Periodic disease diagnosis. Modern concepts of periodic illness and clinical guidelines for diagnosis and treatment
Familial Mediterranean fever (FMF) is a periodic illness hereditary disease characterized by recurrent episodes of fever and peritonitis, sometimes with pleurisy, skin lesions, arthritis, and very rarely pericarditis. Renal amyloidosis may develop, which can lead to kidney failure. Most often this disease occurs in the descendants of the inhabitants of the Mediterranean basin. Diagnosis is largely clinical, although available genetic testing. Treatment includes colchicine to prevent acute attacks, as well as renal amyloidosis in most patients. The prognosis for treatment is favorable.
Familial Mediterranean fever (FMF) is a disease that occurs in people descended from inhabitants of the Mediterranean basin, predominantly Sephardic Jews, North African Arabs, Armenians, Turks, Greeks, and Italians. At the same time, cases of the disease are also noted in other groups (for example, Ashkenazi Jews, Cubans, Belgians), which warns against excluding the diagnosis only on the basis of origin. Approximately 50% of patients have a family history of the disease, usually including siblings.
The most common of the described diseases, FMF affects mainly nationalities living in the Mediterranean basin (Sephardi Jews, Turks, Armenians, North Africans and Arabs), although one can find a description of cases of periodic illness in Ashkenazi Jews, Greeks, Russians, Bulgarians , Italians. The frequency of occurrence, depending on nationality, is 1:1000 - 1:100000. It is more common in men than in women (1.8:1).
(synonym: Armenian disease, paroxysmal Janeway-Mosenthal syndrome, periodic peritonitis, Reimann syndrome, Segal-Mamu disease, Mediterranean fever) is a relatively rare genetically determined disease, manifested by recurrent serositis and frequent development.
It occurs mainly among representatives of nationalities whose ancestors lived in the Mediterranean basin, especially among Armenians, Jews (often Sephardi), Arabs, regardless of their place of residence. The disease begins, as a rule, in childhood and adolescence with the same frequency in males and females.
Etiology
The etiology is not well understood. It is assumed that patients have a congenital metabolic, enzymatic defect, which entails a violation of the immune and endocrine systems, protein synthesis, proteolysis. An autosomal recessive type of inheritance of the disease has been established.
Pathogenesis
The pathogenesis of recurrent inflammation, which P.'s attacks are characterized by, is associated with cell degranulation. A genetically determined disorder of cellular metabolism is evidenced by frequent development at P. b. amyloidosis, regardless of the duration and severity of P.'s course. Allow the existence of two genotypic manifestations. With the first genotype, the disease manifests itself for a long time with attacks of serositis, then it can join. At the second genotype develops in the beginning, and subsequently there are attacks of P. b. Along with this, there are cases of P. b. without amyloidosis and cases when it is the only manifestation of the disease.
Pathological anatomy in the absence of amyloidosis has no specific features. In spite of chronic course P. b., there are no gross anatomical changes. During P.'s attack. there are all signs of aseptic inflammation of the serous membranes, mainly the peritoneum, pleura, synovial membranes, in some cases a small serous effusion is found. Possible injection and increased vascular permeability, non-specific cellular reaction. Amyloidosis, if present, is generalized with predominant lesion kidneys; according to histoimmunnochemical properties, it is close to secondary amyloidosis.
Clinical picture
Depending on the prevailing localization of manifestations, four variants of P. b. are distinguished:
- abdominal,
- thoracic,
- articular,
- feverish.
Abdominal variant occurs most often and in a detailed picture is characterized by symptoms acute abdomen, which often serves as a reason for surgical intervention in connection with suspected acute appendicitis, acute cholecystitis, or obstruction small intestine. During the operation, only signs of superficial serous peritonitis and a moderate adhesive process are found. Unlike acute surgical diseases abdominal cavity all symptoms disappear spontaneously after 2-4 days. AT rare cases, usually after repeated operations, mechanical obstruction of the intestine may develop, which is facilitated by severe dyskinesia of the gastrointestinal tract and biliary tract, caused by P. itself. and found at x-ray examination abdominal organs during an attack of the disease.
Thoracic variant P. b., observed less often. characterized by inflammation of the pleura, which occurs in one or the other half of the chest, rarely in both. The patient's complaints and examination data are the same as with pleurisy - dry or with a slight effusion. All signs of exacerbation of the disease spontaneously disappear after 3-7 days.
Articular variant in the form of recurrent synovitis manifested by arthralgia, mono- and polyarthritis. The ankles and feet are most commonly affected knee joints. Articular attacks are more easily tolerated than attacks of the abdominal and thoracic variants of P. b.; often they run normal temperature body. With prolonged arthritis, lasting more than 2-3 weeks, transient osteoporosis may occur.
