Hepatitis A - Diagnosis

Diagnosis of hepatitis A is based on clinical, epidemiological and laboratory data. The information content of these components is not the same. Clinical signs can be classified as supporting, epidemiological signs - as suggestive, while the results of laboratory studies are of decisive importance at all stages of the disease.

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Laboratory diagnostics of hepatitis A

Laboratory diagnostic methods for hepatitis A are divided into specific and non-specific. Specific methods are based on identifying the pathogen, its antigens or antibodies.

To detect the hepatitis A virus, the immune electron microscopy (IEM) method and its various modifications, as well as immunofluorescence (IF) methods, radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA) and others are usually used. The hepatitis A virus antigen is detected in the feces of patients 7-10 days before the onset of clinical symptoms and in the first days of the disease, which can be used for early diagnosis. However, due to the labor intensity, the methods for detecting the virus and its antigen have not become widespread in practical work.

Currently, specific diagnostics of hepatitis A is based exclusively on the determination of antibodies to the virus of class IgM (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, IgM antibodies (anti-HAV IgM) appear in the blood, their synthesis begins even before the first clinical symptoms appear and increases in the acute phase of the disease, and then the antibody titer gradually decreases, and anti-HAV IgM disappear from circulation 6-8 months after the onset of the disease. Anti-HAV class IgM are found in all patients with hepatitis A, regardless of the severity of the disease, including all latent, anicteric and inapparent forms. Synthesis of IgG antibodies (anti-HAV IgG) begins at a later stage of the disease, usually 2-3 weeks after the onset of the disease, their titer increases more slowly, reaching a maximum in the 5-6th month of the convalescence period. That is why only anti-HAV class IgM is used to diagnose hepatitis A at all stages of the disease. The diagnostic value of IgG antibodies can be accepted only in case of an increase in titer in the dynamics of the disease.

Antibodies to HAV of the IgG class are detected in the blood after overt or latent hepatitis A for an indefinitely long time, which allows us to assess the state of the population's immune structure and its protection against hepatitis A.

Non-specific methods are of great importance for assessing the activity of the process, severity, characteristics of the course and prognosis. Among the numerous laboratory tests proposed for these purposes, the determination of the activity of hepatocellular enzymes, pigment metabolism indices and protein-synthesizing function of the liver is of decisive importance.

Indicators of liver cell enzyme activity occupy a central place in all non-specific diagnostics of viral hepatitis. The results of enzyme activity determination can be considered a kind of "enzymological puncture" of the liver. Among the numerous enzyme tests used in hepatology, the most widely used are determinations of the activity of ALT, AST, F-1-FA, sorbitol dehydrogenase, glutamate dehydrogenase, urocaninase and some others.

Increased activity of transferases in the acute period of typical hepatitis A is observed in 100% of cases, in anicteric forms - in 94%, in latent forms - in 80%. The activity of ALT increases to a greater extent than AST, therefore the AST/ALT ratio in the acute period of hepatitis A is less than one. The activity of transferases decreases as recovery proceeds, with the AST/ALT ratio approaching one. During an exacerbation, the activity of transferases increases again several days before the clinical manifestations of an exacerbation. In protracted forms, the activity of transferases remains elevated throughout the entire period of the disease.

With high sensitivity of the transaminase test, its non-specificity for viral hepatitis should be noted. High transaminase activity is observed in myocardial infarction, liver carcinoma, and pancreatic diseases. A slight increase in activity may be observed in acute respiratory viral infections, pneumonia, gastroenteritis, infectious mononucleosis, hepatocholecystitis, etc. However, only in viral hepatitis (and myocardial infarction) is high (tens of times higher than normal values) and stable hypertransferasemia observed.

Among the so-called liver-specific enzymes, F-1-FA is of the greatest importance. Increased activity of this enzyme is observed only in viral hepatitis and is not found in other infectious diseases; the same can be said about other liver-specific enzymes - GLDG, urocaninase, etc. The degree of increase in the activity of these enzymes also correlates with the severity of the disease - the more severe the form of the disease, the higher their activity.

