LIVER “FUNCTION” TESTS - Case Western Reserve ... · Urobilinogen MRP2 transport protein...

LIVER “FUNCTION” TESTS

Edith Y. Ho, M.D. M.S.

Assistant Professor of Medicine, Division of Gastroenterology

Case Western Reserve University

Louis Stokes Cleveland VA Medical Center

Director, Inflammatory Bowel Diseases Program

Co-Director, Fecal Microbiota Transplantation Program

12/18/2015

Agenda

Tests showing liver cell injury

Tests showing hepatic function / synthesis

Tests showing cholestasis

Bilirubin metabolism

Other important liver tests

Patterns in liver injury ☻

Agenda






2.78.6

2561

132 103 15

4.4 24 1.590

0.5

69

51 46

Ca 8.6

Mg 2.1

Phos 3

Alb 2.2

Prot 5.5

1.2

Aspartate aminotransferase

(AST)

Used to be called SGOT (Serum glutamic oxaloacetic transaminase)

Ubiquitous enzyme in many tissues

Heart

Liver

Muscle

Kidney

Red cell

Mainly in mitochondria and cytosol

Aspartate aminotransferase

(AST)

Anthony S Tavill CWRU Professor

A hepatologist with a major interest in

iron and blood

Causes of Increased AST

Physiological: newborn 1.5 x normal

Very high levels: 20-100 x normal

myocardial infarction, viral ,ischemic, toxic hepatitis

Moderate levels:

cirrhosis, muscle disease, cholestasis, trauma, surgery, liver malignancy, hemolytic anemia

Artefact: hemolyzed blood specimen

Alanine Aminotransferase

(ALT)

Used to be called SGPT (serum glutamic-pyruvic transaminase)

High amounts in liver

Lesser amounts in muscle, kidney, and heart

Associated with cytosol

Alcoholic Liver dx: liver tissue has low levels of ALT possibly due to vitamin B6 deficiency, which is needed for ALT to function

Cirrhotic livers: possibly lower ALT

Cause of Elevated ALT & AST

Degree of Elevation Common Causes

Mild to Moderate

(41-500 U/L)

Chronic viral hepatitis (B, C, Delta, E)

Drug toxicity

Alcoholic hepatitis – often not high

Non-Alcoholic Fatty liver Disease (NAFLD) / NASH

Autoimmune hepatitis

Iron or copper accumulation

Bile duct disease

Severe (>1000 U/L) Acute viral hepatitis (A, B, C, Delta, E)

Drug induced (esp. acetominophen)

Autoimmune hepatitis

Ischemia/Hypoperfusion/ after hypotension

Heat stroke (↑ muscle enzymes CPK)

* Rarely seen in bile duct stones

Hepatocellular Injury ☻

What are the major causes of

rise in ALT & AST in the US? 1.Fatty Liver also known as Non-alcoholic

Fatty Liver Disease ( NAFLD )

ALT > AST in 30% of USA

2. Chronic Hepatitis C

Biggest risk factor: IV drug use at anytime

In both NAFLD and Hep C, liver enzymes at

times can be normal

Transaminases in Alcoholic

liver disease

Usually <300 even if severe

Extremely common for AST>ALT 2:1

ALT can be normal because ALT in alcoholic liver dx

tissue is lower than normal

As a rule: if AST>ALT, consider alcoholic liver dx

EXCEPTIONS TO RULE:

In alcoholic liver dx, rule only applies if ALT & AST are < 300

Ex. AST 1000 & ALT 500: likely liver + other organs damage

In cirrhosis of any cause, AST>ALT but ratio is usually NOT >2

Kayser-Fleischer Ring (copper)

Wilson’s disease

Lactate Dehydrogenase

(LDH)

Liver

Heart

Muscle

Kidney

Brain

Red cell

Rarely used these days

Causes of raised LDH

Degree of

Elevation

Common Causes

Mild to

Moderate

Viral hepatitis

Malignancy elsewhere

Pulmonary embolism

Severe Myocardial infarction (5 x)

– CPK, troponin used now

Blood disorders (5-20 x)

Case 1 69 y.o. ♀ homemaker of Hungarian/German ancestry

No FH of liver dx or diabetes

Lifelong abstinence from alcohol

Meds: Thyroid replacement x 40 years

Asymptomatic - normal physical exam

Lab data:

Fasting glucose 80, AST 100, ALT 120

Iron studies:

Serum iron 157 µg/dl TIBC 250 µg/dl

Iron Saturation 63% Serum ferritin 1235 mg/L

Hemochromatosis (iron)