Fever option P. b. characterized by sudden increases in body temperature; attacks of the disease resemble those of malaria. They rarely occur, usually at the onset of the disease, then, like articular and thoracic attacks, they can completely disappear. From the febrile variant as an independent clinical form P. b. it is necessary to distinguish the fever accompanying P.'s attacks. with other manifestations of the disease. In the latter case, body temperature rises soon or simultaneously with the onset of pain, sometimes accompanied by chills, reaches different levels and decreases to normal numbers after 6-12, less often 24 hours.
The course of the disease is chronic, relapsing, usually benign. Exacerbations proceed stereotypically, differ only in severity and duration. Regardless of the frequency and severity of P.'s attacks. 30-40% of patients develop amyloidosis, which leads to renal failure.
Diagnostics
Diagnosis is based on the following criteria:
1) recurrent short attacks of the disease (abdominal, thoracic, articular, febrile), not associated with a specific provoking factor, characterized by stereotype;
2) the onset of the disease in childhood or adolescence, mainly among certain ethnic groups;
3) frequent detection of the disease in relatives;
4) frequent development of amyloidosis of the kidneys; laboratory indicators are mostly non-specific and reflect the severity of the inflammatory response or the degree of kidney failure.
At the first manifestations of P. b. differential diagnosis can be difficult and is based on the careful exclusion of diseases with similar symptoms. At repeated relapses diseases take into account the above criteria and the fact that for P. b. characteristically good health sick in interictal period and resistance to any therapy, incl. antibiotics and glucocorticoids.
Treatment
Treatment until the 70s. was only symptomatic. In 1972, information appeared about the possibility of preventing P.'s attacks. ingestion of colchicine in a daily dose of 1 to 2 mg. Subsequently, the preventive efficacy of colchicine was confirmed, as well as its good tolerance with long-term (almost a lifetime) intake of the indicated doses in both adults and children. The mechanism of action of the drug is not completely clear. In small doses, it has an anti-inflammatory effect, affecting each of the successive steps leading to leukocyte degranulation, reduces vascular permeability, inhibits the release of prostaglandins, and also inhibits the development of amyloidosis, acting on intracellular synthesis and exocytosis of amyloid precursors, on the assembly of amyloid fibrils.
Forecast
Forecast for life in patients with P. b. favorable without amyloidosis. Frequent bouts of illness can cause temporary disability. The development of amyloidosis leads to disability due to renal failure (usually up to 40 years of age). Prior to the use of colchicine, 5- and 10-year survival of patients with P. b. with amyloidosis (from the onset of proteinuria) was 48 and 24%, respectively. When treated with colchicine, it increased to 100%, and the median survival increased to 16 years. Colchicine is effective regardless of the stage of amyloid nephropathy. However, the sooner treatment is started, the sooner a positive result occurs. Therefore it is very important dispensary observation sick P. b. for early detection persons requiring treatment with colchicine primarily for the prevention of amyloidosis.
- Treatment of Periodic Illness
What is Periodic Disease
Periodic illness(familial Mediterranean fever, benign familial paroxysmal peritonitis, Armenian disease, etc.) is a hereditary disease of an autosomal recessive type with complete gene penetrance. The disease is described mainly among the inhabitants of the Mediterranean basin - Arabs, Turks, Jews, Armenians, but also occurs in other parts of the world, in particular among people of Caucasian nationalities. Both men and women are ill; familial cases have been reported.
Symptoms of Periodic Illness
Benign aseptic inflammation of the serous membranes underlies the clinical manifestations of periodic illness. It is believed that the pathological process is explained by a congenital metabolic defect, but the factors provoking inflammation and the pathogenesis of acute attacks have not been established. Apparently, neutrophilic leukocytes play an important role in the development of the attack. L. N. Kochubey et al. in the pre-attack and attack periods of the disease, a pronounced degranulation of neutrophilic leukocytes, the classic initiators of aseptic inflammation, was revealed. The process of degranulation is accompanied by the release of intracellular mediators of inflammation, such as a factor that immobilizes neutrophils, a complement-activating substance, a chemotactic factor, etc.
The process usually begins in early childhood and adolescence and is manifested by periodic bouts of acute pain in the abdomen, simulating peritonitis, or pain in chest, high temperature(up to 39-40 ° C), arthralgia or arthritis, in some cases, the early development of amyloidosis, especially in carriers of HLA A28. Crises last 1-2 days, rarely more, and can cause erroneous surgical interventions, in particular lzpprotomy, with kshira, only serous effusion is usually found.
