Hepatitis A: diagnosis

Diagnosis of hepatitis A is based on clinical, epidemiological and laboratory data. The informativeness of these components is not the same. Clinical signs can be attributed to the category of supporting, epidemiological - leading, while the results of laboratory research are crucial at all stages of the disease.

[1], [2], [3], [4], [5], [6], [7], [8], [9]

Laboratory diagnosis of hepatitis A

Methods for laboratory diagnosis of hepatitis A are divided into specific and nonspecific. Specific methods are based on the identification of the pathogen, its antigens or antibodies.

For the detection of the hepatitis A virus, the method of Immune Electron Microscopy (IEM) and its various modifications, as well as immunofluorescence (IF), radioimmunoassay (RIA) and enzyme immunoassay (ELISA), and others are commonly used. Antigen of the hepatitis A virus is found in the feces of patients 7-10 before the appearance of clinical symptoms and in the first days of the disease, which can be used for early diagnosis. However, in connection with the laboriousness of the methods of detection of the virus and its antigen in the practical work have not received distribution.

Currently, specific diagnosis of hepatitis A is based solely on the detection of antibodies to the IgM class (anti-HAV IgM) and IgG (anti-HAV IgG) by radioimmunoassay or ELISA. Both methods are highly sensitive and specific.

At the onset of the disease, antibodies of the IgM class (anti-HAV IgM) appear in the blood, their synthesis begins even before the appearance of the first clinical symptoms and grows in the acute phase of the disease, and then the antibody titer gradually decreases, and anti-HAV IgM disappear from the circulation through the 6- 8 months from the onset of the disease, Anti-HAV of the IgM class is found in all patients with hepatitis A, regardless of the severity of the disease, including all erased, non-jagged and inapparent forms. The synthesis of antibodies of IgG class (anti-HAV IgG) begins at later periods of the disease, usually 2-3 weeks from the onset of the disease, their titer increases more slowly, reaching a maximum at the 5th-6th month of the period of convalescence. That is why for the diagnosis of hepatitis A at all stages of the disease only the definition of anti-HAV IgM class is used, The diagnostic value of IgG antibodies can be accepted only in case of a titer increase in the dynamics of the disease.

Antibodies to HAV IgG class are found in the blood after an obvious or latent hepatitis A is transmitted indefinitely, which makes it possible to evaluate the state of the population's immunostructure, its protection against hepatitis A.

Nonspecific methods are of great importance for assessing process activity, severity, flow characteristics and prognosis. Among the numerous laboratory tests proposed for these purposes, the determination of the activity of hepatic cell enzymes, the parameters of pigment metabolism, and the protein-synthesizing function of the liver is crucial.

Indicators of hepatic-cellular enzyme activity occupy a central place in all non-specific diagnosis of viral hepatitis. The results of determining the activity of enzymes can be considered a kind of "enzymological puncture" of the liver. Among the numerous enzyme tests used in hepatology, the most widely used activity was determination of the activity of ALT, ACT, F-1-FA, sorbitol dehydrogenase, glutamate dehydrogenase, urokinanase and some others.

An increase in the activity of transferases in the acute period of typical hepatitis A is observed in 100% of cases, in the case of anicterless forms - in 94, with erased forms - in 80%. The activity of ALT increases more than ACT, therefore, the AST / ALT coefficient in the acute period of hepatitis A is less than one. The activity of transferases decreases with recovery, with the AST / ALT coefficient approaching unity. With exacerbation, the activity of transferases rises again several days before the clinical manifestations of exacerbation. In protracted forms, the activity of transferases remains elevated throughout the entire period of the disease.

At high sensitivity of transaminase test it should be noted its non-specificity for viral hepatitis. High activity of transaminases is observed with myocardial infarction, liver carcinoma, pancreatic diseases. A slight increase in activity may occur in ARVI, pneumonia, gastroenteritis, infectious mononucleosis, hepatocholecystitis, etc. However, only with viral hepatitis (and with myocardial infarction) there is a high (tens of times normal) and stable hypertransferase.

Among the so-called hepatic-specific enzymes, the most important is F-1-FA. An increase in the activity of this enzyme is observed only in viral hepatitis and does not occur in other infectious diseases; the same can be said for other hepatic-specific enzymes - Gldg, urocaninase, etc. The degree of increase in the activity of these enzymes correlates with the severity of the disease - the heavier the form of the disease, the higher their activity.

It should be noted, however, that the normalization of hepatic-specific enzyme activity in some patients occurs faster than the normalization of ALT activity, which reduces the prognostic value of determining the activity of hepatic-specific enzymes. To fully solve all clinical problems, it is rational to use a complex of enzyme tests in practical work. The determination of the activity of ALT and F-1-FA can be considered optimal.

The indicators of pigment metabolism are inferior to enzymatic tests because they increase the level of conjugated bilirubin in serum with viral hepatitis in a relatively late period of the disease, usually on the 3-5th day of the disease, and in the case of anicterless forms of increasing serum bilirubin content in general can not be.