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

Pigment metabolism indicators are inferior in their information content to enzyme tests, since an increase in the level of conjugated bilirubin in the blood serum in viral hepatitis is noted at a relatively late stage of the disease - usually on the 3rd-5th day of the disease, and in anicteric forms, an increase in the bilirubin content in the blood serum does not occur at all.

An early laboratory test that indicates a disorder of pigment metabolism can be the determination of urobilin and bile pigments in the urine.

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

Very few urobilinogen and urobilin bodies can be detected in healthy people using quantitative methods. When the liver is damaged, urobilin bodies are not retained by liver cells and pass into the blood and then into the urine. Urobilinuria appears in the early stages of the disease, reaches a maximum at the beginning of jaundice, and then decreases. At the height of severe jaundice, urobilin bodies are usually not detected in the urine. This is explained by the fact that during this period, most of the conjugated bilirubin enters the blood, but it does not enter the intestine, so the number of urobilin bodies in the intestine decreases sharply.

As jaundice subsides, when bilirubin excretion by hepatocytes and bile duct patency are restored, the amount of urobilin bodies in the intestine increases, and they again enter the liver in increasing quantities. At the same time, the function of the latter remains impaired, and therefore urobilin bodies enter the blood by regurgitation and are excreted with urine. The amount of urobilin in the urine again increases sharply. Prolonged urobilinuria indicates a pathological process persisting in the liver.

Of the indicators of the protein-synthesizing function of the liver, the sedimentary thymol test is the most important for diagnosing hepatitis A. In hepatitis A, its indicators increase 3-5 times and, as a rule, from the first days of the disease. As the clinical manifestations of the disease subside, the thymol test indicators decrease slowly. Their complete normalization in most patients is not observed even by the time of clinical recovery. In the case of a protracted course of the disease, the thymol test indicators remain elevated for a long time. During an exacerbation, the indicators of this test increase again.

Other sedimentary tests (corrosive sublimate, Veltman, etc.) have no diagnostic value for hepatitis A.

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 short-term rise in temperature and the appearance of symptoms of intoxication to varying degrees (lethargy, loss of appetite, nausea, vomiting, etc.). Already in this period, many patients experience a feeling of heaviness in the right hypochondrium, increased sensitivity or even pain when tapping on the right edge of the ribs or palpating the liver area. The tongue is usually coated.

Diagnostics is significantly simplified if patients complain of abdominal pain on their own, and especially if palpation reveals an enlarged liver and its soreness. This symptom can be considered the leading objective sign of hepatitis A in the pre-icteric period. At the end of the initial period of the disease, most often 1-2 days before the appearance of jaundice, another highly informative sign is revealed - darkening of the urine, and then discoloration of the feces.

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Epidemiological criteria for hepatitis A

A detailed epidemiological anamnesis allows us to establish in most patients the presence of contact with a patient with hepatitis in the family or group 2-4 weeks before the first signs of the disease. Approximately one third of patients do not have obvious contact, but in these cases, contact with people suffering from latent or inapparent forms of the disease, which can occur under the guise of other diseases, cannot be ruled out.

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Laboratory criteria of severity

A large number of laboratory tests have been proposed that characterize the functional state of the liver, which are recommended for use in assessing the severity of the disease. However, for practical work it is necessary to determine a minimum set of laboratory indicators that would, firstly, most fully reflect the degree of functional liver failure, and secondly, would be distinguished by specificity

In this minimal complex, we attach great importance to the determination of total bilirubin and its fractions in the blood serum, the assessment of the protein-synthesizing function of the liver primarily by blood coagulation factors and the sublimate titer, and the study of the activity of enzymes with different subcellular localization.

