Heme Derivatives Flashcards
Is Heme a protein?
Heme is not a protein; it is a prosthetic group found in hemoglobin, myoglobin, chlorophyll, cytochromes, and several other enzymes
Where is Heme most concentrated in?
Most concentrated in RBCs and Liver cells
Porphyrins
Intermediates of the enzymatic pathway of heme synthesis
Elevated porphyrins (porphyria) are either _________ or ________
Erythropoietic or hepatic
Synthesis of heme is regulated by _______ feedback of heme (something happens to throw the body out of regulation, your body tries to counteract it to get it back to “balance”…….. Ex: Low on heme, sends biosignals to make more RBCs to make more heme)
Negative
Porphyrias
Are rare inherited metabolic disorders caused by loss/gain of function enzymes responsible for heme biosynthesis
Porphyrias may also be classified based on their associated symptoms as acute or cutaneous (non-acute).
Can also be caused by liver diseases or and heavy metal poisoning as well
Cutaneous (non-acute) Porphyrias:
- Chronic conditions
- Photosensitivity
- Blistering lesions
Testing used to monitor and diagnose Porphyrias
Genetic assays
Function/quantitative assays for enzymes responsible for heme synthesis
Identify/quantify porphyrins and other precursor compounds
(Must be protected from light to prevent degradation)
Urine Porphyrin Testing
Stable for 48 hours refrigerated and several weeks frozen
Dilute samples (creatinine <25 mg/dL) inadequate for testing
Porphyrin in urine causes it to have a Port wine color
Stool Porphyrin Testing
Must be stored frozen
Blood Porphyrin testing
EDTA whole blood samples
Stored in the dark refrigerated
What is Hemoglobin?
Is classified as a transport protein.
Its role is to transport oxygen from the lungs to the tissues, and transport carbon dioxide back to the lungs.
Heme synthesis occurs in plasma and mitochondria
The steps catalyzed by ALA dehydratase and ferrochelatase are inhibited by LEAD (how heavy metals inhibit the synthesis of heme)
Hemoglobin synthesis occurs in the immature RBCs located in the bone marrow
2 α-like chains and 2 β-like chains that surround a heme molecule
Synthesis of hemoglobin
Synthesized in RBCs located in bone marrow
Iron is inserted into heme to help bind Oxygen
After RBC lysis hemoglobin is transported to the liver to be recycled
- Iron is stored (ferritin)
- Globin chains broken down into amino acids
- Heme converted to bilirubin and urobilinogen
Testing of hemoglobin
Hemoglobin concentration is part of CBC
Sickle Cell Anemia
HbA mutated to HbS
Thalassemia
Mutation reduce the amounts of normal hemoglobin produced
Hemoglobinopathies
Mutations globin chain that produce structurally different hemoglobin decreasing RBC survival
How can Hemoglobinopathies be evaluated?
Evaluated via electrophoresis
What is myoglobin?
Myoglobin is the primary oxygen-carrying protein found in striated skeletal and cardiac muscle, accounting for approximately 2% of total muscle protein.
When striated/cardiac muscle is damaged myoglobin is released
Is a nephrotoxin, severe muscle damage (muscle torn or separated from tendon) can cause harm to the kidneys
Heart attack, muscle injury
Liver
Liver is an extremely vascular organ that receives its blood supply from two major sources: the hepatic artery and the portal vein.
Excretory and Secretory Functions (Liver)
Processing and excretion of endogenous and exogenous substances into the bile or urine such as the major heme waste product bilirubin
The liver is the only organ that has the capacity to rid the body of heme waste products.
Unconjugated bilirubin
(indirect and has not had glucuronic acid attached to bilirubin) is insoluble in water and cannot be removed from the body until it has been conjugated by the liver.
Conjugated bilirubin
(glucuronic acid attached to bilirubin) is water soluble and can be secreted from the hepatocyte into the bile canaliculi.
_______ mg of bilirubin is produced per day
200-300 mg
Key Points of Bilirubin Metabolism
After RBC destruction hemoglobin is broken down into heme and globin
Heme is further broken down into unconjugated bilirubin to be transferred to the liver by albumin
In the liver converts unconjugated bilirubin to conjugated bilirubin
In the intestines conjugated bilirubin is converted to urobilinogen
50-250 mg of urobilinogen is excreted in feces per day
1-4 mg of urobilinogen is excreted in the urine per day
Metabolism and how they can process carbs
Second major function of the liver is the metabolic processes.
Metabolism of carbohydrates is one of the most important functions of the liver.