The articular syndrome is characterized by a discrepancy between severe pain and limitation of movement in the joints and relatively weak signs inflammation - swelling, hyperthermia, absence of hyperemia. The joints are affected asymmetrically, often there are mono or oligoarthritis of the knee, ankle, hip, shoulder, elbow joints, small joints brushes, occasionally temporomandibular and ileosacral joints. Articular attacks last somewhat longer than other manifestations of the disease - 4-7 days and only occasionally a longer period. The regression is complete, excluding the hip joints, which may remain stiff.
During an acute attack, leukocytosis, an increase in ESR, and the content of fibrinogen in the blood are detected. Urine is usually normal except for amyloidosis. RF is not detected. Radiologically, as the duration of the disease increases, monetary changes in the joints are revealed.
Treatment of Periodic Illness
To reduce the number of repeated attacks, colchicine is prescribed for a long time in small doses (0.6 mg 2-3 times a day), which prevents the degranulation of neutrophilic leukocytes, which plays a role in pathogenesis. acute attacks. Sometimes the seizures disappear completely. However positive results are not always achieved and, in addition, treatment is difficult due to the toxic effect of the drug.
Which Doctors Should You See If You Have Periodic Illness
Rheumatologist
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Periodic disease (synonyms: familial Mediterranean fever, benign paroxysmal peritonitis, recurrent polyserositis, Jewish disease, Armenian disease) is a hereditary autosomal recessive disease common among representatives of the ancient peoples of the Mediterranean. Most often, periodic illness (PB) occurs in Sephardic Jews, Armenians, Arabs, Greeks, Turks, peoples of the Caucasus, etc., hence the other names of the disease. The incidence of PB among Sephardi Jews, according to various sources, ranges from 1:250 to 1:2000 (the frequency of carriage of the mutant gene is from 1:16 to 1:8), among Armenians - from 1:100 to 1:1000 (the frequency of carriage is from 1 :7 to 1:4).
Among 15 children with BE observed in the Russian children's clinical hospital(RDKB) in recent years, 8 were Armenians, 4 were Dagestanis, 1 was Greek, 1 was with Chechens and Jewish roots, 1 - Russian.
Etiology and pathogenesis
PB is based on a point mutation in the gene for the pyrin protein, located on the short arm of the 16th chromosome (16q) next to the genes for autosomal dominant polycystic kidney disease and tuberous sclerosis. Pyrin is a protein in the primary granules of neutrophils that is actively involved in the regulation of inflammation. It is believed that pyrine stimulates the production of anti-inflammatory mediators, allows you to control chemotaxis, and stabilizes the granulocyte membrane. Violation of the structure of this protein, which occurs in BE, leads to an increase in the production of pro-inflammatory mediators in leukocytes, activation of the microtubular apparatus and spontaneous degranulation of primary granules of leukocytes, activation of adhesion molecules and increased leukocyte chemotaxis, resulting in inflammation.
To date, 8 types of mutations are known in the C-terminal region of the pyrin gene, in which a point amino acid substitution occurs. The most common three mutations, which account for more than 90% of cases of PB: M680I (replacement of isoleucine with methionine), M694V (replacement of valine with methionine), V726A (replacement of alanine with valine). All three mutations are 2000-2500 years old, therefore they are sometimes called "biblical", therefore they are predominantly distributed among representatives of the ancient peoples who inhabited the lands around the Mediterranean Sea. The M680I mutation occurs mainly in Armenians, M694V and V726A in all ethnic groups.
PB proceeds in the form of seizures, the basis of which is spontaneous or provoked degranulation of neutrophils with the release of mediators and the development of aseptic inflammation mainly on the serous and synovial membranes. In the peripheral blood, the number of neutrophils and acute phase proteins (CRP - C-reactive reactive protein, SAA - serum amyloid A protein, etc.). Irritation of receptors by inflammatory mediators leads to the development of pain syndrome, and exposure to a large number endogenous pyrogens to the thermoregulatory center - to the development of fever.
Clinical picture and flow
Clinically, PB is manifested by stereotypical attacks of fever that occur at regular intervals (days - weeks - months). Fever may be accompanied by pain syndromes associated with the development nonspecific inflammation in serous and synovial integuments. Depending on the penetrance of the genes, these syndromes can be isolated or combined, but each of them retains its own rhythm. Any attack is accompanied by leukocytosis, an increase in ESR and other inflammatory proteins, an increase in the a- and b-fraction of globulins, and a decrease in the activity of neutrophil myeloperoxidase. Outside the attack, the children feel well, laboratory parameters are gradually normalizing.
