CC2 LEC LIVER FUNCTIONS

1. Excretion/Secretion

2. Metabolism

3. Detoxification

4. Storage

4 functions of the liver

Hepatic artery

Artery of the liver that receives blood to function

Portal vein

Receives blood to be detoxified

Bilirubin

– the major heme waste product and the principal pigment in the bile.

Bile

– made up of bile acids or salts, bile pigments, cholesterols.

Immunoglobulins

Adult Hb

All proteins are synthesized by the liver except? (2)

Albumin

The most important protein is synthesized by the liver. What is this protein?

Glycogen

Liver stores glucose in the form of?

Gluconeogensis

glucose formed from non glucose

True

The liver serves as a gatekeeper between substances absorbed the GIT and those released into the systemic circulation. (T/F)

First pass

every substance that is absorbed in the GIT must first pass through the liver

Liver microsomes via the cytochrome P-450 isoenzymes

Detoxification takes place in the?

ADEK

Fat soluble diseases

B-complex and C

Water soluble vitamins (2)

Yellow

Jaune means?

Jaundice

Oldest pathologic conditions reported.

• Used to describe the yellow discoloration of the skin, eyes, and mucous membranes resulting from the retention of bilirubin.

3-5 mg/dL

Jaundice levels

PREHEPATIC JAUNDICE

• Occurs when the problem causing the jaundice occurs prior to liver metabolism.

• Usually seen in cases of Hemolytic anemia.

caused by: RBC Destruction

Serum bilirubin: Elevated B1

Urine bilirubin: Negative

Urobilinogen: Normal/Increased

Clinical cases: HDFN, Hemolytic anemia, Malaria

Unconjugated bilirubin

Bilirubin that is predominant in prehepatic jaundice

Hepatic jaundice

• Occurs when the problem resides in the liver.

• Intrinsic liver defect or disease.

• Due to bilirubin metabolism disorders, transport defects or hepatocellular injuries.

caused by: Hepatocyte injury

Serum bilirubin: Both elevated

Urine bilirubin: Positive

Urobilinogen: Decreased

Clinical cases: Cirrhosis, Viral hepatitis

Gilbert’s Disease

Enzymatic defect

• Benign, autosomal recessive, hereditary disorder.

• Results from a genetic mutation in the gene UGT1A1 that produces UDPGT

The most common cause

• Intermittent unconjugated hyperbilirubinemia, underlying liver disease due to a defective conjugation system in the absence of hemolysis.

Total bilirubin: ↑

Conjugated bilirubin: Normal

Unconjugated: ↑

GILBERT’S DISEASE

Total bilirubin: ?

Conjugated bilirubin: ?

Unconjugated: ?

Crigler-Najjar syndrome

• Syndrome of chronic nonhemolytic unconjugated hyperbilirubinemia.

• Inherited disorder of bilirubin metabolism involving a gene defect.

• More rare and more serious disorder that may result in death.

Total bilirubin: ↑

Conjugated bilirubin: ↓

Unconjugated: ↑

CRIGLER-NAJJAR SYNDROME

Total bilirubin: ?

Conjugated bilirubin: ?

Unconjugated: ?

Type 1 Criggler-Najjar

complete absence of enzymatic bilirubin conjugation

Type 2 Crigler-Najjar syndrome

– mutation causing severe deficiency of the enzyme responsible for bilirubin conjugation.

Dubin-Johnson Syndrome

• A rare autosomal recessive inherited disorder caused by a deficiency of the canalicular multidrug resistance/multispecific organic anionic transporter protein (MDR2/cMOAT).

• The removal of conjugated bilirubin from the liver cell and the excretion into the bile are defective.

• Obstructive in nature. Conjugated bilirubin binds to albumin (delta bilirubin).

Total bilirubin: ↑

Conjugated bilirubin: ↓

Unconjugated: Normal

DUBIN-JOHNSON

Total bilirubin: ?

Conjugated bilirubin: ?

Unconjugated: ?

Dark-stained granules

Dubin-Johnson syndrome in liver biopsy sample, what is the color?

Rotor syndrome

reduction in the concentration of activity of intracellular binding proteins such as Ligandin

Total bilirubin: ↑

Conjugated bilirubin: ↓

Unconjugated: Normal

ROTOR SYNDROME

Total bilirubin: ?

Conjugated bilirubin: ?

Unconjugated: ?

Physiologic Jaundice of the Newborn

• Deficiency in the enzyme glucoronyl transferase, one of the last liver functions to be activated in prenatal life since bilirubin processing is handled by the mother of the fetus.

• This condition causes kernicterus: bilirubin build- up in the brain, deposited in the brain nuclei and degenerate nerve cells.

• Infants with this type of jaundice are usually treated with ultraviolet radiation to destroy the bilirubin as it passes through the capillaries of the skin.