Can process them in one of three ways:
(1) use the glucose for its own cellular energy requirements
(2) circulate the glucose for use at the peripheral tissues
(3) store glucose as glycogen (principal storage form of glucose) within the liver itself or within other tissues
Is responsible for metabolizing both lipids and the lipoproteins and is responsible for gathering free fatty acids from the diet, and those produced by the liver itself, and breaking them down to produce acetyl-CoA
Almost all proteins are synthesized by the liver except for the immunoglobulins (produced by WBCs) and adult hemoglobin (produced mainly in the bone marrow).
Detoxification and Drug Metabolism
Serves as a gatekeeper between substances absorbed by the gastrointestinal tract and those released into systemic circulation
System is responsible for the detoxification of many drugs through oxidation, reduction, hydrolysis, hydroxylation, carboxylation, and demethylation
To get rid of drugs, your body will have to get rid of it by using the liver. Abusing drugs impacts your liver.
Jaundice
Describes the yellow discoloration of the skin, eyes, and mucous membranes, most often resulting from the retention of bilirubin
Comes from the French word jaune, which means “yellow”
One of the oldest known pathologic conditions reported
Icterus: Yellow discoloration of serum/plasma due to bilirubin concentration
Jaundice is classified based on the site of the disorder:
- Prehepatic jaundice (somethings occurring before bilirubin reaches liver to cause jaundice…ex: hemolytic anemia)
- Hepatic jaundice
- Posthepatic jaundice
Prehepatic jaundice
Occurs when the problem causing the jaundice occurs prior to liver metabolism.
Hepatic jaundice
Occurs when the primary problem causing the jaundice resides in the liver.
Posthepatic jaundice
Results from biliary obstructive disease, usually from physical obstructions.
Cirrhosis
Clinical condition in which scar tissue replaces normal, healthy liver tissue
Rarely causes signs and symptoms in its early stages, but as liver function deteriorates, signs and symptoms appear including fatigue, nausea, unintended weight loss, jaundice
In the United States, the most common cause of cirrhosis is chronic alcoholism.
Other causes of cirrhosis include chronic infection with the hepatitis B (HBV), C (HCV), and D (HDV) viruses; autoimmune hepatitis; inherited disorders; nonalcoholic steatohepatitis; blocked bile ducts; drugs; toxins; and infections.
Tumors
Are classified as primary or metastatic. Primary liver cancer is cancer that begins in the liver cells, while metastatic cancer occurs when tumors from other parts of the body spread (metastasize) to the liver.
Malignant tumors of the liver include hepatocellular carcinoma (HCC) (also known as hepatocarcinoma, and hepatoma) and bile duct carcinoma.
Chronic liver failure and cirrhosis are important risk factors for HCC
Reye’s Syndrome
A group of disorders caused by infectious, metabolic, toxic, or drug-induced disease found almost exclusively in children
Acute illness of noninflammatory encephalopathy, fatty degeneration of the liver, profuse vomiting, and varying degrees of neurological impairment.
Seen with hyperbilirubinemia, & 3x increases in ammonia, ALT, and AST (liver enzymes)
Drug- and Alcohol-Related Disorders
Primary target organ for adverse drug reactions because it plays a central role in drug metabolism
Many drugs are known to cause liver damage, ranging from very mild transient forms to fulminant liver failure.
- The most important is ethanol. In very small amounts, ethanol causes very mild, transient, and unnoticed injury to the liver; however, with heavier and prolonged consumption, it can lead to alcoholic cirrhosis. - It can also lead to alcoholic fatty liver with inflammation (steatohepatitis) or fatty liver disease
Common signs and symptoms of alcoholic hepatitis
Fever
Ascites
Proximal muscle loss
Elevated AST, ALT, GGT, and ALP
Total Bilirubin (both direct and indirect) > 5 mg/dL
Diazo reaction
In old times diazo reaction was used to calculate bilirubin from urine testing to also calculate serum bilirubin
All common bilirubin testing methodologies use a modification of the diazo reaction
Bilirubinometry used for testing ______ population
Neonatal population
Uses microspectrophotometers to quantify optical density of bilirubin, Hgb, and melanin in subcutaneous layer of infant skin
Not used on adults because carotenoid compounds in adult serum interfere
Three fractions of bilirubin are measured to make up Total Bilirubin….
