Cryoglobulinemia is a syndrome caused by the presence of precipitate proteins (cryoglobulins) in the blood serum, capable of precipitation at temperatures below 37 ° C. Manifestations of cryoglobulinemia may include hemorrhagic rash, Raynaud’s syndrome, arthralgia, peripheral polyneuropathy, hepatosplenomegaly, glomerulonephritis and renal failure. Diagnostic tests of cryoglobulinemia are blood tests for serum cryoglobulin, RF, anti-HCV, etc.; skin or kidney biopsy results. Cryoglobulinemia is treated with glucocorticoids, cytostatics, antiviral drugs, plasmapheresis or cryoaferesis.
ICD 10
D89.1 Cryoglobulinemia
Meaning
Cryoglobulinemia is an immunopathological process caused by the precipitation of cryoglobulins, the deposition of cryoglobulinemic immune complexes in the vascular walls with the development of systemic vasculitis. There are no data on the prevalence of cryoglobulinemia in the population. It is known that cryoglobulins at a concentration of less than 0.8 mg/ l are detected in the blood serum of 40% of the population, but they do not cryoprecipitate and do not cause pathological changes in tissues and organs. Cryoglobulinemia usually develops in people over 40 years of age, while 1.5 times more often in women. Cryoglobulinemia is observed in various pathological conditions, however, due to the peculiarities of pathogenesis, rheumatology is mainly engaged in the study of the disease.
Causes
It has been established that cryoglobulinemia can develop in diseases of autoimmune, lymphoproliferative, infectious genesis. Clinical associations of cryoglobulinemia with systemic lupus erythematosus, rheumatoid arthritis, dermatomyositis, scleroderma, Sjogren’s disease, liver cirrhosis, sarcoidosis are described. In some cases, the association with multiple myeloma, B-cell non-Hodgkin’s lymphoma, Waldenstrom’s disease, chronic lymphocytic leukemia is determined. Infectious diseases are especially often the cause of cryoglobulinemia: herpes, infectious mononucleosis, hepatitis A, B and C, cytomegaly, HIV. For example, high levels of cryoglobulins are detected in almost half of patients with chronic hepatitis C. In some cases, fungal and parasitic infections, syphilis, infectious endocarditis, visceral abscesses can provoke cryoglobulinemic syndrome.
There are studies confirming a genetic predisposition to the development of cryoglobulinemia in individuals with changes in the HLA-DR3, DR6, DR7 and DR15 loci. Factors that increase the risk of cryoglobulinemia are old age, hypothermia, severe dehydration, hormonal disorders.
In the pathogenesis of cryoglobulinemia, the triggering role belongs to the interaction of the antigen with the immune system. Activation of B-lymphocytes stimulates hyperproduction of mono- or polyclonal immunoglobulins, leads to the formation of cryoprecipitating immune complexes and their deposition in the walls of small vessels of various organs. Activation of the complement system induces damage to the vascular wall and the development of inflammation, and the strengthening of blood clotting factors contributes to the formation of capillary microthrombosis.
Classification
Cryoglobulins are special serum immunoglobulins that have the property of precipitating at temperatures below 37 ° C and dissolving when it rises. Depending on their constituent components, cryoglobulins are divided into three types:
- including monoclonal immunoglobulins of the same class (IgM, IgG, less often IgA);
- including monoclonal immunoglobulin (usually IgM) coupled with polyclonal IgG;
- including immunoglobulins of several classes (polyclonal), sometimes non-immunoglobulin molecules (lipoproteins, fibronectin, C3-complement component).
According to etiology, primary (essential) cryoglobulinemia and secondary cryoglobulinemia associated with hepatitis C or other pathology are distinguished. Taking into account the predominant type of cryoglobulins, cryoglobulinemia of type I, II and III is isolated. Cryoglobulinemia type I is monoclonal; type II and III belong to mixed forms of pathology due to the presence of several types of immunoglobulins.
Simple monoclonal cryoglobulinemia (type I) (5-25%) is most often associated with lymphoproliferative diseases; occurs with severe proteinuria, hematuria, sometimes anuria. Monoclonal immunoglobulins are detected in the blood. Histological examination of the renal tissue determines the signs of membranous-proliferative glomerulonephritis.
Mixed monoclonal cryoglobulinemia (type II) (40-60%) is usually associated with hepatitis C. It is characterized by the development of immunocomplex vasculitis and kidney damage. Mixed immunoglobulins are present in the blood; pathomorphological changes are represented by endocapillary proliferation and mesangial edema of tissues.
Mixed polyclonal cryoglobulinemia (type III) (40-50%) is often found in collagenosis, bacterial and viral infections. Polyclonal immunoglobulins of all types are detected in the blood. It proceeds with the development of cryoglobulinemic vasculitis and immunocomplex nephritis.