Fever is the most common persistent symptom with PB, occurs in 96-100% of cases. A feature of fever in PB is that it is "not controlled" by antibiotics and antipyretics. Isolated fever in PB, as a rule, leads to diagnostic errors and is regarded as a manifestation of SARS.
The second most common symptom of PB is abdominal pain syndrome (aseptic peritonitis), which occurs in 91% of cases, and in isolation - in 55%. Clinically, aseptic peritonitis differs little from septic peritonitis with all the symptom complex characteristic of the latter: temperature up to 40 °, severe abdominalgia, nausea, vomiting, and inhibition of intestinal motility. After a few days, peritonitis subsides, peristalsis is restored. Such a clinic is often the cause of diagnostic errors, and patients are operated on for acute appendicitis, peritonitis, cholecystitis, intestinal obstruction, etc. Among the children observed by us, 6 were previously operated on, and 2 patients - twice: 4 - for acute appendicitis, 2 - for intestinal obstruction, 1 - for peritonitis, 1 - acute cholecystitis. As a rule, in medical records such patients, the presence of "catarrhal appendicitis" and the need surgical intervention is beyond doubt. It is quite typical that, according to the parents, the doctors who operated on the child, in private conversations, denied the actual presence of appendicitis or peritonitis.
The duration of febrile and abdominal variants of BE usually ranges from 1 to 3 days, less often it lengthens to 1-2 weeks.
Peritonitis, like articular syndrome, is most common for childhood.
Articular syndrome is characterized by arthralgia, inflammation of large joints. According to various sources, arthritis and arthralgia are observed in 35-80% of cases, and in 17-30% they are the first signs of the disease. At the time of the attack, sudden joint pain in one or more joints, which may be accompanied by edema, hyperemia and hyperthermia of the joints. The duration of the articular variant of an attack of PB is 4-7 days, sometimes lengthening up to 1 month. In contrast to isolated fever or paroxysmal peritonitis, in this variant of PB, arthralgia often persists after an attack, gradually subsiding over several months. The nonspecificity of the clinical picture in the articular variant of BE leads to the fact that patients are diagnosed with rheumatoid arthritis, rheumatism, systemic lupus erythematosus, etc. The father of one of our patients, an Armenian by nationality, was observed for many years with a diagnosis of rheumatoid arthritis, and only when PB was detected in a child, we genetically established the same diagnosis in him.
The thoracic variant with pleural syndrome is less common - about 40% of cases, in isolation - in 8%, in combination with abdominal syndrome- in 30%. With the thoracic variant, one-bilateral pleurisy develops with a sterile effusion. The duration of this syndrome is 3-7 days. As a rule, such patients are mistakenly diagnosed with pleurisy or pleuropneumonia.
Skin changes during an attack of BE occur in 20-30% of cases. The most typical is an erysipelas-like rash, but purple rashes, vesicles, nodules, and angioedema may occur. Sometimes clinically PB proceeds like an allergic reaction up to Quincke's edema and urticaria.
Other manifestations of PB can be headache, aseptic meningitis, pericarditis, myalgia, hepatolienal syndrome, acute orchitis.
Among our patients, 12 BE proceeded according to the abdominal variant, in 3 - according to the abdominal-articular variant. 11 of them were admitted to the RCCH with other diagnoses: chronic cholecystitis, pancreatitis, gastroduodenitis, Crohn's disease, colitis unclear etiology, rheumatoid arthritis, SLE (systemic lupus erythematosus), chronic glomerulonephritis and only 4 - with a leading diagnosis of "periodic illness". Most patients are admitted to the gastroenterology department with complaints of recurrent abdominal pain, with the involvement of the kidneys with the development of proteinuria and nephrotic syndrome - to the department of nephrology, with unmotivated recurrent fever - to the infectious and diagnostic departments.
The manifestation of the disease can occur at different ages. Cases of rather late manifestation of PB are described, after 20-25 years. According to our observations, in most patients, the first attack of BE was observed at the age of 2-3 years (9 patients), in 1 - from birth, in 2 - at 0.5-1.5 years, in 2 - at 4-5 years, in 1 - at 11-12 years old.
The frequency and frequency of attacks vary in different patients over a wide range: from several times a week to 1-2 times in several years. In most patients, seizures have a fairly stable rhythm. However, the literature describes cases when seizures could stop for several years or, conversely, resume after a long break under the influence of external factors(change of residence, marriage or marriage, the birth of a child, military service, etc.). In our patients, the frequency of seizures was fairly constant: in 1st - 2 times a week, in 4 - 1 time per week, in 5 - 1 time in 2-3 weeks, in 2 - 1 time per week. months, in 1 - 1 time in 2-3 months, in the 1st - 1 time in 6-12 months.