As an early laboratory test, indicating a violation of pigment metabolism, you can use the definition of urobilin and bile pigments in the urine.

In the early stages of the disease, bile pigments in the urine are found in 80-85% of cases. The intensity of bilirubinuria increases with increasing severity of the disease, and in general the curve of bilirubinuria repeats the level of conjugated bilirubin in the blood.

Urobilinogenovyh and urobilinovyh bodies in healthy people can detect very little by using quantitative methods. If the liver is damaged, the urobilinous bodies are not retained by the hepatic cells and pass into the blood, and then into the urine. Urobilinuriya appears in the early stages of the disease, reaches a maximum at first jaundice, and then decreases. At the height of pronounced jaundice, urobilin bodies in the urine are usually not detected. This is due to the fact that in this period, most of the conjugated bilirubin enters the bloodstream, but does not enter the intestine, so the number of urobilin bodies in the intestine decreases sharply.

On the decline of jaundice, when the excretion of bilirubin by hepatocytes and the patency of the bile ducts are restored, the number of urobiline bodies in the intestine increases, and they again increase in the liver. At the same time, the function of the latter remains still impaired, and therefore the urobilin bodies are regurgitated into the blood and excreted in the urine. The amount of urobilin in urine again sharply increases. Continuous urobilinuria indicates a pathological process that persists in the liver.

Of the indicators of protein-synthesizing liver function for diagnosis of hepatitis A, the sedimentary thymol test is most important. With hepatitis A, its rates increase 3-5 times and, as a rule, from the first days of the disease. As the clinical manifestations of the disease abate, the indices of thymol test decrease slowly. Complete normalization of them in most patients is not observed even by the time of clinical recovery. With prolonged disease, indications of thymol test remain elevated for a long time. At an aggravation parameters of this sample rise again.

Other sediment samples (sulman, Veltman, etc.) with hepatitis A do not have diagnostic significance.

Clinical diagnostic criteria for hepatitis A

The diagnosis of hepatitis A in typical cases is based on the acute onset of the disease with a brief rise in temperature and the appearance of symptoms of intoxication (lethargy, decreased appetite, nausea, vomiting, etc.) to varying degrees. Already in this period, many patients have a feeling of heaviness in the right upper quadrant, there is increased sensitivity or even painfulness when tapping on the right edge of the ribs or when palpating the liver region. Language, as a rule, is imposed.

Diagnosis is greatly simplified if patients complain of abdominal pain themselves, and especially if palpation reveals enlarged liver size and soreness. This symptom can be considered the leading objective evidence of hepatitis A in the pre-zheltushnom period. At the end of the initial period of the disease, more often 1-2 days before the appearance of jaundice, another highly informative sign is revealed - a darkening of the color of urine, and then a decolorization of feces.

[10], [11],

Epidemiological criteria for hepatitis A

A detailed epidemiological history allows most patients to establish the presence of contact with a sick hepatitis in the family, the team for 2-4 weeks before the appearance of the first signs of the disease. Approximately a third of patients have no apparent contact, but in these cases, one can not exclude contact with people who carry erased or antipyretic forms of the disease, which can occur under the guise of other diseases.

[12], [13], [14], [15], [16], [17], [18],

Laboratory severity criteria

A large number of laboratory tests characterizing the functional state of the liver have been proposed, which are recommended for evaluating the severity of the disease. However, for practical work, it is necessary to define a minimum set of laboratory indicators that would, firstly, most fully reflect the degree of functional insufficiency of the liver, and secondly, differ in specificity

In this minimal complex, we assign great importance to the definition of total bilirubin and its fractions in the serum of blood, the evaluation of the protein-synthesizing function of the liver, mainly by the factors of blood coagulation and the sulphonic titre, to the activity of enzymes with various subcellular localization.

Bilirubin and its fractions

The parameters of bilirubin in the serum are higher, the heavier the form of the disease. In light forms, the content of total bilirubin in the overwhelming majority of cases (95%) does not exceed 85 μmol / l and is on an average by the method of Jendrassik-Gleghorn 57.7 + 25.9 μmol / L, in moderate forms in 80% of cases, the total bilirubin is in the range from 85 to 170 μmol / l, on the average - 111,3 ± 47,4 μmol / l, in severe forms in almost all patients the level of total bilirubin is from 140 to 250 μmol / l. The difference in these values is statistically significant (T> 2 at p 0.05).