Total bilirubin: ↑

Conjugated bilirubin: Normal

Unconjugated: ↑

PHYSIOLOGIC JAUNDICE OF THE NEWBORN

Total bilirubin: ?

Conjugated bilirubin: ?

Unconjugated: ?

Kernicterus

Physiologic Jaundice of the Newborn causes a condition called ________ which is bilirubin build-up in the brain

Lucey-Driscoll Syndrome

• Familial form of unconjugated hyperbilirubinemia and may be caused by a circulating inhibitor of bilirubin conjugation in the baby’s or mother’s blood.

Posthepatic jaundice

Type of jaundice that results in biliary obstructive diseases, usually from physical obstructions that prevent the flow of conjugated bilirubin to the bile canaliculi.

caused by: Obstruction of bile flow

Serum bilirubin: Elevated B2

Urine bilirubin: Positive

Urobilinogen: Decreased

Clinical cases: Cholelithiasis, Tumor

Total bilirubin: ↑

Conjugated bilirubin: ↑

Unconjugated: ↑

POSTHEPATIC

Total bilirubin: ?

Conjugated bilirubin: ?

Unconjugated: ?

Crigler-Najjar syndrome

Only jaundice wherein conjugated bilirubin is DECREASED

Cirrhosis

• A clinical condition in which scar tissue replaces normal, healthy liver tissue.

• Can be caused by Chronic Alcoholism, Hepatitis B, C, D infection, autoimmune hepatitis, inherited disorders, drugs, toxins, etc.

• Cannot be easily reversed.

Tumors

• Cancers of the liver are classified as primary or metastatic.

Primary liver cancer

cancer that begins in the liver cells

Metastatic cancer

– occurs when tumors from other parts of the body spread towards the liver.

Hepatocellular adenoma

– benign tumor of the liver exclusive in females of child- bearing age.

Hemangiomas

– masses of blood vessels with no known cause.

Hepatocellular carcinoma

– most common malignant tumor, aka hepatocarcinoma and hepatoma

Hepatoblastoma

uncommon hepatic malignancy in children

Reye syndrome

• An acute illness characterized by non-inflammatory encephalopathy and fatty degeneration of the liver, with a clinical presentation of profuse vomiting accompanied with vary degrees of neurologic impairment such as fluctuating personality changes and deterioration in consciousness.

Ammonia

AST

ALT

Reye’s syndrome has 3x increase in which analytes? (AAA)

Syndrome

A term used to describe a group of disorders caused by infectious, metabolic, toxic or drug-induced disease found in almost exclusively in children.

Viral infection

Reye syndrome is often preceded by what type of infection?

Ethanol

the most important drug associated with hepatic toxicity

Alcoholic fatty liver

• Mildest category

• Slight elevations in AST, ALT and GGT.

• Fatty infiltrates are noted on vacuoles of the liver

• Affect young to middle-aged people with history of moderate alcohol consumption.

• Complete recover within 1 month is seen when the drug is removed.

Alcoholic hepatitis

• Common signs include fever, ascites, proximal muscle loss

• Moderately elevated AST, ALT, GGT and ALP

• Elevations in total Bilirubin > 5 mg/dL

• AST elevations are 2x the upper reference of normal value.

• AST/ALT Ratio (De Ritis ratio) greater than 2.

• Albumin is decreased and INR is elevated.

>5 mg/dL

Total bilirubin of a person with alcoholic hepatitis

Alcoholic cirrhosis

• The last and most severe stage

• Prognosis depends on the nature and severity of associated conditions such as gastrointestinal bleeding or ascites or ascites

• Common in males than in females

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

• Increased LFTs, decreased albumin, prolonged prothrombin time

Liver biopsy

definitive method for diagnosis of alcoholic cirrhosis

Hepatitis A

Hepatitis E

Hepatitis viruses with a faecal-oral route of infection (tAE)

Hepatitis B

Hepatitis virus with the longest incubation period (2-6 months)

Hepatitis B

Hepatitis C

2 Hepatitis viruses with insidious (slow) onset

Hepatitis D

Hepatitis viruses with the highest acute mortality rate (30%) (D for die)

Hepatitis C

Hepatitis with the highest chance to progress to end-stage liver disease (25%)

Liver function tests

A panel of biochemical tests are that are often deranged in patients with various forms of liver disease and dysfunction.

