Chapter 25

Biomarker is an objective and measurable indicator of a physiological
condition or the severity/presence of some disease state.

A biomarker is any modality used to characterize and classify
health and disease as well as responses to treatments and/or
exacerbations

1. Specific cells
2. Genes
3. Enzymes
4. Hormones
5. Temp
6. Imaging

Body temp

Blood pressure

Cholesterol

C-reactive protein

Protein/enzyme biomarkers ndicate a change in expression or state of a distinguishable/identifiable
protein/enzyme that correlates with the risk or progression of a disease.

1. Easily obtained
2. Speed
3. Detection method must be accurate
4. The method must be easy to carry out
5. Must have effectiveness for diagnosis
6. Musthave sensitivity and specificity

Blood through venipuncture or catheter

Plasma and serum contain enzymes derived from tissues that might be useful
in disease diagnosis

The blood contains biomarkers that could reflect the ongoing
physiologic state of all tissues

Every cell in the body leaves a record of its physiological state in
the products it sheds into the blood, either as waste or as signals to
neighboring cells.

The relative cellular abundance of thousands of different proteins,
along with their cleaved or modified forms, is a reflection of
ongoing physiological and pathological events.

Diagnostic biomarker useful to detect if a disease already exists, or
how such a disease may develop.

Diagnostic biomarkers often indicate changes in metabolic processes

Normally most enzymes are found inside the cell

When there is cell damage, the cell membrane breaks open and
some enzymes are released into the circulation.

Liver diseases, medical conditions, medications and infections are examples of instances where enzymes are increased

1. cholesterol-lowering drugs (statins)
2. acetaminophen
3. fatty liver disease, both alcoholic and nonalcoholic.

1. If the biomarker is specific (specific to a certain enzyme)
2. Must be quantifiable

Plasma concentrations of enzymes
released from damaged cells may rise
early or late.

The half life of the protein may be fast or
slow.

Cytoplasmic proteins appear in plasma
faster than proteins that are enclosed in
organelles.

The enzyme should have a reasonable half
life and tissue specificity.

Viral hepatatis

Various liver diseases

Aspartate aminotransferase (AST), alanine aminotransferase (ALT) &
gamma-glutamyl transferase (GGT) act as biomarkers

Biomarker is an objective and measurable indicator of a physiological
condition or the severity/presence of some disease state.

If there’s liver damage, serum levels of ALT & AST should be high.

ALT is mainly produced by the liver (specific).

AST is less specific than ALT

ALT and AST (sometimes referred to as liver function tests), they
don’t really indicate how well the liver is functioning. They tell us the
liver is damaged, which can lead to reduced function.

If patients take hepatotoxic drugs, ALT and AST are often monitored.

If there’s gall bladder problem, it’s
predicted that GGT will be high.

High [GGT] indicates cholestasis: a
decrease in bile flow due to
impaired secretion.

Alkaline phosphatase (ALP) is
also present in biliary system, but
it’s not specific (also in bones and
placenta).

Alcohol metabolism by alcohol dehydrogenase (ADH) and cytochrome P450 2E1 (CYP2E1) results in the formation of the reactive intermediate, acetaldehyde

CYP2E1-mediated metabolism also
produces reactive oxygen species (ROS) and hydroxyethyl radicals (HER) that lead to enhanced oxidative stress
and lipid peroxidation

The modified lipids are further metabolized to other highly reactive intermediates
including malondialdehyde (MDA) and 4-hydroxy-2-nonenal (4-HNE).

These reactive metabolites form adducts
with proteins, lipids and DNA that impair proper hepatic function

Acetaldehyde production causes
formation of ROS damages proteins
and DNA

Acetaldehyde inhibits cellular factors
that get processed and exhibited as
antigens on liver cell surfaces that attract
autoimmune response.

Neutrophils will attack the liver! Inflammation leads destruction of
hepatocytes which causes hepatitis!

In most liver diseases, ALT > AST

Except in alcoholic liver disease, where ALT < AST
Alcohol can also raise levels of GGT, while other
enzymes get slightly elevated

Excessive consumption leads to alcoholic fatty
liver!

1. Metabolic syndromes
2. Diabetes
3. Hypertriglyceridemia
4. Hyperlipidemia
5. TOIF (thin on outside, fat on inside)
6. Obesity

ALL HIGH BLOOD SUGAR THINGS
1. More sugars than can be handeled
2. Insulin resistance
3. Lower FA oxidation
4. Increased FA synthesis/storage

1.Damage to lipid membranes
2. Mitochondrial dysfunction
3. Cell death/inflammation

Plasma troponin has become the currently preferred diagnostic marker
for myocardial infarction (MI)

Troponin is present in skeletal and cardiac
muscle but not in smooth muscle.