Thus, the degree of hyperbilirubinemia corresponds to the severity of liver damage. However, it is often difficult to assess the severity of the disease only by the indicator of total bilirubin in blood serum, since there are cases of severe hepatitis, in which the level of total bilirubin in the serum is not more than 85 μmol / l, and vice versa, there are cases with excessively high rates of total bilirubin up to 400 μmol / l) with a moderate lesion of the liver parenchyma. In such patients, the cholestatic component predominates in the mechanism of the disturbance of pigmentary metabolism. For this reason, especially important in assessing the severity of viral hepatitis is given to unconjugated (indirect) bilirubin, whose content in severe forms averages 5-10 times higher than normal, while in mild and moderate forms only 1.5- 2 times its increase. Most of all, the severity of the disease reflects the index of the monoglycuronide fraction, which is 5 times higher than normal in light forms, and 10 times or more in the case of the medium-heavy ones. However, the increase in the fraction of monoglucuronide can hardly be regarded only as an indicator of severe damage to the hepatocyte, since its increase is constantly noted even with cholestatic and even mechanical jaundice. That is why when evaluating the severity it is better to focus on the content of unconjugated bilirubin by the method of Jendrassik-Gleghorn. Accumulation of the unconjugated fraction indicates a disruption of the pigment conjugation in the hepatic cells and, therefore, serves as an indicator of widespread necrobiotic processes in the liver parenchyma.

[19], [20], [21], [22], [23], [24], [25]

Indicators of protein-synthesizing function of the liver

The leading role of the liver in the synthesis of proteins is shown in numerous studies of domestic and foreign authors. It has been proved that albumins, fibrinogen, prothrombin, proconvertin and most of the a- and y-globulins, as well as complex protein complexes (glycoprotein and lipoproteins, ceruloplasmin, transferrin, etc.) are synthesized predominantly in the ribosomes of hepatocytes. It should be noted that the determination of total protein in the serum can not be used to assess the severity of the disease, since the numerical values for patients with mild, moderate and severe forms of viral hepatocytes do not differ significantly. The same can be said for the protein blood spectrum, which although characterized in hepatitis A by some disproteinemia due to a decrease in albumin levels and an increase in y-globulin, but the degree of expression of these changes depends little on the severity of the disease.

Among the laboratory indicators characterizing the protein-synthesizing function of the liver, the most important factor for assessing the severity of viral hepatitis is the determination of blood coagulation factors in blood serum. The prothrombin content in serum is lower, the heavier the form of hepatitis. The same can be said about fibrinogen and especially proconvertin. These clotting factors are synthesized exclusively in the liver and, in addition, their half-life is from several hours (proconvertin) to 3 days (fibrinogen), which determines a rapid and irreplaceable reduction in fibrinogen and proconvertin level even in mild forms of viral hepatitis. Decrease in the level of proconvertin is observed even in cases when the disease occurs with a normal level of bilirubin. The dependence of the content of fibrinogen and proconvertin on the course of the disease was established: in a smooth cyclic flow, their content quickly normalizes, a long decrease in the level corresponds to a prolonged course of the disease, which can be used for prognosis.

When hepatitis A in the serum increases the concentration of almost all amino acids. The excretion of most amino acids in the urine is also increased. The degree of hyperaminoacidemia and giperaminoaciduria is directly related to the severity of the disease. At the height of clinical manifestations with mild forms of the disease, the total content of amino acids in the blood serum exceeds the control values by an average of 2 times, and in the daily urine - by 1.4 times, for the moderate - by 3 and 1.7 times, and for the severe form - in 4 and 2.2 times, respectively.

The state of the protein-synthesizing function of the liver can also be indirectly judged by the change in the colloidal reactions-the thiol and thymol assays. However, the indicator of thymol assay does not depend much on the severity of the liver damage and can not be used in assessing the severity of viral hepatitis. Greater value for assessing the severity of viral hepatitis has a trialmic test, the magnitude of which in severe forms almost always decreases, while in the case of mild forms it remains within the normal range.

Activity of enzymes with different subcellular localization. In the experiment, it was shown that when hepatocytes are damaged by carbon tetrachloride, cytoplasmic enzymes that are not associated with cellular organelles, such as aldolase, transaminase, lactate dehydrogenase and other substances, are the first to enter the bloodstream; with deeper damage, the release of enzymes that have a mitochondrial, lysosomal and other internal cellular localization occurs. These data theoretically substantiate the determination of the activity of enzymes with various subcellular localizations for evaluating the severity of liver damage.

Cytoplasmic enzymes

As the severity of viral hepatitis increases, the activity of cytoplasmic enzymes increases: in mild forms of the disease, the parameters of the liver-specific F-1-FA in the blood exceed the values in healthy individuals 11 times, with the moderate - 18, and heavy - 24. The activity of hepatic LDH exceeds the norm by 3, 6 and 8 times, respectively. However, the indices of other cytoplasmic enzymes - ALT, ACT, F-1-6-FA - are less dependent on severity. So. With a mild form, the activity of ALT increased 6-fold, with an average-at 6.4, and at a heavy-8-fold. Little correlates with the severity of the disease and the activity of F-1 -6-FA lactate dehydrogenase, etc.

Therefore, among the many cytoplasmic enzymes for assessing the severity of viral hepatitis, it can be recommended to determine the activity of organ-specific for the liver of F-1-FA and the fifth fraction of lactate dehydrogenase in the blood serum, whereas non-specific for the liver ALT, ACT, F-1-6-FA and other cytoplasmic Enzymes can not be recommended for these purposes.

