive coagulopathies (i.e., DIC)

drugs (i.e., warfarin)vitamin K deficiency (i.e., dietary, bile output)

PROLONGED PROTHROMBIN TIME

due to hepatocellular disease?

due to chronic cholestasis with fat malabsorption?

administration of vitamin K

administration of vitamin K

PT remains high

PT comes to normal

ASSESSING THE PATIENT WITH ABNORMAL LIVER FUNCTION TESTS

Certain patterns exist with LFTs•Hepatocellular Injury: Very high AST, ALT with mild/moderately elevated alkaline phosphatase.•Cholestatis: mild/moderately elevated AST/ALT with very high alkaline phosphatase•Bilirubin can be elevated with both combinations.

CHOLESTATIC PATTERN

• Predominantly elevated alkaline phosphataseDetermine source of AP Need to check GGT to see if bone or liver in origin

•Blood types O and B: can have elevated serum alkaline phosphatase after eating a fatty meal due to an influx of intestinal alkaline phosphatase •Need to determine if the cholestasis is intrahepatic or extrahepatic in origin.• determine fraction of bilirubin elevated• if all indirect, generally not liver

• ultrasound and/or CT scan• to rule out obstructive disease, tumors, gallstones

CHOLESTATIC PATTERN

• INTRAHEPATIC•Drugs•Hepatitis A, B, C•Alcoholic hepatitis•TPN•Primary Sclerosing Cholangitis•Primary Biliary Cirrhosis

•EXTRAHEPATIC•Gall stones•Primary Sclerosing Cholangitis•Malignancy•Chronic pancreatitis•HIV cholangiopathy

SUMMARY

CASE 1 – 65 Y/O WOMAN

complaints•fatigue•pruritus•dry eyes

past history•hysterectomy for fibroids 10 years ago•no alcohol, tobacco or drug use

CASE 1 – 65 Y/O WOMAN

examination•spider naevi•mild splenomegaly•otherwise normal

CASE 1 – 65 Y/O WOMAN

screening labs reveal•platelets 90,000•bilirubin normal•AST/ALT normal•Alk phos 4x uln•Albumin 3.3 (nl >3.5)•PT normal

what do you want to do next?•be thinking about this

CASE 1 – 65 Y/O WOMAN

• Further lab testing:• HAV (-) HBV (-) HCV (-)• ANA (-)• ASMA (-)• AMA (+) 1:1280• iron studies normal

• ultrasound – splenomegaly, small liver, no bil dil

Answer:

•primary biliary cirrhosis• just beginning to decompensate consider for LT

CASE 1 – 65 Y/O WOMAN

CASE 2 – 43 Y/O FEMALE

complaining of•4 days of prolonged, severe RUQ pain• fever, severe nausea, some vomiting•worse after eating

Past History•20 yr ago began periodic attacks •evening RUQ pain, fluctuating intensity, no fevers• lasting 1-4 hours with residual RUQ tenderness

CASE 2 – 43 Y/O FEMALE

Past History (cont)•during last 8 years, continued episodes•pain more intense and prolonged, accompanied by penetrating pain to back below scapula•marked tenderness in RUQ persisting days• told in the past she had gallstones

CASE 2 – 43 Y/O FEMALE

• Exam• temp 38.5°C pulse 100 uncomfortable/sweating•marked tenderness in RUQ with splinting• (+) Murphy's sign• icterus• bilirubin 6 mg/dl - alk phos 3x nl (~400 U/L)• ALT 100 mg/dl - normal albumin, PT•WBC 28,000 - GGT 150 U/L (nl <45)

• how would you proceed?

REFERENCES

•Harrison's Principles of Internal Medicine, 19Ed

• American Family Physician journal

• BMJ post graduate medical journal

etc.

THANK YOU