Bilirubin and its fractions

The more severe the form of the disease, the higher the bilirubin levels in the blood serum. In mild forms, the total bilirubin content in the vast majority of cases (95%) does not exceed 85 μmol/l and averages 57.7+25.9 μmol/l according to the Jendrassik-Gleghorn method; in moderate forms, in 80% of cases, the total bilirubin level is between 85 and 170 μmol/l, averaging 111.3±47.4 μmol/l; in severe forms, almost all patients have a total bilirubin level of 140 to 250 μmol/l. The difference between 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 total bilirubin level in the blood serum, since there are cases of severe hepatitis in which the level of total bilirubin in the blood serum is no more than 85 μmol / l, and vice versa, there are cases with excessively high total bilirubin levels (up to 400 μmol / l) with moderate damage to the liver parenchyma. In such patients, the cholestatic component predominates in the mechanism of pigment metabolism disorder. This is why especially great importance in assessing the severity of viral hepatitis is given to unconjugated (indirect) bilirubin, whose content in severe forms increases on average by 5-10 times compared to the norm, while in mild and moderate forms only a 1.5-2-fold increase is noted. The severity of the disease is best reflected by the monoglucuronide fraction, which in mild forms exceeds normal values by 5 times, and in moderate forms - by 10 times or more. However, an increase in the monoglucuronide fraction can hardly be regarded only as an indicator of severe hepatocyte damage, since its increase is constantly noted in cholestatic and even mechanical jaundice. That is why when assessing the severity, it is better to focus on the content of unconjugated bilirubin using the Jendrassik-Gleghorn method. An increase in the unconjugated fraction indicates a violation of pigment conjugation in liver cells and, therefore, serves as an indicator of widespread necrobiotic processes in the liver parenchyma.

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Indicators of protein-synthesizing function of the liver

The leading role of the liver in protein synthesis has been shown in numerous studies by domestic and foreign authors. It has been proven that albumins, fibrinogen, prothrombin, proconvertin and the main part of a- and y-globulins, as well as complex protein complexes (glyco- and lipoproteins, ceruloplasmin, transferrin, etc.) are synthesized mainly in the ribosomes of hepatocytes. It should be noted that the determination of total protein in the blood serum cannot be used to assess the severity of the disease, since the digital values u200bu200bfor mild, moderate and severe forms of viral hepatocytes in patients do not differ significantly. The same can be said about the protein spectrum of the blood, which, although characterized by some dysproteinemia in hepatitis A due to a decrease in the level of albumins and an increase in y-globulins, the degree of expression of these changes depends little on the severity of the disease.

Among the laboratory parameters characterizing the protein-synthesizing function of the liver, the most important for assessing the severity of viral hepatitis is the determination of blood coagulation factors in the blood serum. The more severe the form of hepatitis, the lower the prothrombin content in the blood serum. The same can be said about fibrinogen and especially proconvertin. These blood coagulation factors are synthesized exclusively in the liver and, in addition, their half-life is from several hours (proconvertin) to 3 days (fibrinogen), which predetermines a rapid and irreparable decrease in the level of fibrinogen and proconvertin even in mild forms of viral hepatitis. A decrease in the level of proconvertin is observed even in cases where the disease occurs with a normal level of bilirubin. A dependence of the content of fibrinogen and proconvertin on the course of the disease has been established: with a smooth cyclic course, their content quickly normalizes, a long-term decrease in the level corresponds to a protracted course of the disease, which can be used for prognosis.

In hepatitis A, the concentration of almost all amino acids in the blood serum increases. The excretion of most amino acids with urine is also increased. The degree of hyperaminoacidemia and hyperaminoaciduria is directly dependent on the severity of the disease. At the height of clinical manifestations in 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 daily urine - by 1.4 times, in moderate - by 3 and 1.7 times, and in severe forms - by 4 and 2.2 times, respectively.

The state of the liver's protein-synthesizing function can also be indirectly judged by changes in colloid reactions - the sublimate and thymol tests. However, the thymol test value depends little on the severity of liver damage and cannot be used to assess the severity of viral hepatitis. The sublimate test is of greater importance for assessing the severity of viral hepatitis, the value of which almost always decreases in severe forms, while in mild forms it remains within the normal range.

