Physiology

Protein and nitrogen balance is essential for health. Abnormalities in protein metabolism can lead to a variety of disorders

Normal States

Nitrogen Balance: Intake of nitrogen equals excretion of nitrogen
Normal Protein Synthesis and Degradation: Balanced synthesis and degradation of proteins
Normal Amino Acid Levels: Appropriate levels of amino acids in blood and tissues

Nitrogen Balance

Nitrogen balance is a state in which the amount of nitrogen consumed (primarily as protein) equals the amount of nitrogen excreted (primarily as urea)
Positive Nitrogen Balance: Nitrogen intake exceeds nitrogen excretion, indicating net protein synthesis. This occurs during growth, pregnancy, and recovery from illness
Negative Nitrogen Balance: Nitrogen excretion exceeds nitrogen intake, indicating net protein breakdown. This occurs during starvation, severe illness, and trauma
Factors Affecting Nitrogen Balance
- Dietary protein intake
- Hormonal status (e.g., growth hormone, insulin, cortisol)
- Illness and stress
- Physical activity

Normal Protein Synthesis and Degradation

Protein synthesis and degradation are continuous processes that occur in all cells
Protein synthesis is regulated by:
- Availability of amino acids
- Hormonal signals
- Energy availability
- Genetic factors
Protein degradation is regulated by:
- Lysosomal degradation
- Ubiquitin-proteasome pathway
The balance between protein synthesis and degradation is essential for maintaining tissue mass and function

Normal Amino Acid Levels

Amino acids are present in blood and tissues at specific concentrations
Essential Amino Acids: Must be obtained from the diet
Non-Essential Amino Acids: Can be synthesized by the body
Amino acid levels are regulated by:
- Dietary intake
- Protein synthesis and degradation
- Transamination and deamination
- Hormonal signals
- Renal function

Abnormal States

Protein-Energy Malnutrition (PEM): Insufficient intake of protein and energy
Amino Acid Disorders: Genetic defects in amino acid metabolism
Urea Cycle Disorders: Genetic defects in the urea cycle
Hyperammonemia: Elevated ammonia levels in blood
Proteinuria: Presence of excess protein in urine
Hypoproteinemia: Abnormally low levels of protein in the blood

Protein-Energy Malnutrition (PEM)

Definition: A condition caused by insufficient intake of protein and energy, leading to depletion of body protein stores
Types
- Marasmus: Severe deficiency of calories, leading to wasting of muscle and fat
- Kwashiorkor: Adequate calorie intake but severe deficiency of protein, leading to edema and ascites
Pathophysiology
- Inadequate intake of protein and energy leads to:
  - Decreased protein synthesis
  - Increased protein degradation
  - Depletion of body protein stores
  - Impaired immune function
  - Organ dysfunction
Laboratory Findings
- Decreased serum albumin and prealbumin levels
- Decreased transferrin and retinol-binding protein levels
- Decreased lymphocyte count
- Negative nitrogen balance
Symptoms
- Wasting of muscle and fat
- Edema and ascites (Kwashiorkor)
- Growth retardation (in children)
- Impaired immune function
- Increased susceptibility to infections

Amino Acid Disorders

Definition: Genetic defects in amino acid metabolism, leading to the accumulation of specific amino acids and/or their metabolites
Pathophysiology
- Enzyme deficiencies disrupt metabolic pathways, leading to:
  - Accumulation of substrates
  - Deficiency of products
  - Toxic effects of accumulated metabolites
Laboratory Findings
- Elevated levels of specific amino acids in blood and urine
- Reduced or absent enzyme activity in affected tissues
Symptoms
- Varies depending on the specific amino acid disorder and the metabolic pathway affected
Examples
- Phenylketonuria (PKU): Deficiency in phenylalanine hydroxylase (PAH)
  - Elevated phenylalanine levels in blood
  - Intellectual disability, seizures
- Maple Syrup Urine Disease (MSUD): Deficiency in branched-chain alpha-keto acid dehydrogenase (BCKDH)
  - Elevated levels of branched-chain amino acids (leucine, isoleucine, valine) in blood and urine
  - Neurological dysfunction, feeding difficulties, maple syrup odor in urine
- Homocystinuria: Deficiency in cystathionine beta-synthase (CBS)
  - Elevated homocysteine levels in blood and urine
  - Cardiovascular disease, thromboembolism, intellectual disability
- Alkaptonuria: Deficiency in homogentisate 1,2-dioxygenase
  - Accumulation of homogentisic acid in tissues and urine
  - Darkening of urine upon exposure to air, ochronosis (pigmentation of cartilage), arthritis

