Complement-Related Disorders Clinical Presentation

Updated: Jan 15, 2016
  • Author: M Michael Glovsky, MD; Chief Editor: Michael A Kaliner, MD  more...
  • Print
Presentation

Causes

Causes may be primary or secondary in nature.

Next:

Primary Complement Disorders

Congenital complement deficiencies involve all of the complement components and most of the regulatory components. [2]

Classic pathway disorders

C1q

Although any one of the 3 subcomponents of the C1 complex may be deficient, C1q deficiency is the most common. C1q deficiency may be hereditary or acquired. Hereditary deficiencies are usually complete and are transmitted as an autosomal recessive trait. Low-to-absent levels of C1q are found; a dysfunctional protein has been found in some patients.

Most patients (>90%) with C1q deficiency have systemic lupus erythematosus (SLE) and demonstrate a variety of autoantibodies, such as immunoglobulin G (IgG) autoantibodies to C1q, antinuclear antibody and double-stranded DNA (dsDNA) antibody; low total hemolytic complement activity (CH50) values; and low C1q levels, with normal levels of other complement proteins. SLE is more severe in persons with homozygous deficiencies, suggesting that C1q is vital in clearing immune complexes, by binding to the C1q receptor or through its participation in the generation of C3. Deposition of this C3 on autoimmune complexes facilitates their removal from the circulation through binding to CR1 on erythrocytes, with subsequent transport to the liver and spleen.

Low levels of C1q also are found in persons with SLE-like syndrome without typical serology, hypocomplementemic urticarial vasculitis syndrome, [3] multiple myeloma, [4] hypogammaglobulinemia, and membranoproliferative glomerulonephritis.

Plasmapheresis has been used for restoration of C1q levels. The use of fresh frozen plasma is associated with the development of antibodies to C1q, thereby limiting its use.

C1r/C1s

The loci of these 2 components are closely linked, and the deficiencies usually occur together. The transmission is autosomal recessive in nature. A high prevalence of SLE is found, with prominent renal and cutaneous sequelae.

C4

C4 is encoded as 2 tandem, highly polymorphic genes, C4A and C4B, located in the major histocompatibility complex on chromosome 6. Two copies of each gene determine the phenotype. Null alleles are called C4a*Q0 and C4b*Q0. Deletion of the C4A gene is the most common mechanism. A single null allele reduces the C4 level by 35-40%. Four null alleles encode a complete deficiency of C4. It is transmitted as an autosomal recessive trait.

Partial C4 deficiency predisposes to SLE. Deficiency of C4A or C4B has been associated with the development of scleroderma, immunoglobulin A nephropathy, Henoch-Schönlein purpura, diabetes mellitus, chronic hepatitis and membranous nephropathy. Complete C4 deficiency is rare. Characteristics of SLE with complete C4 deficiency include early onset, mild renal disease, skin manifestations, anti-SSA antibody, and an absence of anti-dsDNA antibody. Complete C4 deficiency also may manifest with infection or may not be associated with any symptoms.

Defective expression or function also may lead to SLE, as occurs with medications such as hydralazine, penicillamine, and procainamide, which react with the thioester bond of C4a and block its function.

C2

This is the most common inherited complement deficiency. The transmission is autosomal recessive in nature. Homozygous deficiency of C2 occurs in 1 in 10,000 whites, with up to 30% presenting with an SLE-like illness or with no disease.

It may also manifest as recurrent pyogenic infections due to encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae type b, and Neisseria meningitidis. It is also sometimes associated with IgG subclass deficiency.

The gene frequency of heterozygous C2 deficiency is 1%. Immune complex disease is common. It may manifest as life-threatening septicemia, especially due to infection with pneumococci.

C3

C3 is the most important central molecule in the complement system because both the classic and alternative pathways activate it, and its activation products mediate opsonization and anaphylactic activity and activate the terminal pathway.

