Biochemistry of Albumin Metabolism Flashcards
What is nephrotic syndrome?
A collection of symptoms due to kidney damage
What is the nephrotic syndrome characterized by?
Proteinuria (mainly albuminuria)
Hypoalbuminemia
Hyperlipidemia
Edema
Disturbance in albumin metabolsim
What is the serum albumin concentration?
A strong prognostic indicator of morbidity and mortality in both sick and seemingly healthy individuals
What is the serum albumin concentration like?
Constant over time, 3% daily variation
What is serum albumin concentration a result of?
Synthesis
Degredation
Distribution
What are the causes of high serum albumin concentration, and how common is it?
Water depletion
Intravenous infusion of plasma
It is unusual to have high serum albumin concentrations
What is it known as if there are high serum albumin concentrations?
Hyperalbunemia
What are the causes of HYPOALBUNEMIA?
Decreased synthesis
Redistribution
Increased loss
Dilution
What are the decreased synthesis causes of hypoalbuminemia?
Malnutrition (protein-poor diet)
Liver disease
What are the redistribution causes of HYPOALBUNEMIA ?
Ascites
Sepsis
What are the increased loss causes of HYPOALBUNEMIA?
Protein-losing nephropathy,
Enteropathy,
Dermatopathy
Loss of plasma from burns, for example
What are the dilution causes of HYPOALBUNEMIA?
Intravenous infusion of fluid
What is the albumin gene?
Member of the albuminoid gene superfamily
Which other proteins are part of the albuminoid gene superfamily?
a-fetoprotein
Vitamin D - binding protein
Afamin (Vitamin E - binding glycoprotein)
Where is the albumin gene located?
Chromosome 4
What is the most abundant protein during fetal life?
a-fetoprotein
What is the most abundant plasma protein in the post-natal life?
Albumin (50% of total protein content)
What is Analbuminemia?
Very rare autosomal recessive disorder caused by mutations in albumin gene
What is Analbunemia characterized by?
Absence or very low levels of albumin in the blood
When is Analbuminemia diagnosed?
Adulthood
What are the clinical presentations of Analbuminemia?
Mild edema
Hypotension
Fatigue
Hyperlipidemia
Occasionally a peculiar lower body lipodystrophy
When is Analbuminemia most severe?
In the fetus or during early infancy, where it can lead to fetal or neonatal death
What is Bisalbuminemia?
Relatively rare hereditary condition caused by mutations in albumin gene or acquired condition by prolonged use of antibiotics or acute pancreatitis
What is the difference between hereditary and acquired Bisalbuminemia?
Hereditary –> permanent
Acquired –> transient
What is Bisalbuminemia charcaterized by?
The presence of two distinct albumin bands on serum protein electrophoresis
What kind of substances do some albumin variants have altered affinity for?
Steroid hormones,
Drugs,
Thyroxine
What are FDH-T4 and FDH-T3?
Rare autosomal dominant syndromes caused by missense mutations in albumin gene
What are FDH-T4 and FDH-T3 characterized by?
Dramatic increase in the affinity of albumin for thyroxine (T4) in the case of FDH-T4 and triiodothyronine (T3) in the case of FDH-T3
What are the results of FDH-T4 and FDH-T3?
Elevated levels of bound T4 and T3 respectively
Do FDH-T4 and FDH-T3 cause disease? Why?
No, these syndromes do not cause disease, the concentration of free hormones is normal
What is the amnagement of FDH-T4/T3 patients?
They do not require any medication, may be at risk for unnecessary drug or surgical treatment
To avoid unnecessary treatment, sequencing of the albumin gene should be performed
Which organs synthesizes albumin?
The liver
Under physiological conditions, only 20% of hepatocytes are committed to the production of 10 to 15g of albumin per day
What happens if the synthesis of albumin needs to be increased?
The liver has a large functional reserve, so it can increase synthesis about 3 to 4 times if required
What is the plasma half life of albumin?
20 days
Where is albumin initially synthesized?
At the ribosomes on the RER of hepatocytes as preproalbumin
What happens to preproalbumin?
A signal peptidase cleaves 18 amino acids from the N-terminus of preproalbumin, leading to the formation of proalbumin that is released from the RER
What happens to the proalbumin?
Furin cleaves 6 additional amino acids from the C-terminus of proalbumin (inactive form) in the Golgi-derived vesicles leading to the formation of albumin
Is albumin the active or inactive form?
Active
What happens to albumin?
It is directly released into the bloodstream almost without any storage in the liver
What % of albumin is stored in the liver?
Less 3%
What could cause the downregulation of albumin synthesis?
Nutrition
Inflammation
How does nutrition affect the downregulation of albumin synthesis?
A diet poor in proteins reduces albumin synthesis for instance, Kwashiorkor
What is Kwashiorkor?
A nutritional disorder most often seen in developing countries, it is a form of malnutrition caused by lack of protein in the diet
What is the major biochemical feature of Kwashiorkor?
Hypoalbuminemia, which can then cause edema and ascites
How does inflammation affect downregulation of the albumin synthesis?
Cytokines inhibit the synthesis of albumin
Which kind of cytokines inhibit the synthesis of albumin?
TNF-a
IL-1
What causes the upregulation of albumin synthesis?
Hormones
What are the examples of hormones that induce albumin synthesis?
Insulin
Cortisol
Thyroid hormones
Growth hormones
Sex hormones
What is FOX -1, when is it released, what is its action?
