Chem- Unit 4: Organ systems and Clinical Correlation

what are the two important liver cell types

Hepatocytes (~80) and Kupffer cells

What do hepatocytes do?

produce bile, metabolism, detoxification, and protein synthesis

What do Kupffer cells do?

play a role in blood formation and the destruction of cellular debris

(immune surveillance and homeostasis)

What is bilirubin?

breakdown product of hemoglobin

What is unconjugated (indirect) bilirubin?

bilirubin that is not yet treated by liver, insoluble in water and plasma and the body cannot eliminate.

what can unconjugated bilirubin cause

seizures and severe brain damage (kernicterus)

what is conjugated (direct) bilirubin

already treated by the liver; water soluble and able to be eliminated via feces and some urine

how does the liver handle bilirubin

converts unconjugated bilirubin into conjugated bilirubin then into bile

What is bile composed of?

bile salts, phospholipids, cholesterol, conjugated bilirubin, electrolytes, and water

what happens during the Entero-hepatic recirculation

bile facilitates lipid digestion/absorption in GI tract; majority of bile acids are reabsorbed and returned to liver

what can the liver do with carbohydrates

use glucose for energy, circulate glucose for peripheral tissue usage, and store excess glucose as glycogen

what is used to produce acetyl-CoA

free fatty acids (exogenous and endogenous)

what else does the liver metabolize when needed

triglycerides, phospholipids, or cholesterol

Liver synthesizes what?

lipids, phospholipids, and protein

what proteins does the liver not synthesize

immunoglobulins and adult hemoglobin

how does the liver play a role in detoxification

gatekeeper between substances absorbed by the GI tract and those released into circulation

where do most substances absorbed by GI tract head to?

the liver first via portal vein (Called "first pass")

how does the liver prevent toxic/harmful substances from reaching systematic circulation

by conjugating/binding that inactivates and makes water soluble (reversible) for urine elimination; chemically changes/alters for elimination via bile

How does the liver handle drug detox/ metabolism

via microsomes using cytochrome P-450 isoenzymes

how does P-450 isoenzyme clear drugs from blood

uses oxidation, reduction, hydrolysis, hydroxylation, carboxylation and demethylation chemical reactions

how is the liver important for storage

stores carbs/glycogen, vitamins, and mineral

how much of body glycogen stores does the liver contain

1/4

what controls the carb/glycogen stores in the liver

insulin and glucagon

what vitamins are in the liver

A, D, E, K, B12 (mainly fat soluble vitamins)

what do vitamins A and D do

A: retinol (eye)

D: Calciferol (skeletal development and calcium uptake)

what minerals are stored in the liver

iron and copper

what is iron stored as in the liver

ferritin (from RBC breakdown)

what is copper used for

protein and energy synthesis; tightly regulated pro-oxidant

what is jaundice

yellow discoloration of skin, eyes, and mucous membranes due to build-up of bilirubin

what is another name for jaundice

icterus (hyperbilirubinemia)

what is pre-hepatic jaundice

issue occurs prior to liver metabolism; prior to hepatic bilirubin conjugation (before reaching liver)

what is increased in pre-hepatic jaundice

Blood unconjugated bilirubin levels are not water soluble and cannot be filtered by kidneys or seen in urine. unconjugated bilirubin backs up in the blood stream

what does unconjugated bilirubin bind to for liver transport

albumin

List causes of pre-hepatic jaundice

Accelerated hemolysis: sickle cell crisis, hemolytic anemia/destruction of transfused RBCs

Decreased delivery if unconjugated bilirubin to liver

what is hepatic jaundice

issue occurs in the liver due to liver dysfunction/disease

list two unconjugated hyperbilirubinemias

Gilbert's syndrome and Crigler-Najjar

what causes Gilbert's syndrome

decreased conjugation due to benign genetic mutation

(most common cause of hepatic jaundice)

what is the genetic mutation of Gilbert's syndrome

UGT1A1

what causes Crigler-Najjar

body cannot conjugate bilirubin

List two Conjugated hyperbilirubinemias

Dubin-Johnson and Rotor's syndrome

what causes Dubin-Johnson syndrome

liver conjugates, but body can't eliminate

Obstructive in nature

what happens with Delta bilirubin in Dubin-Johnson

conjugated bilirubin found in blood bound to albumin (can cause problems with lab measurements)

(normally unconjugated bilirubin found in blood attaches to albumin carrier protein)

what causes Rotor's syndrome

similar to Dubin-Johnson but causation not yet known

What is post-hepatic jaundice?

issue due to biliary obstructive disease (typically physical obstruction); occurs after liver conjugates bilirubin

what happens in biliary obstruction disease

involves gall bladder and bile canal infrastructure

liver can conjugate but cannot excrete correctly

Physical obstructions prevent flow of conjugated bilirubin into bile canaliculi

Clay colored stools

List three liver diseases

Cirrhosis, tumors, Reye's Syndrome

what is cirrhosis

scarring of the liver

how does cirrhosis happen

scar tissue blocks blood flow and prevents proper liver tissue

when is cirrhosis detected and list symptoms

rarely detected in early phases; when liver deteriorates signs and symptoms appear

Symptoms: fatigue, nausea, unexpected weight loss, jaundice

what is the most common cause of cirrhosis

chronic alcoholism

what are other causes of cirrhosis

chronic Hep B, C, and D viral infections, autoimmune disorders, inherited disorders, blocked bile ducts, drugs, toxins, and other infections affecting the liver

What is hemochromatosis?

iron overload that accumulates in the liver

(stored iron can cause severe damage that may lead to organ failure and cirrhosis. Therapeutic phlebotomy is treatments)

how does tumors account for hepatic malignancies

90% of them are metastatic in origin (does not originate in liver cells)

what are common metastatic cancers

colon, lung, breast

what are benign tumors

hepatocellular adenoma, hemangiomas

what are malignant tumors

hepatocellular carcinoma (HCC), hepatoma

(80% of HCC cases caused by Hep B/C viral infections)

what is Reye's syndrome

group of disorders caused by infections, metabolic, toxic, or drug-induced states

Where is Reye's syndrome predominantly found

in children

What is Reye's Syndrome associated with?