- Direct Bilirubin (conjugated bilirubin)
- Indirect Bilirubin (unconjugated bilirubin)
- Delta Bilirubin
Direct Bilirubin (conjugated bilirubin)
Directly measured
Water soluble, reaction does not require accelerator
Indirect Bilirubin (unconjugated bilirubin)
Calculated by subtracting direct bilirubin from total bilirubin
Water insoluble, reaction requires accelerator
Delta Bilirubin
Conjugated bilirubin that is covalently bound to albumin
Only seen in significant hepatic obstruction
To big for glomerular filtration
How is unconjugated (indirect) bilirubin calculated?
Total bilirubin - Conjugated bilirubin
What is the preferred reference method or standardization of bilirubin analysis?
There is no preferred reference method or standardization of bilirubin analysis; however, the American Association for Clinical Chemistry and the National Bureau of Standards have published a candidate reference method for total bilirubin, a modified Jendrassik-Grof procedure using caffeine–benzoate as a solubilizer.
Adults Total bili = 0.2 - 1.0 mg/dL
Premature total bili = 10 - 12 mg/dL
Full term bili = 4 - 6 mg/dL
On chart: infants have a much higher bilirubin
Sample processingfor Liver Function Tests
Serum or Plasma used for testing
Fasting sample preferred in the presence of lipemia (false high bilirubin)
Hemolyzed samples should be avoided (false low results)
If left unprotected from light results may reduce 30%-50% per hour
Storage:
- In the dark
- Stable 2 days at room temperature
- Stable 1 week refrigerated
- Stable indefinitely frozen
If left in light, the bilirubin will be converted to biliverdin
Urobilinogen - Urine Liver function test storage
Increased in hemolytic conditions and defective liver function (hepatitis)
Absent in biliary obstruction
Uses the Ehrlich reaction (P-dimethylamino benzaldehyde)
Fresh 2 hr sample protected from light
Sitting sample will cause falsely low results due to oxidation of urobilinogen to urobilin
Reference Range: 0.1-1.0 Ehrlich units/ mg
Urobilinogen - Feces Liver function test storage
Usually detected via physical examination
Semiquantitive methods are available
Hepatitis
Inflammatory condition of the liver
Viral infection account for most cases observed in the clinical setting, symptoms include:
Acute Onset (“sudden”)
Jaundice
Dark Urine
Fatigue
Nausea
Vomiting
Abdominal Pain
Serum transaminase levels elevated more than 6 months in chronic cases
Hepatitis B
Known previously as serum hepatitis or long-incubation hepatitis, HBV can cause both acute and chronic hepatitis and is the most ubiquitous of the hepatitis viruses. Viable for 7 days on surfaces.
Hepatitis B Surface Antigen (HBsAg)
Patient infected but not infectious
Only serological marker in weeks 3-5 of infection
Hepatitis B Surface Antibody (anti-HBs)
Suggest past infection or vaccine immunity
Hepatitis B Core Antigen
No test available
Only present during acute stage of infection
Hepatitis B Core Antibody, Total
Test used to differentiate chronic and recent infections
Hepatitis B Core Antibody, IgM
Second step in differentiating between chronic and recent infections
Hepatitis B Envelope Antigen (HBeAg)
HBeAg in the presence of HBsAg predicts severe infection and chronic liver disease
Coorelates with the number of infectious virus particles
(“comes later on in the infection”)
Hepatitis B Envelope Antibody (Anti-HBe)
Indicates low infectivity
Hepatitis A
HAV, also known as infectious hepatitis or short- incubation hepatitis, is the most common form of viral hepatitis worldwide. Additional symptoms include fever, anorexia, and malaise.
Hepatitis C
HCV (originally “non-A non-B hepatitis”) is caused by a virus with an RNA genome that is a member of the Flaviviridae family. HCV is transmitted parenterally.
Hepatitis D
Hepatitis D virus (also known as delta hepatitis) is a unique subviral satellite virus. It is a small, defective RNA-containing virus that cannot replicate independently but rather requires the HBsAg of HBV for replication.
(Needs Hepatitis B to exist)
Hepatitis D
Hepatitis D virus (also known as delta hepatitis) is a unique subviral satellite virus. It is a small, defective RNA-containing virus that cannot replicate independently but rather requires the HBsAg of HBV for replication.
(Needs Hepatitis B to exist)
Hepatitis E
A nonenveloped RNA virus & the sole member of the genus Hepevirus in the family Hepeviridae.
Hepatitis F
Is an enteric agent that may be transmitted to primates.
Hepatitis _____ is the only one that has DNA as a nucleotide
B
Which Types of Hepatitis has vaccines?
A & B
Which is the only type of Hepatitis that does not cause chronic infection?
A
Are serological diagnosis available for all Hepatitis?
Yes