Urea Cycle Disorders

Definition: Genetic defects in enzymes of the urea cycle, leading to impaired conversion of ammonia to urea
Pathophysiology
- Enzyme deficiencies disrupt the urea cycle, leading to:
  - Accumulation of ammonia in blood (hyperammonemia)
  - Deficiency of urea
Laboratory Findings
- Elevated ammonia levels in blood
- Decreased blood urea nitrogen (BUN) levels
Symptoms
- Vomiting, irritability, lethargy, seizures, coma
Examples
- Ornithine Transcarbamylase Deficiency (OTC): Most common urea cycle disorder
  - Elevated ammonia levels in blood
  - Neurological symptoms
- Carbamoyl Phosphate Synthetase I Deficiency (CPS I): Deficiency in the first enzyme of the urea cycle
  - Elevated ammonia levels in blood
  - Neurological symptoms

Hyperammonemia

Definition: Elevated ammonia levels in blood
Causes
- Urea cycle disorders
- Liver failure
- Reye’s syndrome
- Certain medications
Pathophysiology
- Elevated ammonia levels are toxic to the brain, leading to:
  - Cerebral edema
  - Seizures
  - Coma
  - Death
Laboratory Findings
- Elevated ammonia levels in blood

Proteinuria

Definition: Presence of excess protein in urine
Causes
- Kidney disease (e.g., glomerulonephritis, nephrotic syndrome)
- Diabetes
- Hypertension
- Multiple myeloma
Pathophysiology
- Damage to the glomeruli or tubules in the kidneys leads to increased protein excretion in urine
Laboratory Findings
- Elevated protein levels in urine
- Albumin is the most common protein detected
Symptoms
- Foamy urine
- Edema
- Fatigue

Hypoproteinemia

Definition: Abnormally low levels of protein in the blood
Causes
- Malnutrition
- Liver disease (impaired protein synthesis)
- Kidney disease (protein loss in urine)
- Inflammatory bowel disease (impaired protein absorption)
Pathophysiology
- Reduced protein synthesis or increased protein loss leads to:
  - Decreased serum albumin levels
  - Edema
  - Impaired immune function
  - Increased susceptibility to infections
Laboratory Findings
- Decreased serum albumin and total protein levels

Key Terms

Nitrogen Balance: The balance between nitrogen intake and excretion
Protein Synthesis: The production of proteins from amino acids
Protein Degradation: The breakdown of proteins into amino acids
Essential Amino Acids: Amino acids that must be obtained from the diet
Non-Essential Amino Acids: Amino acids that can be synthesized by the body
Protein-Energy Malnutrition (PEM): A condition caused by insufficient intake of protein and energy
Amino Acid Disorders: Genetic defects in amino acid metabolism
Urea Cycle Disorders: Genetic defects in the urea cycle
Hyperammonemia: Elevated ammonia levels in blood
Proteinuria: Presence of excess protein in urine
Hypoproteinemia: Abnormally low levels of protein in the blood
Albumin: A major protein in the blood
Glomeruli: Filtering units within the kidney
Tubules: Portion of the nephron carrying filtrate after the glomerulus
Edema: Swelling caused by excess fluid trapped in your body’s tissues
Ascites: The accumulation of fluid in the peritoneal cavity, causing abdominal swelling
Lymphocytes: A type of white blood cell that is part of the immune system
Anabolism: The synthesis of complex molecules from simpler ones, an energy-consuming process
Catabolism: The breakdown of complex molecules into simpler ones, releasing energy
Proteases: An enzyme that breaks down proteins and peptides
Lysosomal Degradation: Degradation that occurs in the lysosomes
Ubiquitin-Proteasome Pathway: A major pathway for protein degradation in eukaryotes
Transamination: The transfer of an amino group from one molecule to another
Deamination: The removal of an amino group from a molecule
Ochronosis: A condition characterized by the abnormal accumulation of homogentisic acid in connective tissues, leading to bluish-black discoloration
Glomerulonephritis: Inflammation of the glomeruli, the filtering units in the kidneys
Nephrotic Syndrome: A kidney disorder characterized by proteinuria, hypoalbuminemia, and edema
Myeloma: A cancer of plasma cells
Inflammatory Bowel Disease (IBD): A group of inflammatory conditions of the colon and small intestine
Mitochondria: Membrane-bound cell organelles (mitochondrion, singular) that generate most of the chemical energy needed to power the cell’s biochemical reactions. Chemical energy is produced by the mitochondria is stored in a small molecule called adenosine triphosphate (ATP)
Endoplasmic Reticulum: A network of membranes inside a cell through which proteins and other molecules move. Proteins are synthesized on ribosomes attached to the endoplasmic reticulum
Cytosol: The part of the cytoplasm that does not contain organelles
Enzyme: A substance produced by a living organism which acts as a catalyst to bring about a specific biochemical reaction
Receptors: A protein molecule that receives and responds to a chemical signal
Organelles: A number of organized or specialized structures within a living cell

Metabolic

Properties