Lecture 4 - LFT, Enzymes, Tumor Markers

What are the Main Functions of the Liver?

• Excretory and Secretory

• Metabolism

• Detoxification (CYP450 System)

• Storage

The most important function of the liver is Excretory and Secretory. What exactly is it involved in?

• Excretion of bilirubin into the bile

• Bilirubin metabolism (Unconjugated → Conjugated)

What is the Bilirubin RI?

0.2 - 1.0 mg/dL

What occurs in Jaundice?

• Yellow discoloration of skin, eyes (sclera), and mucus membranes mainly due to retention of bilirubin

• Due to excessive bilirubin (3.0 to 5.0 my/dL)

• In lab, use Icterus term

Pre-Hepatic Jaundice:

1) What are the main causes?

2) What is a very common consequence?

3) How does the liver respond?

4) What type of bilirubin is accumulating?

1) caused by problems prior to bilirubin metabolism

2) most common cause of hemolytic anemia

3) liver responds by functioning at maximum capacity

4) unconjugated hyperbilirubinemia

Hepatic Jaundice:

1) What is main cause?

2) What disorders are associated?

1) caused by intrinsic liver defect or disease that result in hepatocellular injury or destruction

2) associated with:

• Crigler-Najjar syndrome

• Gilbert’s Disease

• Neonatal jaundice

• Dubin-Johnson Syndrome

• Rotor Syndrome

Gilbert’s Syndrome:

1) What is the main issue?

2) What defect is involved?

3) What is the severity of this disease?

1) Most common cause of unconjugated hyperbilirubinemia

2) Mutation in UGT1A1 gene but with 20-30% normal function

3) generally benign with no risk of brain damage (kernicterus)

Crigler-Najjar Syndrome:

1) Is this a common condition?

2) What is the defect involved?

3) What are the two types?

4) What are the risks?

1) Rare but serious condition

2) similar to Gilbert’s Syndrome with mutation in UGT1A1 gene but more dangerous

3) Two Types:

• Type I → Complete absence of the enzymatic conjugation system

• Type II → Severe deficiency in enzyme activity

4) Risk of kernicterus in infants

Which diseases/conditions are characterized by Conjugated Hyperbilirubinemia?

• Dubin-Johnson’s Syndrome

• Rotor Syndrome

Dubin-Johnson Syndrome:

1) What are the defects involved?

2) What are the issues with Bilirubin?

3) What is the Total Bilirubin levels usually?

4) What presents on liver biopsy?

1) Rare deficiency of the canalicular multidrug resistance 2 (MDR2)

2) Bilirubin uptake is normal but excretion into the bile is defective

→ increased delta bilirubin (conj. Bili bound to albumin)

3) Total Bili usually 2.0 - 5.0 with more than 50% conjugated Bili

4) Dark granules on liver biopsy from pigmented lysosomes

Rotor Syndrome:

1) What condition is this similar to?

2) What is believed to be the defect?

3) What are the risks?

1) Similar to DJS but does not present with dark granules on liver biopsy

2) reduction in concentration of Ligandin

3) Relatively benign, excellent prognosis, no treatment required

Post-Hepatic Jaundice:

1) What are the main causes?

2) What is affected?

1) caused by biliary obstructive disease, usually caused by physical obstruction (ex. Tumors or gall stones)

2) Conjugation is normal but excretion is defective, leading to clay-colored stool

What are the Main Drug and Alcohol Related Disorders?

• Alcoholic Fatty Liver

• Alcoholic Hepatitis

• Alcoholic Cirrhosis

• Acetaminophen drug toxicity

What are the Clinical Features of Alcoholic Fatty Liver?

• Mildest form

• Slight increase in ALT, AST, GGT

• Fatty infiltrates in vacuoles of liver cells on biopsies

• Complete recovery 1 month after drug removal

What are the Clinical Features of Alcoholic Hepatitis?

• Fever, ascites

• Moderate increase in ALT, AST, GGT, AND ALP

• AST/ALT Ratio (De Ritis Ratio) greater than 2.0

• Total Bili > 5 mg/dL

• Albumin reduced

• INR increased

• Increased creatinine may indicate very severe form that precede hepatorenal syndrome and death

What are the Clinical Features of Alcoholic Cirrhosis?

• Last and most severe

• 5-year survival rate increases by 60% if drinking is stopped; otherwise 30%

• Nonspecific symptoms include:

  • Weight loss, weakness, hepatomegaly, splenomegaly, jaundice, ascites, fever, malnutrition, and edema

• Increase in LFTs (ALT, AST, GGT, ALP, AND T BILI)

• Decrease in Albumin

• Prolonged PT first due to short half life of Factor VII; but PTT also affected in severe cases

• Definitive Diagnosis is liver biopsy

What are the Physiologic Characteristics of Neonatal Jaundice?

• Usually noted between 2-3 days of neonatal life; but peaks by day 5

• Bili concentration may rarely rise at a rate of > 5 mg/dL per day

What are the Pathologic Features of Neonatal Jaundice?

• May appear within first 24 hours of life

• May persist beyond 10 days

• Bili rises quickly

• Conjugated bilirubin > 2 mg/dL

  • Most common cause due to HDFN

What are the 5 Main Enzymes that help assess Liver Function?

1) Alkaline Phosphatase (ALP)

2) Gamma-Glutamyl Transferase (GGT)

3) Aspartate Aminotransferase (AST) aka Serum Glutamic Oxaloacetic Transferase (SGOT)

4) Alanine Aminotransferase (ALT) aka Serum Glutamic Pyruvic Transaminase (SGPT)

5) LDH (especially LD 4 and 5)

Which Liver enzyme is increased in Obstructive Jaundice?