C3 deficiency is transmitted as an autosomal recessive trait. Patients with C3 deficiency develop severe episodes of recurrent pneumonia, meningitis, peritonitis, or sepsis. The most common pathogens are S pneumoniae, N meningitidis, H influenzae, and Staphylococcus aureus. The infectious profile is similar to that found with Bruton agammaglobulinemia. Lupuslike illness and mesangiocapillary glomerulonephritis may occur in 15-20% of patients.

Membrane attack pathway: C5b-C9

Deficiency is transmitted as an autosomal recessive trait. Patients with deficiency of C5-9 components usually have a history of meningococcal meningitis and even extragenital or disseminated gonococcal infection. The reasons for the predisposition to Neisseria infection are not clear, but deficient serum bacteriolysis may be the predisposing cause. Patients with terminal complement component deficiencies and polymorphisms for Fc gamma RIIa (CD32), which have lower affinity for IgG (Fc Gamma RIIa-R131), appear to have more severe and frequent neisserial infections, at least after age 10 years, suggesting that phagocytosis is also important for resistance to these organisms. [5] Some patients develop collagen-vascular disease. C6 homozygous deficiency is associated with increased risk of membranoproliferative glomerulonephritis.

Alternative pathway

These are inherited by autosomal recessive mode of transmission. Deficiency in factor D or factor B manifests as recurrent infection.

Control proteins

Factor I

It has an autosomal recessive transmission and leads to the prolonged presence of C3b, causing a constant activation of the alternative pathway that ultimately leads to a depletion of C3. It was initially reported as C3 deficiency due to hypercatabolism of C3. It manifests as severe pyogenic infections.

Factor H

It helps factor I in the breakdown of C3 convertase of the alternative pathway, so its effects are essentially the same. The C3 level, factor B level, CH50 value, and alternate pathway activity are low or undetectable. Patients have sustained systemic infections, especially from meningococci. Membranoproliferative glomerulonephritis and hemolytic uremic syndrome are associated with it. [6] Associations between familial hemolytic uremic syndrome and mutations in the genes for factor H and factor I have also been reported.

Properdin

It is transmitted as an X-linked trait. All patients are male, and a family history of male deaths due to meningococcal meningitis is common. CH50 results are without abnormality. Patients may have discoid lupus or dermal vasculitis.

C4 binding protein

It is a control protein of the classical pathway and binds to C4b. It may be relevant in preventing activated C4b2a from depleting C3 and other late components in hereditary angioedema.

C1 inhibitor

C1-INH disorders are transmitted as an autosomal dominant trait. However, 50% of patients may have spontaneous mutations, and a family history may be absent. In 85% of patients, a marked protein reduction of the inhibitor is found (5-30% of normal values are present). In 15% of patients, a dysfunctional protein is present. Protein values of the C1 inhibitor may be normal or high, yet functional enzymatic tests are markedly reduced. Autoantibody to the C1 inhibitor occurs in patients with neoplastic disease, such as carcinoma and lymphoproliferative disease. The association of acquired angioedema with low values of C1q differentiate the acquired disease from the familial or hereditary angioedema.

The absence of the C1 inhibitor causes uncontrolled C1 activity with breakdown of C4 and C2 and release of a vasoactive peptide from C2. Since the C1 inhibitor also blocks the coagulation cascade, factor XIIa, fibrinolysis, and the kallikrein-bradykinin cascade, bradykinin is thought to be the active permeability factor causing the edema and pathologic effects of the disease. Drugs that block kallikrein activation and bradykinin receptor binding as well as purified C1 inhibitor preparations have been shown to markedly reduce the time and severity of acute angioedema attacks.