Troponin levels rise for 2 to 6 hours after MI
and remain elevated for 4 to 10 days (good
window for measurement)

Immunological measurements of plasma levels
of cardiac troponins I and T provide sensitive
and specific indicators of damage to heart
muscle

Since other sources of heart muscle damage
also elevate serum troponin levels, cardiac
troponins provide a general marker of cardiac
injury

We are seeing the rise and fall of cardiac biomarkers

The first enzymes used to
diagnose myocardial Infarction
(MI) were: 1. AST,
aspartate aminotransferase;
2. LDH, lactate dehydrogenase

Alkaline phosphatase (usually abbreviated as AlkPhos or ALP).
AlkPhos/ALP removes a phosphate group.

ALP is found in cells lining the biliary tract (bile duct). If those
cells are damaged (e.g. by obstruction), AlkPhos is released into
the blood at abnormally high levels.

Alkaline phosphotase is present in all tissues, especially in bone, liver, kidney, and placenta

Liver disease

In children: elevated levels of ALP are indicative of normal growth

1. Placenta
2. Intestine
3. Germ cell

One isozyme that is non-specific or ubiquitous, expressed in bone
and liver, known as Tissue nonspecific ALP

When related to the liver, high levels of ALP is indicative of hepatic obstruction

In bones, ALP is increased in diseases such as rickets, osteomalacia, neoplastic
diseases.

In bones increased ALP is also associated with normal process of healing fractures.

1. Hepatitis
2. Bile duct obstruction
3. Cholangitis

1. Osteoporosis
2. Vitamin D deficidency
3. Fracture
4. Hyperparathyroidism

High levels of ALP in placenta are due to pregancy

If high level of alkaline phosphatase is greater than 2 times the upper unit, it impacts the liver or the bone turnover

If alkaline phosphatase is greater than 4, it indicates obstruction of the bile duct

If alkaline phosphatase is less than 4, liver cirrhosis, heart failure, hepatitis

ACP (acid phosphatases) are secretes by prostate cells, RBC, platelets, WBC

Acid Phosphatases (ACPs) are isozymes
with maximum activity at pH 5-6

ACP values are increased in prostrate cancer
and highly elevated in bone metastasis
of prostrate cancer.

ACP • It’s an important tumor biomarker for
monitoring prostrate cancer progression
but not for diagnosis of prostrate cancer,
since ACP levels can also be high during
prostrate hypertrophy.

Lactate dehydrogenase (LDH) Values are increased in
children and athletes and
this is normal

lactate dehydrogenase (LDH) gets released during tissue damage: marker for several
diseases such as myocardial infarction

High levels of a particular isozyme is associated with diseased
state

LDH has 5 isoenzymes: LDH1, LDH2, LDH3, LDH4 and LDH5

LDH1 and LDH2
Found in myocardium and RBC:
Levels increase in MI and hemolytic
anemias, leukemias

LDH3 and LDH4
Kidney and skeletal muscle: levels
increase in kidney disease and
muscular dystrophies. However, high
levels can be normal in children and
athletes.

LDH5
May indicate problems with liver and/or
skeletal muscle. However, high levels can
be normal in children and athletes.

The first enzymes used to
diagnose myocardial Infarction
(MI) were: 1. AST,
aspartate aminotransferase;
2. LDH, lactate dehydrogenase

Diagnosis using LDH exploits the
tissue-specific variations in the
enzyme’s quaternary structue

Creatine kinase (CK) has three tissue-specific
isozymes and a good diagnostic window.

CK-MM (heart & skeletal muscle) leads to
CK3 is expressed in myocardium &
skeletal muscles: Increase in rhabdomyolysis,
muscular dystrophy, MI, post-surgery,
muscle trauma, intense exercise

CK-BB (brain) leads to CK1 in the brain:
increases in CNS diseases.

CK-MB (heart) leads to CK2 in myocardium:
increase in elevated in acute MI

Activity in CPK is greatest in striated muscle, heart, and brain

Assay of plasma CK levels presently
continues in use to assess skeletal
muscle disorders such as Duchene
muscular dystrophy.

1. Amylase
2. Lipase

Primary role of amylase in the digestion of carbohydrates. More sensitive
(Amylase: 40 – 60% sensitivity) than lipase, but not specific because there’s
also salivary amylase.

Lipase (more specific for the pancreas) Lipase:
80 – 90% specificity
This is more specific than serum amylase and can last longer in the serum
of patients after the resolution of symptoms.

1. Pancreatic cancer
2. Pancreatic duct obstruction

1. Amylase
2. Lipase

Epigastric pain that radiates to the back and fever are two key symptoms of pancreatitis

-Alcohol use
-Gall stones
-Hypercalcemia
- Hypertriglyceridemia
- Mumps
- Coxsackievirus
-Trauma to abdomen

Are all causes of pancreatitis