Agenda






Patterns in liver injury

Tests reflecting Liver Synthesis

Tests If liver synthesis

compromised

Serum albumin Low

Prothrombin time (PT) / INR High

Bilirubin High

Plasma cholinesterase activity –

still used in Europe but not in US

Low

Problems with Serum Albumin

Half life 20 days

Decreases in advanced liver disease,

malnourished state, sepsis, proteinuria (eg.

nephrotic syndrome)

Can be lost in GI tract (eg. inflammatory

condition, enteropathy etc). Note this also

lowers globulin levels

Total protein vs serum albumin

Bulk of Total protein – albumin = globulins

Gamma globulin levels high

- common in autoimmune liver dx

Albumin and globulin levels are both low

- protein losing enteropathy

- skin exfoliation

Caput medusa

CT abdomen

Ascites

Prothrombin time (PT) / INR

Very important point for students. You do not need

to remember which factor is responsible for this and

that. Just know:

PT measures how long it takes for blood to clot

Factor VIII (8) not made in liver

Factor VII (7) half life of 6 hours

patient usually has major loss of liver function

before PT gets longer

Increased Prothrombin time (PT)

Is prolongd PT due to vitamin K deficiency or poor liver function?

Give patient 1 or 2 vitamin K shots:

If PT corrects there is vitamin K deficiency

If PT does not correct consider liver disease

Note: both can occur at same time

Vitamin K is

needed for

synthesis of

factors

2,7,9,10

Spider angiomasPalmar

erythema

GynecomastiaLeukonychia

Icterus

Agenda







Cholestasis

Term used to describe conditions where bile

flow is impeded

Lab tests showing cholestasis are typically

enzymes found around biliary cananicular

apparatus and bile ductules:

Bilirubin

Alkaline phosphatase

Gamma glutamyl transpeptidase GGTP

5-nucleotidase

Bile acids

When bile flow obstructed, these markers rise

in blood

Alkaline phosphatase

isoenzymes (Alk Phos)

Bone

Liver can be verified by doing GGT or GGTP

Kidney

Intestine

Placenta

Mammary gland

(Few labs measure heat labiality and test may not

be reliable)

Causes of raised Alk Phos

Physiological:

- until puberty x 2, last trimester pregnancy

Bone disease (normal GGTP & 5-nucleot):

- Osteomalacia (softening of the bones), paget’s disease of bone, hyperparathyroidism, bone cancer

Liver and Biliary disease (↑ GGTP):

- cholestasis, hepatitis, biliary obstruction, space occupying lesions in liver

Causes of raised Alk Phos and

normal bilirubin

Incomplete biliary obstruction

Bone disease

Infiltrating liver lesions

Placenta

Clinical Point: if liver alk phos is elevated,

do a liver imaging study (ex. ultrasound , CT

or MRI)!

• Primary or secondary

malignancy

• Granulomas

• Liver abscess

• Amyloid /other oddities

• Primary biliary cirrhosis

• Fat

Infiltrative Pattern ☻

xanthelasma

xanthoma

Agenda







Bowel ← Ampulla of Vater ← Bile Ducts ← Canaliculus

bacteria

Senescent

RBCs

Heme Bilirubin

Bilirubin

Mono + Diglucuronide

RES Hepatocyte

Bilirubin +

Albumin

Circulation

UDP-

Glucuronyltransferase

UrobilinogenMRP2 transport

protein

UDP-

glucaronyl

sterocobilinogen

Urobilin

(yellow)

Stercobilin

(brown)

Bilirubin Metabolism


bacteria

Senescent

RBCs

Heme Bilirubin

Bilirubin


RES Hepatocyte

Bilirubin +

Albumin

Circulation

UDP-



protein

UDP-

glucaronyl


sterocobilinogen

Urobilin

(yellow)

Stercobilin

(brown)

Conjugated /

Direct Bili

Bilirubin metabolism In a healthy person, ~ 250 mg of bilirubin is produced daily

Formed mostly from red cells, the rest from bone marrow ,P450

Initial breakdown in reticuloendothelial (RE) system

Unconjugated toxic bilirubin transported to liver bound to albumin

Taken up avidly by liver through bilirubin transporter

Bili is conjugated in liver with glucuronide

After conjugation, bili moves to canaliculi for transport into bile ductules (This

process is easily disturbed both across membrane and flow in ductules)

Conjugated bili flows out bile duct into intestine

About 90% bili excreted in stool as stercobilin. About 10% is converted to

urobilinogen then resorbed and excreted again (5% enterohepatic urobilinogen

cycle / 5% escapes to urine)

