Hypoproteinemia, dysproteinemia, paraproteinemia

Dysproteinemia refers to any change in the protein content of the blood. The concentration of proteins in the plasma depends on the ratio between their synthesis and their degradation or excretion. When one or more globulin fractions increase, the albumin–globulin ratio—the so-called A/G ratio (normal range 1.5–2)—changes.

General causes of dysproteinemia

• hereditary (genetically determined disorder of protein synthesis or its release into circulation),
• loss of specific protein fractions:

• through the kidneys – proteinuria (see nephrotic syndrome),
• through the skin – severe burns, extensive inflammations,
• through the intestine – exudative enteropathy,

• disorders of proteosynthesis:

• liver – disorder of hepatic proteosynthesis during cirrhosis, hepatitis, etc.; the synthesis of transport proteins (albumin, prealbumin, transferrin, etc.) decreases in particular; in more severe disorders, insufficient synthesis of coagulation factors manifests as bleeding,
• malnutrition with insufficient protein intake in the diet – protein-calorie or pure protein malnutrition (up to the clinical picture of kwashiorkor),

• relative changes in proteinemia during dehydration, fluid shift to the 3rd space, or fluid retention (the clinically known phenomenon of proteinemia decrease after administering infusions to a dehydrated patient),
• inflammatory reaction – synthesis of immunoglobulins, acute-phase proteins, and suppression of transport protein synthesis.

Dysproteinemias involving multiple fractions or proteins

Hyperproteinemia

An increase in all serum proteins or, alternatively, an increase in only some proteins that leads to an increase in protein concentration as a whole. If all proteins are increased, it is actually a relative increase in concentration due to water loss and hemoconcentration. An increase in oncotic pressure results in the shift of water from the interstitium to the plasma. Hyperproteinemia (and paraproteinemia) can lead to hyperviscosity syndrome (see below).

Hypoproteinemia

A decrease in the total amount of serum proteins, mainly albumin. It is caused by losses (into urine, during burns), impaired production, or suppressed synthesis (inflammation) of liver proteins. In severe cases, it leads to a decrease in plasma oncotic pressure and edema.

Acute inflammation

A typical finding is the so-called acute-phase reaction, where during electrophoresis, we observe a decrease in albumin along with a simultaneous increase in all globulin fractions.

Chronic inflammation

Typical is an increase in the γ-globulin fraction due to increased synthesis of IgG (or IgM). This is actually polyclonal hyperimmunoglobulinemia, where the entire immune system is stimulated. It can occur in chronic infections, allergies, autoimmune diseases, and malignant tumors. Increased Ig levels often constitute more than half of the plasma proteins.

Note: Monoclonal hyperimmunoglobulinemia is the same as paraproteinemia.

Dysproteinemias involving a single fraction or protein

Albumin changes

Analbuminemia and hypoalbuminemia

Rarely the result of a hereditary anomaly. Generalized or localized edema occurs. Oncotic pressure is reduced. Although albumin normally makes up about 60% of serum proteins, it can be completely absent without severe disorders. Globulin content is increased compensatorily; however, the total protein content remains below normal levels.

Albumin, as a negative acute-phase protein, decreases significantly during an inflammatory reaction or in tumors. Hypoalbuminemia may also be a manifestation of malnutrition, liver disorder, or increased losses through the kidneys or intestines (see above).

α₁-globulin changes

α₁-antitrypsin deficiency

A hereditary disease caused by a disorder in the release of synthesized protein from liver cells into the blood. It is usually asymptomatic, manifesting only when the plasma concentration falls below 10% of normal, and even then only in some patients. Insufficient inhibition of neutrophil elastase leads to the destruction of the lung lining and the development of juvenile emphysema. Accumulation of the protein in hepatocytes can also lead to the development of cirrhosis. The inheritance of all high-risk genotypes is autosomal recessive. In heterozygotes, the serum protein content is also reduced but without clinical manifestations.

α₂-globulin changes

Haptoglobin deficiency

A rare hereditary synthesis disorder – clinically asymptomatic. More common (and diagnostically significant) is a transient decrease during hemolysis due to the consumption of haptoglobin after it binds to free globin.

Ceruloplasmin deficiency

Wilson's disease

Ceruloplasmin is the most important serum protein that binds copper. Its absence causes rapid leaching of copper from the blood into tissues and excretion by the kidneys. Subsequently, enteral copper resorption increases, maintaining an excess of intake over loss. Copper is deposited mainly in the brain in the basal ganglia (neurological form, where symptoms of Parkinson's disease appear) and in the liver (hepatic form, leading to liver cirrhosis). Furthermore, copper is deposited in the cells of the proximal renal tubules (transport disorder, renal glycosuria, aminoaciduria, phosphate diabetes). In erythrocytes, copper causes disorders of individual enzymes (enzymopenic and hemolytic anemia). Diagnostically important is the deposition of copper salts in the cornea (Kayser-Fleischer corneal ring). Treatment involves penicillamine—a chelating agent with a high affinity for copper (excreted by the kidneys). Inheritance is autosomal recessive. In heterozygotes, the serum content is reduced by about 20%. The disease is among the most common hereditary anomalies.

Note: External link: Wilson's disease

β-globulin changes

Transferrin deficiency

A genetically determined synthesis disorder leads to impaired transport of iron in the serum, i.e., insufficient supply of iron to the hematopoietic tissue. The result is iron-deficiency anemia and hemosiderosis. Autosomal dominant inheritance. A transient decrease in transferrin occurs during inflammation, malnutrition, and impaired hepatic proteosynthesis. An increase in transferrin is a reaction to iron deficiency in the body.

γ-globulin changes

Agammaglobulinemia

Hereditary form

X-linked. γ-globulins are almost completely absent in the serum, with levels below 100mg/100ml (normal is 1600mg/100ml). Plasma cells are absent in the bone marrow, spleen, and lymph nodes. This is likely a disorder of stem cell maturation into plasma cells (affected nucleotide metabolism). Manifestation occurs in children after the loss of protection from antibodies in breast milk. There is low resistance to bacterial infections (pneumonia, sepsis). Treatment involves i.m. injections of γ-globulins.

Acquired form

Rare. It manifests in adult men and women. γ-globulin levels are below 500mg/ml. Plasma cells are absent in the nodes. The spleen and liver are enlarged. Manifestations: Frequently recurring infections, susceptibility to autoimmune diseases.

Dysgammaglobulinemia

Some types of Ig are missing, while others occur in normal or increased concentrations. Most commonly, IgG or IgA is missing and IgM is increased (often with an increased number of plasma cells synthesizing IgM). Manifestations: Susceptibility to infections, thrombocytopenia, autoimmune-type hemolytic anemias.

Hyperimmunoglobulinemia

Increased levels of γ-globulins due to increased synthesis. Each clone of plasma cells produces only one Ig, and depending on the presence of the given protein types, we distinguish between:

• monoclonal hyperimmunoglobulinemia (i.e., paraproteinemia) and
• polyclonal hyperimmunoglobulinemia.

Links

Related articles

• Paraproteinemia
• Plasma proteins
• X-linked agammaglobulinemia
• Serum protein electrophoresis
• Wilson's disease