After some time from the onset of manifestation, most patients have hepatomegaly, which, according to our observations, can vary from +1 to +5 cm. Splenomegaly also gradually develops, the value of which in some patients reached +7 cm. However, an increase in the liver and spleen is not detected. in all patients. Obviously, these processes depend on the frequency and number of attacks and the development of amyloidosis.
Amyloidosis as a complication of periodic illness
Each attack of PB is accompanied by the release of a large number of mediators, the formation of inflammatory proteins. From the tissues and serous integuments, these proteins enter the blood, where they circulate for a long time. Thus, the body is faced with the task of somehow eliminating these proteins. The more frequent and more pronounced the attacks of PB, the more acute the problem of disposal. One way to get rid of excess circulating protein molecules is to process them to form an insoluble protein called amyloid. Figuratively speaking, amyloid is densely packed protein "garbage". The formation and deposition of amyloid in tissues leads to the development of amyloidosis.
Amyloidosis (from Latin amylum - starch) is a collective concept that includes a group of diseases characterized by the extracellular deposition of proteins in the form of characteristic amyloid fibrils. These insoluble fibrillar proteins may be localized to one specific site or may be distributed to various organs, including vital organs such as the kidneys, liver, heart, and others. Such accumulation leads to organ dysfunction, organ failure, and ultimately death.
The structure of amyloid is identical for all its types and is a rigid non-branching fibrils with a diameter of about 10 nm, with a folded β-cross conformation, due to which the effect of birefringence occurs in polarized light when stained with Congo red. The Alkaline Congo Red stain is the most common and available method for detecting amyloid.
Amyloid consists of fibrillar proteins (fibrillar component, F-component) and blood plasma glycoproteins (plasma component, P-component). The precursors of the F component differ at various types amyloidosis (today up to 30 precursor proteins are known, they determine the type of amyloidosis); there is only one precursor of the P-component, the serum amyloid P-component (SAP), similar to α-globulin and CRP.
Amyloid fibrils and plasma glycoproteins form complex compounds with tissue chondroitin sulfates with the participation of hematogenous additives, among which the main ones are fibrin and immune complexes. The bonds between the protein and polysaccharide components in the amyloid substance are especially strong, which explains the lack of effect when various body enzymes act on amyloid, i.e., amyloid is insoluble.
In BE, the basis for the formation of the fibrillar component of amyloid is the serum acute phase protein SAA. SAA is an a-globulin, similar in its functional properties to CRP. SAA is synthesized by cells different types(neutrophils, fibroblasts, hepatocytes), its amount increases many times during inflammatory processes and tumors. Several types of SAA have been isolated in humans, and only fragments of some of them are part of amyloid fibrils, which may explain the development of amyloidosis in only a part of patients, despite the increased production of SAA. From the serum SAA precursor, AA protein (amyloid A protein) is formed in tissues, which is the basis of amyloid fibrils. Therefore, the type of amyloidosis that develops in BE is called AA amyloidosis.
Thus, the basis for the development of amyloidosis in BE is the excessive formation of the SAA precursor protein. But for the formation of amyloid protein, cells are needed that will synthesize it - amyloidoblasts. This function is performed mainly by macrophages-monocytes, as well as plasma cells, fibroblasts, reticulocytes and endothelial cells. Macrophages process the AA protein into full-fledged amyloid fibrils on their surface and deposit it in the interstitial tissue. Therefore, the greatest accumulation of amyloid in BE is observed in organs where macrophages occupy a fixed position: kidneys, liver, spleen. Gradually increasing deposits of amyloid lead to compression and atrophy of parenchymal cells, sclerosis and organ failure.
According to various data, amyloidosis in PB disease develops in 10-40% of patients. Some patients, despite fairly frequent attacks, do not develop amyloidosis at all. Probably, the development of amyloidosis depends on the structural features of the precursor protein in this patient and the genetic ability of macrophages to synthesize amyloid.
Despite the fact that amyloidosis can develop in any organ and tissue, amyloid kidney damage plays a decisive role in the prognosis and life of a patient with BE. With the development of AA-amyloidosis, the kidneys are affected in 100% of cases.
In the kidneys, the role of amyloidoblasts is performed by mesangial and endothelial cells.
During the deposition of amyloid in renal tissue and the organ damage caused by it, a certain staging can be traced. There are 4 stages of renal amyloidosis: latent (dysproteinemic), proteinuric, nephrotic (edematous) and uremic (azotemic).
AT latent stage changes in the kidneys are insignificant. Disturbances of the glomerular filter are noted in the form of focal thickening, membrane bypass, and aneurysms of a number of capillaries. There is no amyloid in the glomeruli or it is found in no more than 25% of the glomeruli.