[26], [27], [28], [29], [30], [31], [32], [33]

Mitochondrial Enzymes

According to the data of the majority of authors, the activity of mitochondrial enzymes in the blood serum increases mainly with severe liver damage.

The activity of mitochondrial enzymes is increased in all patients with viral hepatitis, and the higher it is, the heavier the disease. In the acute period of the disease, half of patients with moderate and all patients with severe forms in the serum found MDG-4, which is not observed in mild forms. The activity of glutamate dehydrogenase in light forms exceeds the control values by 5 times, for the medium-heavy - in 9, and for heavy - in 18 times. A similar dependence is also observed in other enzymes with mitochondrial localization. These data make it possible to recommend the determination of the activity of mitochondrial enzymes for assessing the severity of viral hepatitis.

Lysosomal enzymes

In viral hepatitis, lysosomes of hepatocytes are naturally involved in the pathological process, and the time of their involvement corresponds to pronounced morphological changes in the liver parenchyma.

In the acute period of viral hepatitis, the activity of RNAse, leucin aminopeptidase, cathepsins D and C increases in all patients, and it is higher the more severe the liver damage. The inverse relationship is observed in cathepsins B and especially A, whose activity with increasing severity of the disease shows a distinct tendency to decrease.

Inhibitors of proteolysis

Currently known and well studied proteolysis inhibitors 6: alpha 1-antitrypsin (a1-AT), a2-macroglobulin (a-MG), antithrombin III, C _II -inaktivator and-antichymotrypsin, and inter-a-antitrypsin. All inhibitors of proteinases are synthesized almost exclusively by the liver. This predetermines their significance for assessing the severity of viral hepatitis. Among all inhibitors of proteolysis, a2-MG and a1-AT have the greatest clinical significance. It is known that the fraction of a1-AT accounts for about 90% of the total activity of all inhibitors. It inhibits the activity of trypsin, plasmin, chymotrylsin, elastase, etc. Despite the fact that a2-MG accounts for about 10% of all anti-proteolytic activity of blood serum, it attracts the attention of clinicians primarily because it inhibits not only trypsin, chymotrypsin, plasmin, thrombin, elastase, but also the activity of most liver tissue cathepsins, with which autolysis syndrome is associated with viral hepatitis. It is also assumed that a2-MG plays the role of regulator of the coagulating and kinin systems that are of great importance in the pathogenesis of viral hepatitis.

The blood content of alat in light, moderate and severe forms of viral hepatitis increases in proportion to the severity of the disease, while the level of a2-MG, on the contrary, decreases. It should be noted, however, that the differences in the content of these inhibitors, depending on the severity of the disease, are not always reliable.

Blood lipid indices

In viral hepatitis in children, significant changes in the lipid spectrum of blood serum are observed. In the acute period with all forms of the disease, the content of triglycerides, phospholipids, unesterified fatty acids (NEFL), mono-, diglycerides, free cholesterol increases. The degree of severity of these disorders is directly related to the severity of the disease. If in light forms the content of triglycerides, phospholipids, mono-, diglycerides, free cholesterol and total lipids increases by an average of 50%, then for moderate and severe forms more than 2 times.

Even more significantly increases the content of NEFLC. With light forms, their number exceeds the normal parameters by 2-3 times, and for heavy ones - by 4-5 times. Another dependence characterizes the dynamics of cholesterol esters: in light forms, their content is within the normal range, while in severe forms it is 40-50% lower than normal. The level of total cholesterol does not depend on the severity of the disease. With all forms of viral hepatitis, the amount of total cholesterol tends to increase, mainly due to the growth of free fraction. The coefficient of esterification of cholesterol decreases the more, the heavier the form of the disease. With a mild form, it averages 0.53 ± 0.009, with an average - 0.49 ± 0.015, with a moderate - 0.41 ± 0.013 (in normal - 0.69 ± 0.01).

[34], [35], [36], [37]

Some indices of interchange

A universal role in the precise exchange of proteins, fats and carbohydrates belongs to the processes of biological acetylation, whose activity is mainly associated with the activity of coenzyme A (CoA) and depends on the functional state of the liver. Coenzyme A activates organic acids under the action of the corresponding enzymes, forming with them thioethers - energy-rich compounds that can participate in reactions with the most diverse compounds in the cell. Through CoA, the carbohydrate and fat metabolism is linked to the tricarboxylic acid cycle (Krebs cycle). CoA takes part in the synthesis of a wide variety of compounds: cholesterol, steroid hormones, in the oxidation of free fatty acids, oxidative decarboxylation of pyruvate, etc.

The state of the acetylating ability of the organism can be judged by the percentage of acetylated sulfonamides, excreted with 24-hour urine after loading with a white streptocid at a dose of 0.1-0.3 g per reception. The intensity of the processes of acetylation of sulfonamides directly depends on the biological activity of the processes of acetylation in the body. Therefore, determining the percentage of acetylated sulfonamides, one can indirectly judge the cytobiochemical processes taking place in the liver cells.