The deficiency of C1 esterase inhibitor leads to hereditary angioedema, which is manifested by episodic attacks of nonpitting, nonpruritic, localized edema that progresses rapidly without urticaria or erythema. [7] Swelling of the intestinal wall can cause intense abdominal cramping associated with vomiting and diarrhea. Laryngeal edema may prove fatal. Attacks last 2-3 days and gradually subside. Attacks occur after menses, emotional stress, trauma, or vigorous exercise. They may begin in the first 2 years of life but usually are not severe until late childhood or adolescence. Collagen-vascular disease and glomerulonephritis have been reported. The diagnosis is suggested by a positive family history, edema with lack of accompanying pruritus or urticaria, and decreased C4 levels. Further laboratory testing is performed by measuring the amount of C1-INH, but some kindred have a dysfunctional protein and require a functional assay.

Acquired disease may occur from autoantibody to C1-INH, usually associated with B-cell cancer.

See Hereditary angioedema for more information.

Complement receptor 1, 2, or 3

Deficiency of CR1 on erythrocytes leads to impaired clearance of immune complexes, thereby contributing to collagen-vascular disease. The disorder possibly is inherited.

An inherited deficiency of complement receptor 3 causes recurrent and severe bacterial (eg, S aureus and/or Pseudomonas) infections. This condition is known as leukocyte adhesion deficiency syndrome (CD11/CD18 deficiency). It is suspected if delayed separation of the umbilical cord occurs and omphalitis develops. Most patients die in childhood of refractory infections involving soft tissue and mucosal surfaces.

DAF, CD59, C8 binding protein

The vascular endothelium of the skin of patients with diffuse or limited scleroderma has been shown to be deficient in DAF. This may lead to vascular injury, finally leading to fibrosis.

Paroxysmal nocturnal hemoglobinuria (PNH) is a disease characterized by hemolytic anemia, venous thrombosis, and deficient hematopoiesis. It is an acquired clonal disease due to a somatic mutation of a gene on the X chromosome (PIGA) in a hematopoietic stem cell that encodes the glycosyl-phosphatidylinositol molecule, which anchors approximately 20 proteins (including DAF, CD59, and C8 binding protein) to cell membranes. The absence of this anchor results in an absence of these proteins, making the erythrocytes more susceptible to complement-mediated lysis. A monoclonal antibody to C5, eculizumab, has been shown to reduce the need for transfusions, increase the quality of life, and decrease the thrombotic episodes in 43 patients with PNH. [8]

Isolated DAF deficiency does not cause PNH. Isolated CD59 deficiency has been reported to cause mild PNH.

Age-related macular degeneration (AMD) is an age-related cause of blindness and the most common cause of blindness in individuals older than 55 years. It can be present in a dry form (90%) or in a wet (exudative) form (10%). In 50% of patients with the dry form, an association has been found with a single amino acid mutation in the gene for the regulatory Factor H of the complement alternative pathway. The pathogenesis of AMD is related to the deposition of drusen, a yellow-gray material in the Bruch membrane associated with retinal pigment epithelial changes (atrophy, clumping, detachment). These drusen deposits have been found to be associated with C5 and C5b-9 complexes, as well as with the deposit of other inflammatory proteins. Thus, the deficiency of control of activated C3 convertase is an important factor in the production of drusen, and the inflammatory response in this milieu is thought to be responsible for the pathologic changes. [9]

Serosal protease

Evidence suggests that serosal fluids contain a complement regulatory protease that destroys C5a and interleukin 8, which are chemotactic for neutrophils. Deficiency of this regulatory protein in peritoneal and synovial fluids results in familial Mediterranean fever, characterized by recurrent episodes of fever and painful inflammation of joints, pleura, and the peritoneal cavity.

Inherited lectin pathway deficiencies

Point mutations of the MBL mannose-binding lectin (MBL) gene occur in the coding exons and promoter region. MBL contains 3 identical polypeptide chains. Substitutions in these exons lead to the formation of chains that do not interact normally. Persons with mutations of both MBL alleles (3-5% of the population) have undetectable or extremely low levels of MBL. People with 1 normal and 1 abnormal allele have a sixth to an eighth of the normal functional level of MBL.