Leading in the pathogenesis of this stage of amyloidosis is a significant synthesis and increase in the blood plasma concentration of amyloidosis precursor proteins, i.e., dysproteinemia. Clinically, children may develop hypochromic Iron-deficiency anemia, hyperproteinemia, dysproteinemia with an increase in globulins α 2 , β and γ, it is noted high content fibrinogen and sialoproteins. Characterized by enlargement and hardening of the liver and spleen.
Changes in the urine are initially absent or transient, but over time, proteinuria becomes constant and more pronounced, microhematuria and cylindruria are often observed. The appearance of permanent proteinuria characterizes the transition to the second, proteinuric, stage.
In the proteinuric stage, amyloid appears not only in the pyramids, but also in half of the glomeruli of the kidneys in the form of small deposits in the mesangium, individual capillary loops, and arterioles. Severe sclerosis and amyloidosis of the stroma, vessels, pyramids and intermediary zone is noted, which leads to atrophy of many deep-seated nephrons.
The duration of this stage, like the previous one, ranges from several months to many years. As the severity of amyloidosis increases, the laboratory indicators of the pronounced activity of the process are aggravated: significant proteinuria and dysproteinemia, hyperfibrinogenemia, CRP, hypercoagulation. Further deposition of amyloid in the renal tissue and increasing proteinuria lead to the development of edematous syndrome, the appearance of which indicates the transition of the disease to the third, edematous, stage.
In the edematous (nephrotic) stage of amyloidosis, the amount of amyloid in the kidneys increases. More than 75% of glomeruli are affected. Sclerosis of the interstitium and vessels progresses; in the pyramids and intramedial zone, sclerosis and amyloidosis have a pronounced diffuse character.
Clinically, this stage of amyloidosis is represented by complete nephrotic syndrome, although an incomplete (non-edematous) nephrotic syndrome can sometimes be observed. Proteinuria becomes massive and, as a rule, non-selective; growing cylinders. Hematuria is rare and usually minor. Hepatosplenomegaly, hypoproteinemia increase, dysproteinemia increases with a further increase in the level of α 1 -, α 2 -, and γ-globulins, hyperfibrinogenemia, hyperlipemia. Appears over time arterial hypertension, azotemia increases, renal failure progresses.
The uremic (azotemic) stage develops at the end of the disease. In connection with the growing amyloidosis and sclerosis, the death of most nephrons, their replacement connective tissue develops CRF (chronic renal failure).
The clinical features of chronic renal failure in amyloidosis, which distinguish it from chronic renal failure due to other diseases, is the persistence of the nephrotic syndrome with massive proteinuria, large kidney sizes are often determined, and hypotension is characteristic.
DIC (disseminated intravascular coagulation syndrome) is often expressed in the form of purpura, nasal, gastric and intestinal bleeding. Possible thrombosis renal vessels with the development of ischemic or hemorrhagic infarctions.
We observed the development of amyloidosis in 4 children with BE (26% of observed patients). Transient proteinuria appeared 7-8 years after the onset of the disease, after 2-3 years it became permanent. In 2 children, 1.5-2 years after the establishment of permanent proteinuria, nephrotic syndrome developed, which in one child developed into CRF.
Since the development of nephrotic syndrome, children have been diagnosed with chronic glomerulonephritis and prescribed appropriate treatment with glucocorticoids, which had no effect. Subsequently, the disease was regarded as SLE and a hormone-resistant variant of glomerulonephritis; the children received cytostatic therapy, also without effect. The diagnosis of "periodic disease, amyloidosis of the kidneys" in both cases was first established in the RCCH.
The development of amyloidosis to a certain extent depends on the number of BE attacks suffered by the child. Among our patients, renal amyloidosis was detected in those who had more than 130-150 attacks, while in children with fewer attacks, signs of amyloidosis and kidney damage were not observed. Moreover, children with nephrotic syndrome suffered the largest number of seizures - about 240 and 260. It should be noted that this pattern is not absolute and amyloidosis can develop with fewer attacks of BE.
Diagnosis of Periodic Disease and Amyloidosis
With a typical course of periodic illness, its diagnosis is not difficult. Biggest Problem lies in the ignorance of most doctors of this pathology, which leads to poor detection even in the presence of symptoms.
Diagnosis of PB is based on 5 points.
Anamnesis. Of greatest importance are the child's nationality, heredity (PB in parents or relatives; diseases in the family similar to PB), a characteristic anamnesis of the child's life and illness (frequent "colds" with fever, frequent pain in the abdomen and joints, transferred surgical interventions etc.).
clinical picture. attacks of fever with pain syndrome, ineffectiveness of antibiotics and antipyretics, good health during the non-attack period.