If no enterohepatic cycle, then no urobilinogen

When excretion compromised, conjugated bili regurgitates back to blood

Many liver disease associated with jaundice

Terms Used with Bilirubin

Total bilirubin = direct bilirubin + indirect bilirubin

Lab result given as Total and Direct bilirubin

Subtract direct from total to give indirect

Conjugated

(bound to

glucuronide)UnConjugated


bacteria

Senescent

RBCs

Heme Bilirubin

Bilirubin


RES Hepatocyte

Bilirubin +

Albumin

Circulation

UDP-



protein

UDP-

glucaronyl


sterocobilinogen

Urobilin

(yellow)

Stercobilin

(brown)

Conjugated /

Direct Bili


bacteria

Senescent

RBCs

Heme Bilirubin

Bilirubin


RES Hepatocyte

Bilirubin +

Albumin

Circulation

UDP-



protein

UDP-

glucaronyl

Bilirubin Metabolism and Associated Disease Targets

sterocobilinogen

Urobilin

(yellow)

Stercobilin

(brown)

Conjugated /

Direct BiliIsolated unconjugated hyperbilirubinemia:

Overproduction of bilirubin:

hemolysis

hematoma absorption

malfunctioning erythropoiesis

Defective conjugation (UDP):

Gilbert’s syndrome (<5 mg/dl)

Crigler-Najjar syndrome


bacteria

Senescent

RBCs

Heme Bilirubin

Bilirubin


RES Hepatocyte

Bilirubin +

Albumin

Circulation

UDP-



protein

UDP-

glucaronyl

Bilirubin Metabolism and Associated Disease Targets

sterocobilinogen

Urobilin

(yellow)

Stercobilin

(brown)

Conjugated /

Direct Bili

Isolated conjugated hyperbilirubinemia

Problem with excretion of conjugated bili:

Defective biliary transport protein

Dubin-Johnson syndrome

Rotor syndrome

Elevated Bili and normal Alk Phos

Isolated hyperbilirubinemia☻

Type of ↑ Bili Causes

Unconjugated Overproduction of bilirubin:

- hemolysis

- hematoma absorption

- malfunctioning erythropoiesis

Defective conjugation:

- Gilbert’s syndrome (<5 mg/dl)

- Crigler-Najjar syndrome

Conjugated Problem with excretion of bili:

- Defective biliary transport protein

- Dubin-Johnson syndrome

- Rotor syndrome

Elevated Alk phos and Bili

Cholestatic Pattern ☻

Degree of Elevation Common Causes

Low ( < normal) Wilson’s Disease

Mild to Moderate Biliary obstruction (if bile duct dilated)

Hepatitis

Cirrhosis

Primary Biliary Cirrhosis

Sepsis

Medication/ Drug Toxicity

Severe (>1000 IU/L) Malignant infiltration by tumor

What patterns of liver injury

would you expect to see here?

1) Hepatocellular injury – predominately ↑ AST & ALT

2) Cholestasis – predominately ↑ alk phos & ↑ bili

3) Isolated hyperbilirubinemia – predominately ↑ bili

4) Infiltrative disease – predominately ↑ alk phos

Agenda








Alpha fetoprotein (AFP)

Ferritin, serum iron, total iron binding capacity

Ceruloplasmin for Wilson’s disease

Alpha-1-antitrypsin

Ammonia

Antimitochondrial antibody (AMA) for Primary biliary

cirrhosis (PBC)

Antinuclear antibody (ANA) for autoimmune hepatitis

Many viral antibody tests

Virus detection

Summary

Tests showing liver cell injury: AST, ALT, LDH

Tests showing hepatic function / synthesis: Albumin,

PT /INR, bilirubin

Tests showing cholestasis: Alk Phos, bilirubin

Bilirubin metabolism & associated diseases

Variety of tests to check for liver diseases

Patterns in liver injury:

1) Hepatocellular injury – predominately ↑ AST & ALT

2) Cholestasis – predominately ↑ alk phos & bili

3) Isolated hyperbilirubinemia – predominately ↑ bili

4) Infiltrative disease – predominately ↑ alk phos

In real life, patients can present with mixed patterns!

Come Explore GI and

Hepatology!

Contact me if interested in

IBD research

[email protected]

LIVER “FUNCTION” TESTS

Edith Y. Ho, M.D. M.S.

Assistant Professor of Medicine, Division of

Gastroenterology

Case Western Reserve University

Louis Stokes Cleveland VA Medical Center

Director, Inflammatory Bowel Disease Program

Co-Director, Fecal Microbiota Transplantation Program

12/17/2015

LIVER “FUNCTION” TESTS - Case Western Reserve ... · Urobilinogen MRP2 transport protein...

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