In healthy people, the acetylation ability averages 52.5 ± 0.93%. With viral hepatitis, the ability to acetylate at the height of the disease is reliably reduced: in the mild form, to 44 ± 1.38%, for the moderate form, to 38 ± 1.25, and for the severe form to 30.6 + 3.33%.

Of other indices of interstitial metabolism, related to the assessment of the functional state of the liver, and consequently, to the assessment of the severity of the disease, deserves attention to the determination of the content of pyruvic and lactic acids, which, as is known, are the main place in the processes of decomposition and synthesis of carbohydrates. The dynamics of the average values of pyruvate is inversely related to its ability to acetylate sulfonamides. With a mild form, the concentration of feather wool exceeds normal values by a factor of 2, with a medium-heavy one, 2.5, and with a heavy one, 4-fold.

Thus, it can be said that the functional state of the liver reflects various biochemical indicators, but none of them in individual values, the activity of specific hepatic cell enzymes (F-1-FA, Gldg, etc.) exceeds the standards by 5-10 times.

The course of the disease is cyclic. The duration of icteric period averaged 7-10 days. Normalization of liver size occurs on the 25-35th day. Approximately at the same time, a complete restoration of its functional state takes place. Only in 5% of patients the disease takes a long time.

Differential diagnosis of hepatitis A

In the pre-hectic period of hepatitis A, 70-90% of the cases are mistakenly diagnosed with ARVI. Difficulties in diagnosis are that in the initial period of hepatitis A there is sometimes a slight hyperemia of the mucous membrane of the oropharynx or nasal congestion. It should be borne in mind, however, that catarrhal phenomena (cough, runny nose) are not characteristic for hepatitis A, and if they occur, it is usually caused by residual symptoms of acute respiratory viral infection or a consequence of the combined course of hepatitis A and ARVI. For the differential diagnosis, the dynamics of the disease is important. In patients with hepatitis A, when the body temperature falls, symptoms of intoxication may persist. Dyspeptic disorders remain (nausea, vomiting), often there are pains in the abdomen, liver is enlarged, which is not typical of respiratory viral infections.

Errors in diagnosis can occur when differentiating hepatitis A with intestinal infections, acute appendicitis, helminthic invasion, mesadenitis, etc. An analysis of diagnostic errors convinces us that objective difficulties are present only in the 1-2 days from the onset of the disease, when there are no characteristic signs characteristic of these diseases and hepatitis A. Unlike intestinal infection, vomiting with hepatitis A is not frequent, liquid stool in the pre-jaundiced period is extremely rare, whereas for acute intestinal infection is characteristic of all d for vomiting frequent occurrence of liquid stools with pathological impurities. With objective examination, rumbling and tenderness are revealed along the bowel; if a hepatitis A and marked pain, they are exclusively associated with the liver area.

In helminthic invasion, as with hepatitis A, there may be complaints of poor appetite, lethargy, weakness, abdominal pain, nausea and even vomiting, but these complaints are noted for several weeks and even months, whereas the pre-hectic period with hepatitis A is almost never Do not continue more than 7 days, the bowl lasts 3 -5 days.

Some patients with hepatitis A in the prodromal period can have quite severe pains, and they are in some cases taken for acute appendicitis, acute pancreatitis, or other diseases of the abdominal cavity. With hepatitis A, palpation of the abdomen, as a rule, is painless, the abdomen is soft, there is a pain in the liver. The strains of the rectus muscles and the symptoms of irritation of the peritoneum do not happen worse in case of severe pain in the abdomen. It is important to consider that pain syndrome in hepatitis A arises from acute swelling of the liver, and it is always possible to detect its sharp increase and soreness in palpations, whereas in acute appendicitis pain is usually localized in the right ileal region, and in acute pancreatitis, pain in the projection of the pancreas glands. In the differential diagnosis of hepatitis A with surgical diseases of the abdominal cavity, it is important to take into account the nature of the temperature response, the pulse rate, the state of the tongue, and especially the nature of changes in the peripheral blood. In hepatitis A, there is a tendency for leukopenia and lymphocytosis, while in acute appendicitis, pancreatitis and other surgical pathology, neutrophilic leukocytosis is noted. In addition, with hepatitis A in the case of correctly collected history, it is almost always possible to detect abnormalities in the patient's condition a few days before the onset of abdominal pain - fever, poor appetite, malaise - unlike the acute abdomen, in which the disease arises acutely and pain in the abdomen serve as the first signs of the disease.

Of the laboratory methods in the pre-jaundiced period, biochemical tests and, in the first place, enzymatic tests are of great importance. The increase in the activity of ALT, F-1-FA and other indicators is observed even before the appearance of the first clinical symptoms of hepatitis A, whereas for all other diseases with which differential diagnostics is carried out, the activity of these enzymes does not increase significantly. An increase in the thymol test, as well as an increase in the level of conjugated bilirubin in the blood serum, should be considered a reliable diagnostic test in the prodromal period of hepatitis A. For the precise diagnosis of hepatitis A, the definition of specific markers of the disease is used-the detection of anti-HAV IgM in the blood serum.