Symptoms
The symptoms of cryoglobulinemia are characterized by significant polymorphism. At the same time, the most typical clinical markers of the disease are hemorrhagic rash, arthralgia, peripheral polyneuropathy, Raynaud’s syndrome, glomerulonephritis, etc.
Skin lesions are characteristic of all types of cryoglobulinemia. In most cases, a palpable hemorrhagic rash (purpura) develops, indicating venule vasculitis. Usually the purpura is located on the shins and thighs (less often on the buttocks or abdomen), symmetrically, not accompanied by itching. After the rash resolves, areas of hyperpigmentation form in its place. Purpura is often combined with cold urticaria and reticulated livedo. In about half of the cases, cryoglobulinemia occurs with Raynaud’s syndrome, characterized by paresthesia, cold fingers and toes, acrocyanosis. About a third of patients have ulcers of the lower extremities, hemorrhagic necrosis of the skin; sometimes gangrene of the fingertips is noted.
A characteristic feature of cryoglobulinemia is the development of symmetrical, migrating polyarthralgia with predominant involvement of metacarpophalangeal, interphalangeal, knee, ankle, hip joints. Joint pain and myalgia increase with cooling. In some cases, the development of non-erosive arthritis, myositis is possible. With the help of elecromyography, the lesion of the nervous system in the form of distal sensory polyneuropathy is determined in almost all patients with cryoglobulinemia. Cerebral vasculitis develops less frequently, accompanied by hemiplegia and transient dysarthria.
Kidney damage in patients with cryoglobulinemia may include proteinuria, microhematuria, nephrotic syndrome, glomerulonephritis or renal failure. Clinically, these conditions are manifested by edema, severe arterial hypertension, oliguria and anuria. Typical gastrointestinal disorders are represented by abdominalgias associated with mesenteric vascular vasculitis, hepatomegaly and splenomegaly. In some cases, lymphadenopathy, sialadenosis is noted. When involved in the pathological process of the lungs, shortness of breath, cough, pleurisy, and in rare cases, pulmonary bleeding may occur.
Diagnostics
The diagnosis of cryoglobulinemia is legitimate in the presence of characteristic symptoms; confirmed association of the syndrome with a lymphoproliferative, infectious or systemic disease; determination of typical laboratory markers. Clinical criteria for cryoglobulinemia are the presence of 2 signs from the Meltzer triad (weakness, hemorrhagic purpura, arthralgia), as well as signs of kidney, liver or nervous system damage.
Immunological and biochemical blood tests reveal cryoglobulins (cryocrit greater than 1%), positive RF, CRP, antinuclear antibodies, decreased levels of Clq and C4 complement components, anti-HCV and anti-HBs, HCV-PHK, etc. Immunoelectrophoresis is performed to identify the type of immunoglobulins (monoclonal and polyclonal). With the involvement of the kidneys, proteinuria and erythrocyturia are determined in the general analysis of urine. Morphological examination of skin and kidney biopsies allows to determine the deposition of cryoprecipitate and confirm the diagnosis.
Instrumental diagnostics (liver ultrasound, kidney ultrasound, radiography and CT of the chest organs) are used to identify structural and functional changes in internal organs. To assess the severity of damage to various systems, except for a rheumatologist, a patient with cryoglobulinemia should be examined by a dermatologist, neurologist, infectious disease specialist, gastroenterologist, nephrologist, pulmonologist.
Treatment
The approach to the therapy of cryoglobulinemia is closely related to the activity of the disease and the presence of life-threatening complications (rapidly progressing glomerulonephritis, renal insufficiency, arterial hypertension, CNS vasculitis and mesenteric vessels). Usually, drug therapy of cryoglobulinemia consists of the appointment of glucocorticoids (methylprednisolone) and cytostatics (cyclophosphamide). After achieving remission, supportive antiviral therapy (interferon alpha-2 and ribavirin) is performed. In the treatment of resistant forms of cryoglobulinemia, the use of monoclonal antibodies to CD20 receptors (rituximab) is considered promising.
A mandatory element of the complex treatment of cryoglobulinemia of a high degree of activity is the repeated procedures of plasmapheresis, cryoaferesis or cascade filtration of plasma.
Prognosis and prevention
The prognosis of cryoglobulinemia is largely determined by the severity of internal organ damage and the success of treatment of the primary disease. Timely initiation of combined therapy of cryoglobulinemia allows us to hope for a 10-year survival rate of 70% of patients. With the development of severe systemic complications, the death of patients usually occurs due to chronic renal failure, intercurrent infections. Prevention of cryoglobulinemic syndrome is mainly reduced to the prevention and adequate treatment of infectious diseases.