MBL deficiency is associated with an increased frequency of pyogenic infections in children. In the presence of MBL deficiency, chronic inflammatory conditions may be more severe. A 2- to 3-fold increase in MBL deficiencies is noted in persons with SLE9. [10] More frequent and more severe infections occur in patients treated with steroids and cytotoxic agents.

A deficiency of MBL-associated proteases has been described that results in severe pneumococcal pneumonia and immune disorders, including ulcerative colitis and erythema multiforme bullosum.

Previous
Next:

Secondary Complement Disorders

A number of diseases that are not inherited affect the complement system.

Immunologic

These are mediated by immune complexes, and complement proteins are consumed in the process.

Systemic lupus erythematosus

Complement is consumed via the classic pathway during active immune complex deposition; therefore, patients with active lupus characteristically have decreased C3 levels, C4 levels, and CH50 results. However, hypocomplementemia can also be found in patients with SLE without active disease. [10]

A subset of patients has congenital complement deficiencies. Normal C3 levels with very low or absent CH50 values are suggestive of a congenital deficiency. C2 and C4 deficiencies are common.

Elevated levels of complement activation products may be useful in predicting SLE flares. [11, 12]

Hypocomplementemic glomerulonephritis

Serum from patients with membranoproliferative glomerulonephritis contains nephritic factor (NeF), which causes activation of the alternative pathway. NeF is an IgG autoantibody that binds and stabilizes C3bBb and prevents its dissociation by factor H. This leads to prolonged C3 conversion, leading to its depletion. This disorder has been described in association with partial lipodystrophy. Exposure to NeF destroys adipocytes, which can synthesize C3, factor D, and factor B.

An IgG NeF that binds and protects C4,2 has been described in association with acute postinfectious nephritis. Complement levels usually return to normal in 8 weeks.

Mesangioproliferative glomerulonephritis, idiopathic proliferative glomerulonephritis, and focal sclerosing glomerulonephritis have been described in association with complement depletion. Lupus nephritis is one of the important causes. Other causes, such as fibrillary glomerulonephritis and immunotactoid glomerulonephritis, have been reported. [13, 14]

Infective endocarditis

Circulating immune complexes have been found in 90% of patients with endocarditis. Rheumatoid factor is present in 10-70% of cases. Hypocomplementemia is a frequent but nonspecific marker of glomerulonephritis in persons with bacterial endocarditis. Approximately 90% of patients with diffuse glomerulonephritis and approximately 60% of patients with focal glomerulonephritis have reduced complement levels. Typically, the classic pathway has been implicated, but reports of primary alternative pathway activation are found in the literature. Complement levels return to normal with bacteriological cure and resolution of glomerulonephritis.

Miscellaneous causes

Formation of immune complexes with complement consumption has been found in association with acute hepatitis B and C, often in sufficient amounts to form mixed cryoglobulins. [15] These are responsible for extrahepatic manifestations of arthralgias and nephritis. Immune complexes also are present in association with infectious mononucleosis, malaria, dengue fever, lepromatous leprosy, and bacteremic shock.

Reye syndrome, primary biliary cirrhosis, celiac disease, multiple myeloma, [4] hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and urticarial vasculitis have also been implicated. Burns, hemodialysis with cellophane membranes, cardiopulmonary bypass, and perhaps the injection of iodinated radiocontrast material can also cause direct activation of the alternative pathway and serious effects thereof.

Nonimmunologic

Patients with severe malnutrition and anorexia nervosa have low complement levels. Improvement in serum concentration of complement has occurred after correction of the nutritional deficiency. Severe cirrhosis of the liver and hepatic failure result in decreased C3 production. Preterm infants, and even newborn children, have mild-to-moderate deficiency of all complement components. Deficiencies in the alternate pathway and suboptimal opsonization have been described in persons with sickle cell disease, postsplenectomy patients, and persons with nephrotic syndrome.

Previous