Laboratory data. Leukocytosis with neutrophilia, accelerated ESR, decreased activity of neutrophil myeloperoxidase and increased activity in the blood at the time of the attack; normalization of indicators outside the attack.
Genetic research. Most Reliable diagnostic sign PB. Identification of homozygous carriage of mutations M680I, M694V, V726A makes the diagnosis of periodic illness 100%. However, certain difficulties are also possible here, when a heterozygous carriage of mutations is detected in a typical clinic and anamnesis. Similar situation can occur when one of the above mutations is detected in one of the alleles of the pyrin gene, and a rarer one, not detected by standard typing, is detected in the other.
Effect of colchicine therapy. Trial therapy with colchicine as a diagnostic criterion is necessary when it is not possible to conduct genetic research or when its results do not fully confirm the diagnosis of BE (heterozygous carriers of the M680I, M694V, V726A mutations or carriers of rarer mutations). The presence of a response to therapy confirms the diagnosis of BE.
Diagnosis of AA-amyloidosis is a significant difficulty. In most cases, AA amyloidosis is not diagnosed in a timely manner, even when there are Clinical signs diseases. The reason for this is, on the one hand, the non-specificity of the symptoms of the disease, and on the other hand, the lack of alertness in most doctors regarding amyloidosis, which is associated, among other things, with its low prevalence in children. However, our understanding of the frequency of amyloidosis in children is erroneous, and the detected cases represent only the “tip of the iceberg”. as show latest research conducted in adult patients, amyloidosis during life is not diagnosed in 83% of patients.
When making a diagnosis of BE, in most cases, the doctor is wary of amyloidosis. But often the first suspicions of AA amyloidosis may arise in a pediatrician when treating patients with nephrotic syndrome who are resistant to standard glucocorticoid therapy.
Only the study of biopsy materials with obligatory Congo red staining and polarizing microscopy makes it possible to make the final diagnosis of AA amyloidosis. In addition, specific antibodies to AA fibrils can be used for diagnosis. The most reliable is a kidney biopsy. The frequency of detection of AA-amyloidosis in this case reaches 90-100%. The more common the process, the more more likely detection of AA-amyloid in other places ( gastrointestinal tract(GIT) - mucosal and submucosal, gingival mucosa, rectum, fat biopsy). The most informative among non-renal biopsies is biopsy of the wall of the gastrointestinal tract and rectum, in which the probability of detecting amyloid is 50-70%.
Treatment
With periodic illness, the mainstay of therapy is the appointment of colchicine. Colchicine has an antimitotic effect on amyloidoblasts in periodic disease - macrophages and stabilizes the neutrophil membrane, preventing the release of pyrine. Colchicine is prescribed for life at a dose of 1-2 mg / day. It is well tolerated, sometimes there are dyspeptic phenomena that do not require complete discontinuation of the drug. In most cases, colchicine completely prevents the onset of BE attacks or significantly reduces their frequency and severity, prevents the development of renal amyloidosis, and reduces the severity of its manifestations. In renal failure, the dose is reduced based on the degree of reduction glomerular filtration. The drug may be temporarily discontinued if acute infections The child has.
We observed a boy who was sent to the RCCH with a genetic diagnosis of periodic illness at the age of 16 years. Attacks of PB were noted in him from the age of 4, proceeded at intervals of 1 time in 2-3 weeks in the form of fever with abdominal pain, 1-2 times vomiting, headache and severe weakness. The attacks lasted about a day, then for 1-2 days there was such a pronounced weakness that the boy could not get out of bed, did not attend school. There were no signs of amyloidosis.
In the RCCH, the child was prescribed colchicine at a dose of 2 mg/day. Over the next 2 years of observation, the number of seizures dropped sharply to 1-2 times a year, and during the last 10 months there was not a single one. Now the young man is successfully studying at the university, lives in a hostel in another city, feels good.
In the treatment of BE and the prevention of amyloidosis, it is necessary to organize proper nutrition child. Increasing the total amount of protein in the diet stimulates amyloidogenesis, while liver protein and heart muscle inhibit it. A 50% reduced animal diet (especially casein) is recommended and vegetable proteins and an increase in foods containing starch. The diet should be sufficiently enriched with fruits, vegetables and other waste products. Protein is preferably given daily (100 g of liver, raw or cooked). The liver is used for years, in the form of repeated multi-month courses. Hepatotropic drugs are used in repeated courses: for 2-4 months Essentiale, Lipoic acid.
Forecast
With timely diagnosis and the appointment of colchicine, the prognosis of PB is favorable.
