Liver Function Tests

Dr. Luis P. Cruz, MD

Major causes of jaundice

Pre-hepatic
Post-hepatic

Hemolysis
Gallstones

Ineffective erythropoiesis
Billiary stricture

Carcinoma of pancreas or

biliary tree


Hepatic

Pre-microsomal
Pre-microsomal

Drugs. (e.g., Rifamipicin,
Impaired excretion:
which
i
nterfere
w
ith
Hepatitis

Drugs (e.g.
bilirubin uptake)

methyltestosterone,
rifampicin

Dubin-Johnson

syndrome


Microsomal
Intrahepatic

Prematurity
Hepatitis

Hepatitis (e.g viral or drug Cirrhosis
induced)
Infiltrations (e.g.

Lymphoma, amyloid
Gilberts syndrome
Crigler-Najjar syndrome
Biliary Atresia

Tumors

Extra-hepatic Sepsis


Plasma protein of Diagnostic Value in Liver

Disease
Protein
Condition
Change in

Concentration

Albumin
Chronic Liver
Decreased

disease


g- globulin
Cirrhosis,
Increased

autoimmune

a1-antitrypsin 1-Antitrypsin
Decreased

deficiency


Ceruloplasmin Wilsons disease
Decreased



Fetoprotein
Hepatoma
Greatly increased


Transferrin
Hemochromatosis Normal but 100%

Saturated with iron

Laboratory Findings in Hemolytic
Jaundice
Plasma
Unconjugated
Bilirubin
rarely >100 mol,
except neonates
Plasma
Aspartate
Enzymes
transaminase and
hydroxybutyrate
dehydrogenase slightly
increased
Plasma
Decreased
Haptoglobins
Urine
Increased
Urobilinogen
Peripheral
Increased reticulocytes
Blood
Decreased hemoglobin
Possible evidence of
hemolysis on blood
film

MAJOR FUNCTIONS OF THE LIVER
1. Carbohydrate Metabolism
a. Gluconeogenesis
b. Glycogen synthesis and
breakdown
2. Fat Metabolism
a. Fatty acid synthesis
b. Cholesterol synthesis and
excretion
c. Ketogenesis
d. 25-hydroxylation of Vitamin D
3. Protein Metabolism
a. Synthesis of plasma proteins
and coagulations factors
b. Urea Synthesis
4. Hormone Metabolism
a. Metabolism and excretion of
steroid/ polypeptide hormones
5. Drug and Foreign Compounds
a. Metabolism and excretion
6. Storage
7. Metabolism and Excretion of Bilirubin

DRUGS CAUSING LIVER DIASEASE

Dose-Dependent
Hepatotoxicity

Idiosyncratic Hepatotoxicity Dose-Dependent

Idiosyncratic

(Chronic Hepatitis can
Cholestasis
Cholestatic

occur)
Hepatitis

Paracetamol
Isoniazid*
Methyltestosterone Chlorpromazine
Salicylates
Halothane
Erythromycin estolate
Azathioprine
Rifampicin
Chlorpropamide

Methotrexate
Dantrolene*
Tolbutamine
Tetracycline
Methyldopa

Nitrofurantoin*


INDICATORS OF HEPATIC EXCRETORY
BIOCHEMICAL
CHANGES IN ACUTE

FUNCTION
HEPATITIS

Indicator Analytes
Normal Liver Disease

Pre-Icteric Icteric

Plasma
Bilirubin
Slight

Bilirubin Total
Low
Unconjugated



(-)
- Hemolysis
Plasma
Transaminase



urine

Plasma ALP
Normal

level

Urinary Bilirubin



Conjugated
- Impaired uptake

Urinary
Urobilinogen

absent



- Defective

conjugation

INDICATOR

Plasma

Protein





Lipids
and

Lipoproteins




Urea



Plasma

Protein

o There are three basic types of hepatic

Conjugated
abnormalities:
-reduced excretion
n Hepatocyte damage , due to cell
by HB tract
necrosis or cell membrane damage
HBT
n
Cholestasis (obstructed bile duct)
obstruction
n Decreased hepatic blood flow, also
Dubin / Rotor
called chronic passive congestion, due
Syndrome
to cardiovascular disease
Hyperbilirubinemia

- Liver disease

INDICATORS OF HEPATIC SYNTHETIC FUNCTION

NORMAL PRODUCTION

LIVER DISEASE

DECREASED (Hepatic disease with)

- production of albumin, 1-antitrypsin,fibrinogen,
ceruloplasmin, haptoglobulin, transferrin and coagulation
proteins

ELEVATED (Hepatic injury/ inflammation)

- increased production of acute phase reactants

Synthesis of cholesterol,
triglyceride and phospholipids

ACUTE LIVER DISEASE

Packaging of LDL / VLDL

OBSTRUCTIVE LIVER DISEASE

- Hypertryglyceridemia
- Cholesterol / phospholipids

Conversion of amino acids to

ammonia which is then
converted to urea

LOSS OF HEPATIC SYNTHETIC ACTIVITY

DECREASED (Hepatic disease with)

- production of albumin, 1-antitrypsin, fibrinogen,
ceruloplasmin, haptoglobulin, transferrin and coagulation
proteins