Associated with aspirin ingestion during viral infection

Reye's syndrome is often preceded by what

by viral infections: varicella, gastroenteritis, flu/upper respiratory tract infection

what is the acute illness of Reye's Syndrome characterized by

noninflammatory encephalopathy, fatty degeneration of liver, clinical presentation of profuse vomiting, neurologic impairment

drug-induced liver disease accounts for what percentage of acute liver failure in US

33-50%

what is the most common mechanism of toxicity for drug-induced liver disease

immune-mediated injury to hepatocytes

what is the most significant drug cause of hepatic toxicity

ethanol (alcohol)

what are the three stages of liver injury due to excessive alcohol consumption

alcoholic fatty liver (mild), alcoholic hepatitis (moderate), alcoholic cirrhosis (severe)

how can recovery happen for Alcoholic fatty liver

with removal of drug

what is shown in blood findings for alcoholic fatty liver

mild AST, ALT, and GGT elevations

what are the blood findings for alcoholic hepatitis

Moderate AST, ALT, GGT, and Alk phos elevations

(AST/ALT ratio >2)

what is medically significant in alcoholic hepatitis

liver damage; bilirubin >5 mg/dL

what is the prognosis for alcoholic cirrhosis

poor; 5 year survival rate 60% if no drinking; 30% if drinking

what are the blood findings for alcoholic cirrhosis

severe elevations in all/most liver enzymes in blood samples

what are the 4 liver function tests (LFTs) for bilirubin

Classic Diazo Reaction, Van den Berg Reaction, Malloy and Evelyn; Jendrassik and Grof

Who discovered Classic Diazo Reaction (CDR) and what year

Paul Ehrlich 1883

what specimen is used for the Classic Diazo Reaction

urine

what color does urine turn in the presence of bilirubin in CDR

purple

how does CDR work

Diazo reagent splits every bilirubin molecule in sample into two azobilirubin molecules; azobilirubin turns purple in diazo reagent

what year was the test Van den Berg reaction was discovered

1913

what did the Van den Burg reaction prove

that serum diazo reaction was possible

how does the Van den Burg reaction work

uses accelerator/solubilizer for unconjugated fraction

what is the disadvantage of the Van den Berg reaction test

had many associated errors and difficulty reproducing results

When was Malloy and Evelyn test discovered

1937

what was discovered by Malloy and Evelyn testing

first useful serum quantitative bilirubin method

modern bilirubin testing uses what methods

Malloy-Evelyn modifications

how does the Malloy-Evelyn test work

uses classic diazo reaction w/ accelerator to solubilize unconjugated bilirubin

What pH level is used and what is the maximum absorbance for the Malloy-Evelyn test

pH: 1.2; max absorbance: 560 nm

what is the most common accelerator and how much is used in Malloy-Evelynn test

50 % methanal

When was Jendrassik-Grof method was discovered

1938

what happens in the Jendrassik-Grof method

Bilirubin pigments in sample reacted with diazo reagent

what are the results of Jendrassik-Grof method

purple coloring of azobilirubin molecules (Mallow-Evelyn)

(intensity in purple color directly proportional to bilirubin concentration)

How does the Jendrassik-Grof method work?

uses caffeine/benzoate/acetone accelerator, minimal turbidity and relatively constant serum blank; not affected by pH changes or hemoglobin in sample (up to 750 mg/dL); insensitive to 50- fold variation in sample protein concentration; maintains optical sensitivity even at low bilirubin concentrations

what do the AACC and NIST recommend for testing Tbil

modified Jendrassik-Grof method with caffeine/benzoate accelerator

what does the modified Jendrassik-Grof method test

total bilirubin= conjugated + unconjugated

what is directly measured in the modified Jendrassik-Grof method

total bilirubin and conjugated bilirubin

Total bilirubin (aliquot #1): Tests for all unconjugated bilirubin, conjugated bilirubin, and delta bilirubin; reacted with diazo reagent after stabilization with caffeine-benzoate accelerator

Direct bilirubin only (aliquot #2): reacted directly with diazo reagent to measure only conjugated bilirubin

what is calculated in the modified Jendrassik-Grof

indirect bilirubin

Total bilirubin mins conjugated (direct) bilirubin = unconjugated (indirect) bilirubin

Tbil - BC = BU

modified Jendrassik-Grof

what specimens can be used to test for bilirubin

blood or urine, more stable in blood

avoid hemolysis and protect from light

what is the reagent used to form a red color in presence of urobilinogen

p-dimethylaminobenzaldehyde (Ehrlich's reagent)

what does AST mean

aspartate aminotransferase

what does ALT mean

alanine aminotransferase

what does ALP mean

alkaline phosphatase