In the differential diagnosis of hepatitis A in the icteric period, it is important at the first stage to answer the question: with what type of jaundice (superhepatic, hepatic, subhepatic) it is necessary to deal in each specific case. Isolation of the type of jaundice in the localization of the primary disturbance of pigmental exchange is very conditional, but this approach significantly facilitates a purposeful examination of the patient, serves as a justification for the need for differentiated therapy.

[38], [39], [40], [41], [42], [43], [44], [45]

Superhepatic jaundice

They arise as a result of enhanced hemolysis of red blood cells and excessive formation of unconjugated bilirubin, provided that the functional activity of the liver decreases. A similar type of jaundice occurs with hereditary and acquired hemolytic anemia, various intoxications, massive hemorrhages, etc. Viral hepatitis is sometimes mistaken for spherocytic hemolytic anemia, erythrocytic enzymoma and other rare forms of anemia due to hemoglobin pathology. Errors in diagnosis in these cases are primarily associated with an underestimation of anamnestic data, indicating the family nature of the disease, as well as with an incorrect treatment of the clinical manifestation and course of the disease. In differential diagnosis should be borne in mind the long wave-like course of hemolytic anemia from an early age, and with objective examination it is always possible to note a more or less pronounced anemia and, what is especially important, a significant increase in the size of the spleen; The liver can also be enlarged, but moderately, jaundice is weak even during a crisis. Urine often remains light or changes insignificantly due to an increase in the amount of urobilin, bilirubin in urine is not determined. In the blood serum, the content of exclusively unconjugated bilirubin is increased. Other biochemical parameters (enzyme activity, level of thymol test) are not changed. The color of feces with hemolytic anemia, in contrast to viral hepatitis, is dark brown due to the large amount of sterocilinogen. The diagnosis of hemolytic anemia is confirmed by changes in blood: a low content of hemoglobin and erythrocytes, microspherocytosis, reticulocytosis and decreased osmotic resistance of erythrocytes to hypotonic sodium chloride solutions.

In typical cases, differential diagnosis of hereditary spherocytic anemia with hepatitis A is not difficult. Difficulties can arise in cases when, during long-term hemolytic anemia, the level of conjugated bilirubin begins to rise in the blood and abdominal pains appear, while in the biliary tract or gall bladder, due to excessive bilirubin content, pigment stones can be formed that cause clinical manifestations of mechanical jaundice and calculous cholecystitis.

To a large extent, hepatitis A can resemble hemolytic jaundice of autoimmune genesis, accompanied by high fever, headache, mild jaundice and hyperbilirubinemia. Diagnosis in these cases is based on the presence of rapidly developing anemia that is not characteristic of hepatitis A, as well as the inconsistency of mild to severe jaundice of severe intoxication. Of the laboratory indicators for autoimmune anemia, leukocytosis, reticulocytosis and elevated ESR are characteristic, whereas the parameters of functional liver samples are little changed. The diagnosis of autoimmune hemolytic anemia is confirmed by the detection of anti-erythrocytic antibodies by direct and indirect Coombs reaction, and the diagnosis of hepatitis A by the presence of specific antibodies - anti-HAV of class IgM.

The more rare forms of hemolytic anemia associated with hemoglobin pathology and erythrocytic fermentopathy can also be mistakenly diagnosed as viral hepatitis, since jaundice is the leading clinical manifestation of the disease. To establish the diagnosis in these cases, a special hematological study is required: determination of the nature of hemoglobin and the content of enzymes in erythrocytes.

Hepatic jaundice

Hepatic jaundices but to the origin mechanism are non-uniform, they can arise due to a violation of the capture function, conjugation or excretion of bilirubin by the hepatic cells. In those cases where the function of bilirubin uptake is predominantly disrupted, unconjugated bilirubin accumulates in the blood serum, a picture appears that is characteristic of Gilbert's syndrome; when the conjugation (glucuronidization) of bilirubin is broken, Krieger-Pajar syndrome occurs, and if the excretion of conjugated bilirubin is disturbed, the picture of Dabin-Johnson syndromes or Rotor syndrome