Synthetic function

Conjugation and excretion

Detoxification function

LFTs assess these 3 functions of the liver

Total protein

Serum protein

Total Albumin-Globulin

Prothrombin time (Vitamin K response test)

Synthetic function tests (4) (TSTP)

Bilirubin tests

Urobilinogen

BSP Dye excretion test

Excretion and conjugation tests (3) (BUB)

Enzyme panels

Ammonia

Detoxification function tests (2) (EA)

Bilirubin 1

Unconjugated

Water-Insoluble

Non-Polar

Indirect Reacting

Hemobilirubin

Slow Reacting

Prehepatic

Bilirubin 2

Conjugated

Water-Soluble

Polar Direct

Reacting

Cholebilirubin

One-minute/Prompt

Post/Hepatic Bilirubin

Delta Bilirubin

Bilirubin bound to albumin

Longer half life (12-14 days)

0-0.2 mg/dL

Conjugated bilirubin reference range

0.2-0.8 mg/dL

Unconjugated bilirubin reference range

0.2-1.0 mg/dL

Total bilirubin reference range

<0.2 mg/dL

Delta bilirubin reference range

Total bilirubin - conjugated bilirubin

Formula for solving for indirect bilirubin

Van den Bergh reaction

the diazotization of bilirubin to produce azobilirubin

Evelyn Malloy method

• Coupling Accelerator: Methanol

• Main Reagent:

• Diazo A = 0.1% sulfanilic acid + HCl

• Diazo B = 0.5% Sodium Nitrite

• Diazo Blank = 1.5% HCl

  • Final Reaction: Pink to Purple Azobilirubin at 560 nm

Jendrassik and Groff method

• Coupling Accelerator: Caffeine Sodium Benzoate

• Main Reagent:

• Diazo A = 0.1% sulfanilic acid + HCl

• Diazo B = 0.5% Sodium Nitrite

• Diazo Blank = 1.5% HCl

  Buffer: Sodium Acetate

  Alkaline pH provider: Alkaline Tartrate

  Initial Reaction Terminator: Ascorbic acid

  Final Reaction: Blue Azobilirubin at 600 nm

Urobilinogen

a colorless end product of bilirubin metabolism that is oxidized by intestinal bacteria to the brown pigment stercobilin for feces or urobilin for urine

2 hours after a meal

2 hour freshly collected urine or stool

PX prep for urobilinogen testing

Ehrlich’s method

Method used for testing urobilinogen (p-dimethyl aminobenzaldehyde reagent)

Bromsulpthalein dye excretion test

Test for hepatocellular function and potency of bile duct

It determines the ability of protein albumin to transport the exogenous dye to the liver where it is excreted in the bile.

Intravenously

How is BSP dye administered?

MacDonald (Single dose method)

Dose: 5mg/kg body weight of patient

Sample collection: After 45 minutes of IV dose

Normal/Expected results: After 45 minutes, ± 5% dye retention

Rosenthal White (Double dose method)

Dose: 2mg/kg body weight of patient

Sample collection: After 5 minutes and after 30 minutes of IV dose

Normal/Expected results: After 5 minutes: 50% dye retention, after 30 minutes: 0% dye retention

Kjeldahl method

TOTAL PROTEIN METHODS

– reference method; based on nitrogen content

Biuret method

TOTAL PROTEIN METHODS

• most widely used; colorimetric at 545nm

Folin-Ciocalteu method

TOTAL PROTEIN METHODS

• highest analytical sensitivity; deep-blue color

Lowry method

TOTAL PROTEIN METHODS

• combination of Biuret and Folin-Ciocalteu methods

Turbidimetric and nephelometric

TOTAL PROTEIN METHODS

• used in CSF and urine spx

UV absorption method

TOTAL PROTEIN METHODS

• absorbance of proteins at 210nm due to peptide bonds

Refractometry

TOTAL PROTEIN METHODS

• alternative test to chemical analysis; refractive index

Electrophoresis

TOTAL PROTEIN METHODS

• preferred in detecting abnormal proteins

Salt fractionation

TOTAL PROTEIN METHODS

• separation of globulins and albumin

Serum protein electrophoresis

Principle: Migration of charged particles in an electrical field

Multiple myeloma

SERUM PROTEIN ELECTROPHORESIS

• Abnormal patterns:

  • Gamma spike

Hepatic cirrhosis

SERUM PROTEIN ELECTROPHORESIS

• Abnormal patterns:

  • Beta-gamma bridging

Nephrotic syndrome

SERUM PROTEIN ELECTROPHORESIS

• Abnormal patterns:

  • a2-globulin band spike

Juvenile cirrhosis (due to a1-antitrypsin deficiency)

SERUM PROTEIN ELECTROPHORESIS

• Abnormal patterns:

  • a1-globulin flat curve

Inflammation

SERUM PROTEIN ELECTROPHORESIS

• Abnormal patterns:

  • Spikes of a1, a2, and B globulin bands

Albumin

Concentration is inversely proportional to severity of liver disease.

Decreased serum _________may be due to decreased synthesis.

Low in Hepatic Cirrhosis & Nephrotic Syndrome (along with low total protein).

What protein?