Blood / Urine levels of urea

blood levels of aa and ammonia

Test
Hepatocellular
Cholestatic
Infiltratice

AST/ALT
to
N to
N to

Alk Phos
N to
to
N to

Total/ direct
N to
N to
N to

Bili

PT
N to
N to
Normal


Albumin
in chronic disorder
Normal
Normal


~ 1:1,
AST (SGOT), ALT (SGPT): enzymes released after
Hepatic steatosis / NASH: AST:ALT ratio

hepatocellular
death; ALT is more specific for liver
mild elevations in levels (not > 4x normal).
since AST is found in cardiac and skeletal
damage
Alcoholic hepatitis: AST:ALT ratio > 2:1, AST
kidney, and brain tissue.
muscle,
usually not > 250.
The m ost common reasons for elevated transaminase Other causes of elevated AST/ALT levels
levels are drugs, non-alcoholic steatohepatitis
include autoimmune hepatitis,
hepatitis C, and alcohol use.
(NASH),
hemochromatosis, Wilsons disease, alpha-1-
AST, A LT levels in the low thousands seen in viral and
antitrypsin deficiency, acquired muscle

drug-induced (NSAIDs, ACE inhibitors, statins,
diseases, and strenuous exercise.

phenytoin,
carbamazepine, isoniazid, sulfonamides,
High levels of GGT and ALP hint at a possible

erythromycin,
griseofulvin, fluconazole) hepatitis.
blockage of the bile ducts, or of possible injury
AST, A LT levels > 10,000 seen in ischemic and herpes
to, or inflammation of, the bile ducts

hepatitis, acetaminophen overdose.

Gamma glutamyltransferase (GGT): elevated

The ratio
o
f
t
he
A
LT
a
nd
A
ST
m
ay
a
lso
p
rovide
levels are used to confirm that elevated AlkP

useful information regarding the extent and cause of
levels are of hepatic or cholestatic origin.
liver d isease.
Alkaline phosphatase (AlkP): indicator of
Most l iver diseases are characterized by greater
intrahepatic cholestasis, biliary obstruction,
ALT e levations than AST elevations.
and liver infiltration; elevated in bone
Two e xceptions to this rule exist. Both cirrhosis
regeneration, hyperthyroidism, and
and/or
alcohol abuse are associated with higher
neoplastic diseases.
AST levels
than ALT levels, often in a ratio of

If AlkP is markedly elevated in
approximately
2:1.

conjunction with a normal/mildly

elevated bilirubin, suspect an

infiltrative or granulomatous hepatic

disease (sarcoidosis, lymphoma,

Hepatocellular Liver Injury

characterized by AST/ALT increases greater than 5x upper limit of normal,
with alk phos levels less than 2-3x upper limit of normal
Etiology
Clues
Diagnostic Test
Alcoholic
AST/ALT > 2.0, AST < 300
H&P, EtOH level,
osmolal gap
Viral
ALT > AST, transaminases peak in low thousands

Hepa A
fecal-oral (raw oyster ingestion, contact with day care
IgM anti-HAV
kids)
Hepa B
parenteral (blood products, needles, sexual activity,
HBsAg, anti-HBc, anti-
tattoo stuff)
HBs
Hepa D
Assoc with Hep B, high risk groups (IV drug users,
HDV RNA, anti-HDV
hemophiliacs)
Hepa C
parenteral (sexual activity less common, needles/blood anti-HCV (confirmed
more common)
w/RIBA), viral PCR to
quantify levels of HCV
RNA
a 1-antitrypsin
absent a 1-globulin peak on SPEP
a 1-antitrypsin level

(<20)/phenotype
(PiZZ)

hemochromatosis
hepatomegaly, CHF, DM,
transferrin (>50%), ferritin (>1000),
hyperpigmentation, impotence
liver biopsy/hepatic iron index
(gold standard)
neurologic/psychiatric sxs, renal
serum ceruloplasmin (low),
Wilson's disease
tubular dysfxn, Kayser-Fleischer
urinary copper (high), liver

rings, onset usu < 40 years old
biopsy/hepatic copper level (gold
standard)
transaminases usu 3-5x nl, alk
liver U/S (fatty liver), liver biopsy
NASH (nonalcoholic
phos usu 2x nl
(gold standard, although not
steatohepatitis)

always necessary)

LFTs resolve over 2-6 days,

ischemic
ALT/LDH < 1.5, transaminases
often > 10K, often in setting of
heart disease/failure
usu mild LFT elevations, can see
TSH, thyroid panel
hyperthyroidism
jaundice and prolonged PT

usu moderate LFT elevations
AM cortisol, Cosyntropin stim test
Addison's disease

Infiltrative Liver Injury
characterized by disproportionate increase in alk phos (>1000) compared to bilirubin diagnostic
test is liver biopsy
Etiology
Clues
Neoplastic
abnormal
(primary,breast/colon/renal/lymphoma/angiosarcoma/etc)
ultrasound/CT/MRI
infectious (TB, atypical mycobacterium, brucellosis,
blood cultures, PPD, other
coccidioidomycosis, histoplasmosis, candidiasis, Q fever, syphilis,
specific findings
abscess)
sarcoidosis


berylliosis

Cholestatic Liver Injury

characterized by alk phos increase greater than 4x upper limit of normal, confirmed by GGT, 5'-
NT, LAP elevation physical exam reveals deep jaundice, pruritus, clay stools, dark urine
Etiology
Clues
Diagnostic Test
extrahepatic (stones,
ultrasound ERCP
strictures, mass, etc.
intrahepatic


primary biliary
mostly women in 50s-60s, assoc
+ antimitochondrial antibody,
cirrhosis
w/keratoconjunctivitis sicca, thyroid
elevated serum IgM, liver biopsy
dysfunction, scleroderma, rheumatoid
(gold standard)
arthritis

primary sclerosing
mostly men in 30s-40s, assoc w/UC
ERCP
cholangitis

autoimmune
clinical/pathologic features of PBC
negative AMA, pos ANA
cholangiopathy

END