The patients with Gilbert syndrome mistakenly enter the hepatitis department most often, and difficulties in differential diagnosis are possible when jaundice as a manifestation of functional hyperbilirubinemia occurs against the background of any disease: acute respiratory viral infection, acute intestinal infection, etc. In addition, symptoms such as fever body, nausea. Vomiting, preceded by the appearance of jaundice, create a picture of the pre-jaundiced period of viral hepatitis and, as it were, demonstrate cyclicity in the development of the disease. Particularly complicates the diagnosis of the presence of contact with a patient with hepatitis A. For the diagnosis of functional hyperbilirubinemia, data of an anamnesis about the family nature of jaundice are of significant importance. Hyperbilirubinemia has a wavy course, while periods of jaundice increase coincide with different stress conditions: physical activity, SARS, etc. The final diagnosis is made after laboratory testing. With functional hyperbilirubinemia in the blood serum, the content of unconjugated bilirubin is increased, the activity of hepatic cell enzymes remains within the limits of normal values. It is much more difficult to establish the correct diagnosis in those cases when, with functional hyperbilirubinemia, along with an increase in the level of unconjugated bilirubin, the level of the conjugated fraction also increases. Among the observed patients with functional hyperbilirubinemia, almost half of the content of the conjugated fraction was increased, but the bilirubin index did not exceed 25% (for hepatitis it is 3-5 times higher), and the activity parameters of hepatic cell enzymes (APT, ACT, F-1 -FA, etc.) did not change significantly.

In rare cases, objective difficulties arise in the differential diagnosis of hepatitis A with the syndromes of Dabin-Johnson and Rotor, in which the disorder of pigmentation occurs at the stage of excretion of bilirubin by gayatocytes, and therefore, in serum, as in hepatitis A, the level of the conjugated fraction of bilirubin, there is darkening of urine and discoloration of stool. However, unlike hepatitis A, with these pigmentary hepatoses, jaundice appears against the background of normal temperature, not accompanied by symptoms of intoxication. The liver is not significantly enlarged. Activity of hepatic enzymes and indices of thymol test remain within the limits of the norm.

Angiocholecystitis and angiohepatocholecystitis

Sometimes there is a need to differentiate hepatitis A with angiocholecystitis or angiohepatocholecystitis, in which there may be a poorly expressed icterism and a brief change in the color of urine. In contrast to hepatitis A, with angiohepatocholecystitis, the most frequent complaints are paroxysmal or aching abdominal pain, especially in the right upper quadrant, nausea, vomiting, poor appetite, intolerance to a particular type of food, especially greasy. Such patients often have a long subfebrile condition, transient joint pain, often a tendency to constipation, and sometimes a liquid stool appears. Angiocholecystitis can have an acute onset, while the body temperature rises, there are vomiting and paroxysmal pains in the abdomen. In an objective examination, there is often a marked increase in the liver, tenderness and muscle tension during palpation in the right upper quadrant. There may be mild icteric or subicteric sclera. Severe skin ichthyosis with angiocholecystitis and angiohepatocholecystitis is not observed, the spleen, as a rule, is not palpable. Changes in the color of urine urine are fickle and short-lived. In a laboratory study, the level of bilirubin in the blood is usually not elevated or increased slightly due to the conjugated fraction. The activity of liver-specific enzymes can be slightly increased only in individual patients. In these rare cases, it is especially important to correctly assess the clinical course of the disease: the absence of the pre-jaundiced period, the duration of subjective complaints without pronounced dynamics of clinical symptoms, pain in the projection of the gallbladder, duration of fever, etc. In bile, obtained by duodenal probing, mucus, bacteria or lamblia are found, and ultrasound reveals signs of inflammation: thickened gallbladder walls, stagnation phenomena and violation of bile evacuation. In the peripheral blood; moderate leukocytosis, neutrophilia, increased ESR, which, combined with clinical manifestations, helps to establish the diagnosis of angiocholecystitis.

Many of the symptoms characteristic of hepatitis A are also observed in other infectious (iersiniozy, icterogemorrhagic leptospirosis, infectious mononucleosis, etc.) and non-infectious (acute leukemia, cholelithiasis, liver tumor, etc.) diseases.

[46], [47], [48], [49]

Yersiniosis

It is especially difficult to differentiate hepatitis A from yersiniosis, which occurs with liver damage. In these cases, the disease, like in hepatitis A, can manifest as a rise in body temperature, symptoms of intoxication, abdominal pain, increased liver size, spleen, changes in the color of urine and feces. In the blood serum of yersiniosis, an increase in the level of bilirubin and a high activity of hepatic cell enzymes, which makes these diseases clinically very similar. However, unlike hepatitis A, with a hepatic form of yersiniosis, prolonged fever is more common, in some patients a fine-tinged rash appears on the skin in a hyperemic background, more in the inguinal folds, around the joints, on the hands and feet. Characteristic of white dermographism, sometimes arthralgia, often catarrhal phenomena, injection of vessels of the sclera, short-term disorder of the stool. Critical to the diagnosis are laboratory methods of investigation. With yersiniosis in the peripheral blood, moderate leukocytosis, neutrophilia, elevated ESR is constantly found, and in biochemical research - a relatively low index of thymol test, which is not at all characteristic of the day of hepatitis A. In rare cases, differential diagnosis is possible only from the results of a specific study for hepatitis A and yersiniosis .