ALP

Which Liver Enzymes are increased in Hepatitis?

AST and ALT

Which Liver Enzyme is increased in Cirrhosis?

GGT

Aside from viruses, what else can cause Hepatitis?

• Bacterial

• Parasitic

• Chemicals

• Drugs/Toxins

• Radiation

• Auto-immune

Hepatitis A:

1) How common is this?

2) What is route of transmission?

3) Is there a Chronic Phase or vaccine available?

4) What are the Clinical Markers?

5) What method is considered more sensitive in detecting viral genome in different sources?

1) The most common type with short incubation period

2) Fecal-oral transmission

3) No chronic phase but vaccine is available

4) Clinical Markers:

• IgM anti-HAV (undetectable after 3-6 months)

• IgG anti-HAV appears soon after IgM and stable for years (confers life-long immunity)

5) RT-PCR

What are the Clinical Features of Hepatitis B?

• Can cause both Acute and Chronic disease with long Incubation period

• Very stable DNA virus that is found in ALL body fluids

• Increased Risk with: body fluids, blood, drug injection needles, vertical transmission

What are the Clinical Features of Hepatitis C?

• Major route is blood transfusion of blood products that are not properly screened

• Can also be transmitted parenterally

• Around 3% of the world population infected

• Although acute disease is mild and symptomless, Chronic progression is of main concern due to higher rate

  • Leading cause of liver transplantation in the US

What is included in the Lab Diagnosis of HCV?

• Detection of anti-HCV using EIA

• Quantification of viral RNA load using RT-PCR

• Note that detection of HCV Ab indicates exposure but not recent infection of recovery

  • Some patients may clear the virus and be anti-HCV pos but be negative for HCV RNA

What is the Clinical Significance of Prostate-Specific Antigen (PSA)?

• May be elevated in benign prostatic hyperplasia and prostatitis

  • low levels of Free PSA may correlate with prostate cancer

What is the Clinical Significance of Carcinoembryonic Antigen (CEA)?

• Markedly increased in some patients with Colorectal Carcinoma

• Higher concentrations = worse prognosis

  • But can be mildly increased in Smoking, Peptic Ulcer, IBC, and cirrhosis

What is the Clinical Significance of Cancer Antigen 125 (CA-125)?

• Elevated in epithelial ovarian neoplasms

  • May also be elevated in pregnancy, benign ovarian cysts, pelvic inflammation

What is the Clinical Significance of CA 27-29 and CA 15-3?

• Both are elevated in advanced stage of breast cancer

  • Associated with MUC1 gene

What is the Clinical Significance of CA 19-9?

• Elevated in Pancreatic adenocarcinoma

What is the Clinical Significance of alpha fetoprotein (AFP)?

• Elevated in normal pregnancy, cirrhosis, and hepatitis

• Also in most hepatocellular carcinomas

What is the Clinical Significance of beta 2 microglobulin (B2M)?

• Independent prognostic factor for multiple myeloma

What is the Clinical Significance of ALP?

• Mostly elevated in osteogenic sarcoma or bone metastases

What is the Clinical Significance of Acid Phosphatase enzyme?

Prostatic Carcinoma

What is the Clinical Significance of Aldolase (ALD) enzyme?

Skeletal Muscle Disorder

What is the Clinical Significance of AST enzyme?

• Hepatic disorder

• MI

• Skeletal Muscle disorder

What is the Clinical Significance of ALP enzyme?

• Hepatic Disorder

• Bone Disorder

What is the Clinical Significance of Creatine Kinase?

• MI

• Skeletal muscle disorder

What is the Clinical Significance of GGT enzyme?

Hepatic Disorder

What is the Clinical Significance of LDH enzyme?

• MI

• Hepatic disorder

• Hemolysis

• Carcinoma

What enzyme marker is considered to be more sensitive than AST in correlation with MI

LDH:

• Remains elevated up to 2 week post MI

• LD1 isoenzyme specific to myocardium

• Plasma LD2 is higher than LD1

  • LD1:LD2 ration peaks within 2 days and returns to baseline in 10-14 days

What are the Characteristics of Creatine Kinase that help in diagnosis of cardiac damage?

• Highly upregulated in brain and striated muscle cells

• CK-MB isoenzyme levels begin to rise within 4-8 hours post-MI; peaks at 12-24 hours; returns to normal levels within 48-72 hours even 4 days max

Why is CK considered low specificity?

it is expressed in ALL muscle cells not limited to cardiac damage

• In fact, it is also elevated in stroke, pulmonary disease, chronic alcoholism, and after strenuous exercise

What cardiac markers are very specific for cardiac damage?

Cardiac Troponins (TnT, TnI, TnC) → complex of 3 proteins that regulate striated muscle contraction

• TnI and TnT are very cardiac specific that can detect even small damage to cardiac tissue

• Immunoassays using moAbs against amino acids specific to cardiac isoenzymes

How do Cardiac Troponins Present after Myocardial Injury?

• Detectable in plasma at 3 to 12 hours post

• Peaks at 12 to 24 hours

• Can remain elevated for more than 1 week:

  • TnT → usually 8-21 days

  • TnI → usually 7-14 days

Although myoglobin is non-specific, what are the myoglobin levels in MI patients?

• Elevated within 6-10 hours and peaks at 12th hour

What are the signs and symptoms of Acute Myocardial Infarction?

• Chest pain that is characterized by pressure, tightness, pain, squeezing or aching

• Pain or discomfort that spreads to the shoulder, arm, back, neck, jaw, teeth, or sometimes the upper belly

• Cold Sweat

• Fatigue

• Heartburn or indigestion

• Lightheadedness or sudden dizziness

• Nausea

• Shortness of breath