Released during fasting conditions, it is a transcription factor that goes to the nucleus and causes induction of albumin synthesis
How many amino acids is albumin comprised of?
585 amino acids
What are the charged amino acids that albumin is rich in?
Lysine
Histidine
Arginine
Glutamic acid
Aspartic acid
What is the shape of albumin like?
It is a heart shape in X-ray crystallography
What is the purpose of the heart shape of albumin?
In order not to increase its viscosity
What is the structure of albumin like?
Mature, circulating molecule that is arranged in a series of α-helices, stabilised by 17 disulfide bonds and comprises 3 homologous domains
What are the components of each of the three domains of albumin?
Each domain has two subdomains (A & B)
What are the subdomains of the albumin domains made of?
Composed if 4 and 6 α-helices
What do the domains of albumin contain?
2 sites that play role in trasnporting hydrophobic molecules
7 fatty acid-binding sites
1 heme-binding site
4 metal binding sites
Numerous small ligand-binding sites
WHat are the sites that transport hydrophobic molecules?
Sudlow sites 1 and 2
What are the fatty-acids binding sites?
FA1 to 7, albumin has them in order to carry the fatty acids to their location
What are the examples of the metal binding sites?
Sites A and B,
N-terminal sites (NTS)
Cys34
What is the volume of albumin synthesized daily?
10 to 15g/day
What is the volume of albumin catabolized daily?
10 to 15 g/day
What is the volume % of intravascular albumin?
40%
What is the volume % of interstitial albumin?
60%
What is the distribution of albumin like interstitially?
Skin = 41%
Muscle = 40%
Liver = 3%
Gut = 7%
Subcutaneous = 9%
Where is albumin primarily degraded?
Muscle and skin primarily (40 to 60%)
What percentageof albumin does the liver degrade?
15% or less
What percentage of albumin do the kidneys degrade?
10% and another 10% is through the stomach wall leakage into the GIT
What is the albumin degradation process?
- Specialised epithelial cells endocytose albumin
- Albumin enters early endosomes
- Transferred to late endosomes having endosomal neonatal Fc receptors in the membrane
- At pH of 5 or 6, the protein binds strongly to the receptor at a 1:1 ratio
What happens to the albumin which does not bind to FcRn?
Degradation in the lysosome
How would albumin bound to FcRn leave the cell?
Recycling
Transcytosis
What is the recycling process of albumin?
Albumin is captured on one side of the cell, travels across the cell, and is ejected on the same side of the cell
What is the transcytosis process of albumin?
Albumin is captured in one side of he cell, drawn across the cell, and ejected on the other side of the cell
What are the functions of albumin? (4)
- Maintenance of oncotic or colloid osmotic pressure within vascular compartments
- Binding, transportation, and distribution of endogenous and exogenous ligands
- Antioxidant activity
- Maintenance of acid-base balance
What is the colloid osmotic pressure?
It is exerted by large molecules that do not diffuse readily across the capillary membrane, preventing the leaking of fluids until the extravascular spaces
How many ml of water is each gram of albumin able to hold?
18ml of water within the intravascular space
What are examples of endogenous and exogenous ligands?
Ions, metals, hormones, LCFA, therapeutic drgs and metabolites
What is the antioxidant activity of albumin?
It has so many binding sites, like Cys34, which bind free radicals and neutralize them, either directly or through Fenton reaction
Which amino acid helps albumin maintain acid-base balance?
Histidine
What can metabolic changes associated with diseases lead to?
Post-translational modifications of albumin
What are examples of post-translational modifications?
Oxidation
Glycation
Nitrosylation
Guanylation
Dimerization
Truncation
What is the result of post-translational modifications of albumin?
Formation of numerous albumin variants that become abundant in the blood
What happens under non-physiological conditions?
There is production of free radical and release of free fatty-acids into the plasma
What can free radicals cause?
Oxidation or truncation at the N-terminal sites of albumin –> reduction of its affinity to transitional metal, especially cobalt
What is the result of high plasma-free fatty acid levels?
Change the conformation of albumin hampering the binding of cobalt to its binding site
What is the albumin variant with high FFA plasma levels called?
Ischemia-Modified Albumin
What are the Albumin Cobalt Binding Test?
Measurement of ischemia-modified albumin
FDA-approved biomarker for early detection of MI but also used for many other pathological conditions (so it is non-specific)
What causes albuminuria/hypoalbuminemia?
In renal disease, there is increased permeability of the glomerular capillaries to plasma proteins; albumin passes into the urine and there is decreased levels of albumin in serum
How does an increase in HMG-CoA reductase cause hyperlipidemia?
Reduction of colloid osmotic pressure, compensation mechanism is the production of lipid proteins which increaseson of the enzyme, which will eventually form cholester the concentratiol
How does decrease in lipoprotein lipase cause hyperlipidemia?
- Lipoprotein lipase decrease
- VLDL receptor decrease
- Decrease of hepatic triglyceride lipase
- Decrease in lipoprotein degradation
- Albumin is not there to transfer the FAA to the membrane component of the cells
How does edema occur due to hypoalbuminemia?
Inadequate colloid osmotic pressure
Vascular fluid leakage to extravascular space
Edema
What is Muehrcke’s nails?
Rare finding of the nails characterized by distinct pattern of paired, white horizontal lines across the nails
What is the reason behind Muehrcke’s nails?
Hypoalbuminemia can cause local edema in the fingernails, cause vascular compression within the edema in the nail bed altered blood supply to nail matrix
Is Muehrcke’s nails reversible?
Yes, with a rise in serum albumin levels