Leptospirosis

The icteric form of leptospirosis (ikterogemorragichesky leptospirosis) differs from hepatitis A by summer seasonality, a violent onset of the disease with a sharp rise in body temperature, chills, severe headache. Muscular pains are characteristic, especially in calves and occipital muscles, puffiness and hyperemia of the face, injection of vessels of sclera, skin rashes and hemorrhages, herpetic eruptions. At the height of intoxication, renal damage is detected, manifested by a decrease in diuresis, proteinuria, hematuria, cylindruria. Jaundice of mucous membranes and skin usually appears on the 3-5th day of the disease, it may be mild to moderate. With the appearance of jaundice, the symptoms of intoxication persist, which is not typical for hepatitis A. The symptoms are characterized by symptoms of central nervous system damage: stunnedness, delirium, arousal, meningeal phenomena, which is completely uncommon for hepatitis A. When leptospirosis in the peripheral blood, high leukocytosis, neutrophilia, increased ESR , anemia, thrombocytopenia, eosinopenia are possible. In biochemical research, the content of both conjugated and unconjugated bilirubin fraction is increased in blood, the activity of hepatic cell enzymes does not increase sharply, the indices of thymol test often remain within normal limits.

Infectious mononucleosis

Infectious mononucleosis can resemble hepatitis A only if it is accompanied by the appearance of jaundice. Such forms of infectious mononucleosis are infrequent - in 2.7% of cases. Jaundice occurs at the height of infectious mononucleosis and disappears in parallel with the disappearance of other manifestations of the disease.

The appearance of jaundice does not depend on the degree of increase in liver size. The intensity of jaundice is usually mild and does not dominate the clinical picture of the disease. For infectious mononucleosis, the lymphoid ring of the oropharynx, the enlargement of the cervical lymph nodes, and the enlargement of the spleen are especially prominent. Of great diagnostic significance are the characteristic changes in peripheral blood: leukocytosis, lymphocytosis, monocytosis and especially the appearance in a large number of atypical mononuclear cells. These cells are often found for the first time days of illness or in the midst of it, and only in some patients they appear after 1-1,5 weeks. In most patients, atypical mononuclear cells can be detected within 2-3 weeks from the onset of the disease, sometimes they disappear by the end of the 1st to the beginning of the 2nd week. In 40% of cases, they are found in the blood for a month or longer. In biochemical analyzes for infectious mononucleosis, there is a moderate increase in ALT, ACT, and F-1-FA activity. However, unlike hepatitis A, these changes are fickle and weakly expressed, the increase in the level of excretory enzymes - ALT, APP, GGTP, and the phenomenon of dysproteinemia - is more typical. In case of doubt, specific methods of investigation are used to establish the diagnosis.

Subhepatic jaundice

Objective difficulties can arise during the differential diagnosis of hepatitis A with subhepatic jaundice arising from a mechanical obstruction to a normal outflow of bile. The hepatopancreatoduodenal tumors, common bile duct cysts, bile duct stones, etc., can obstruct the bile duct. As a rule, errors in diagnosis occur only in the early stages of the disease and are often caused by an underestimation of the anamnestic data (the appearance of jaundice as the first symptom of the disease in the absence of symptoms intoxication, paroxysmal abdominal pain and intermittent type of jaundice). Especially strong there are pains with jaundice of caliculus genesis. In patients with mechanical jaundice of tumor origin, the pain syndrome may be completely absent. Differential diagnosis in these cases is not easy, especially if jaundice appears after a brief rise in body temperature. All subhepatic jaundices are lagging and flow with more or less pronounced symptoms of cholestasis; stagnation of jaundice, itching of the skin, traces of scratching. With an objective examination of such patients, one can find symptoms of Ortner, Murphy (with cholelithiasis) were a symptom of Courvosier (with a tumor process). The degree of liver enlargement has no differential diagnostic value, but nevertheless, with jaundice associated with the tumor process, we sometimes noted an asymmetric enlargement of the liver from and tuberosity upon palpation. When the common bile duct is blocked by a stone, the pain syndrome is almost always determined in the projection of the gallbladder, but not in the projection of the liver edge. The increase in the size of the spleen is not typical for mechanical jaundice.

From the laboratory data for the subhepatic jaundice, high activity in the blood serum of liver-excreted enzymes is especially typical; ShF, LAP, GGTP, 5-nucleotidase, whereas the activity of hepatic cell enzymes (ALT, ACT, F-1-FA, etc.) remains normal or slightly elevated in the first days of the disease. With mechanical jaundice in the blood, the level of conjugated bilirubin is almost exclusively raised for a long time, high cholesterol and beta-lipoprotein levels are found, which also leads to a predominance of cholestasis syndrome in the genesis of jaundice.

Changes in peripheral blood are unstable, but with mechanical jaundice, moderate leukocytosis, neutrophilia, stab shift; increased ESR, which is not found in viral hepatitis.

Often, diagnostic methods of hepatitis A are of crucial importance: ultrasound, endoscopy, radiography, scintigraphy, laparoscopy, etc., as well as negative results of research on specific markers of viral hepatitis.