In the absence of therapy, the greatest danger is the development of renal amyloidosis, which, in fact, is the only cause of death in patients with BE. An analysis of the incidence in adults and children shows that in the natural course of a periodic illness, approximately 50% of patients terminal stage renal failure develops 5 years after the onset of proteinuria, in 75% - within 10 years.
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A. V. Malkoch, candidate medical sciences
RSMU, Moscow
Periodic illness(familial Mediterranean fever, benign familial paroxysmal peritonitis, Armenian disease) is a disease inherited in an autosomal recessive manner and characterized by irregular attacks of fever in the presence of one or more inflammatory foci.
The disease occurs mainly in the inhabitants of the Mediterranean basin (Arabs, Jews, Turks, Armenians) and usually begins in childhood and adolescence. Men are more often ill, familial cases of the disease are possible.
Etiology and pathogenesis
It is assumed that the pathological process is explained by a congenital metabolic defect, but the pathogenesis of acute attacks and factors that provoke inflammation have not been established. It is assumed that neutrophilic leukocytes play an important role in the development of attacks.
Clinic
The disease usually debuts before the age of 30 years. Benign aseptic inflammation of the serous membranes underlies the clinical manifestations of periodic illness. The disease is manifested by periodic attacks of acute pain in the abdomen, simulating peritonitis, or in the chest, fever (up to 39-40 ° C), arthralgia or arthritis, sometimes the early development of amyloidosis, which is often the only phenotypic sign of the disease in some ethnic groups. Crises last, as a rule, 1-2 days and often cause erroneous surgical interventions.
Main clinical manifestations of periodic illnessoccur with a fairly high frequency: fever - 100%, peritonitis - 85-97%, arthritis - 50-77%, pleurisy - 33-66%, erysipelas - 46%, splenomegaly - 33%, lymphadenopathy - 1-6%. In some cases, aseptic meningitis develops.
The articular syndrome is characterized by acute pain, sharp pain on palpation and pronounced violation joint function that does not correspond to the degree of joint edema. There are also no hyperemia of the skin and an increase in local temperature in the area of the affected joint. The most characteristic are transient attacks of mono- or oligoarthritis, often of large joints (knee, hip, ankle, shoulder, elbow). In 20% of patients, polyarthritis is noted. Articular attacks last somewhat longer than other manifestations of the disease (4-7 days), and in some cases their duration is several weeks and months. In the period between attacks, the function of the affected joint is completely restored, its destruction is rare.
During an acute attack, leukocytosis, an increase in ESR, and an increase in the level of fibrinogen in the blood are noted.
In 25-40% of patients, the disease is combined with amyloidosis, mainly of the kidneys, the failure of which leads to lethal outcome often before the age of 40.
The development of amyloidosis does not depend on the frequency and nature of acute attacks of the disease.
According to the predominance of clinical manifestations, several variants of periodic illness are distinguished.
The abdominal variant is the most common, accompanied by symptoms of an "acute abdomen" with partial intestinal obstruction, serous peritonitis with moderate adhesive process. In contrast to acute surgical abdominal pathology, all signs disappear spontaneously after 2-4 hours.
The thoracic variant is less common. It is based on inflammation of the pleural sheets. It is characterized by an increase in body temperature (no more than 1 day), the development of dry pleurisy (sometimes with a slight effusion). All symptoms disappear after 3-7 days.
The articular variant is characterized by recurrent synovitis. It proceeds in the form of arthralgia, mono- and polyarthritis, sometimes without a febrile reaction, spontaneously disappears after 4-7 days, but sometimes lasts longer.
The febrile variant should be distinguished from the fever associated with all variants of the disease. In this case, the disease resembles malarial paroxysms: chills are accompanied by an increase in body temperature up to 40 ° C, which decreases during the day. Seizures develop infrequently, occur mainly in childhood. This variant of periodic disease, like articular and thoracic, can disappear, giving way to abdominal pain.
Often, periodic illness occurs as a combination of several clinical variants.
Treatment
The use of colchicine in small doses helps to prevent attacks of periodic illness. In 50% of cases, there is a complete remission with permanent reception colchicine in a daily dose of 1-2 mg.
Treatment with colhamin (colchicine) should begin with determining the tolerability of the drug: patients take the drug for 10 days after meals under the control of a blood test, including leukocytes and platelets. In this case, the selection of the optimal daily dose(no more than 2 mg), taking into account the frequency of seizures. In those rare cases where colchamine is not effective, it may be helpful to replace it with colchicine at the same or even lower dose.
During acute attacks, treatment of intermittent illness involves the administration of NSAIDs. Hormone therapy is ineffective, which can serve as a differential diagnostic sign.
"Rheumatology"
T.N. Onboard