Activity of enzymes with different subcellular localization. The experiment showed that when hepatocytes are damaged by carbon tetrachloride, the first to enter the blood are cytoplasmic enzymes not associated with cellular organelles - aldolases, transaminases, lactate dehydrogenases and other substances; with deeper damage, enzymes with mitochondrial, lysosomal and other intracellular localizations are released. These data theoretically substantiate the definition of enzyme activity with different subcellular localization for assessing 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 liver-specific F-1-FA levels in the blood exceed the values in healthy individuals by 11 times, in moderate forms - by 18 times, and in severe forms - by 24 times. The activity of liver LDH exceeds the norm by 3, 6, and 8 times, respectively. However, the levels of other cytoplasmic enzymes - ALT, AST, F-1-6-FA - depend less on the severity. Thus, in mild forms, ALT activity increased by 6 times, in moderate forms - by 6.4 times, and in severe forms - by 8 times. The activity of F-1-6-FA, lactate dehydrogenase, etc. also correlates poorly with the severity of the disease.

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

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Mitochondrial enzymes

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

The activity of mitochondrial enzymes increases in all patients with viral hepatitis, and the more severe the disease, the higher the activity. In the acute period of the disease, half of the patients with moderate forms and all patients with severe forms have MDG-4 in their blood serum, which is not observed in mild forms. The activity of glutamate dehydrogenase in mild forms exceeds the control values by 5 times, in moderate forms - by 9 times, and in severe forms - by 18 times. A similar dependence is observed in other enzymes with mitochondrial localization. These data allow us to recommend determining the activity of mitochondrial enzymes to assess the severity of viral hepatitis.

Lysosomal enzymes

In viral hepatitis, hepatocyte lysosomes 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, leucine aminopeptidase, cathepsins D and C increases in all patients, and it is higher the more severe the liver damage. An inverse relationship is observed for cathepsins B and especially A, whose activity shows a clear tendency to decrease with increasing severity of the disease.

Proteolysis inhibitors

At present, 6 inhibitors of proteolysis are known and well studied: alpha1-antitrypsin (a1-AT), a2-macroglobulin (a-MG), antithrombin III, C _II inactivator, a-antichymotrypsin and inter-a-antitrypsin. All proteinase inhibitors are synthesized almost exclusively by the liver. This determines their importance for assessing the severity of viral hepatitis. Among all proteolysis inhibitors, a2-MG and a1-AT have the greatest clinical significance. It is known that a1-AT accounts for about 90% of the total activity of all inhibitors. It inhibits the activity of trypsin, plasmin, chymotrilsin, elastase, etc. Despite the fact that a2-MG accounts for about 10% of the total antiproteolytic 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, which are associated with the autolysis syndrome in viral hepatitis. It is also assumed that a2-MG plays the role of a regulator of the coagulation and kinin systems, which are of great importance in the pathogenesis of viral hepatitis.

The blood content of a1AT in mild, moderate and severe forms of viral hepatitis increases proportionally to the severity of the disease, while the level of a2-MG, on the contrary, decreases. It should be noted, however, that 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 the blood serum are observed. In the acute period, in all forms of the disease, the content of triglycerides, phospholipids, non-esterified fatty acids (NEFA), mono-, diglycerides, and free cholesterol increases. The degree of expression of these disorders is directly dependent on the severity of the disease. If in mild forms the content of triglycerides, phospholipids, mono-, diglycerides, free cholesterol, and total lipids increases by an average of 50%, then in moderate and severe forms it increases more than 2 times.

The content of NEFA increases even more significantly. In mild forms, their amount exceeds the normal values by 2-3 times, and in severe forms - by 4-5 times. Another dependence characterizes the dynamics of cholesterol esters: in mild forms, their content is within the normal range, in severe forms - below the norm by 40-50%. The level of total cholesterol does not depend on the severity of the disease. In all forms of viral hepatitis, the amount of total cholesterol tends to increase, mainly due to the increase in the free fraction. The cholesterol esterification coefficient decreases more, the more severe the form of the disease. In a mild form, it averages 0.53 ± 0.009, in a moderate form - 0.49 ± 0.015, in a severe form - 0.41 ± 0.013 (normal - 0.69 ± 0.01).

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Some indicators of interstitial metabolism

A universal role in the intermediate metabolism 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 thioesters with them - energy-rich compounds that can participate in reactions with a variety of compounds in the cell. Through CoA, the connection of carbohydrate and fat metabolism with the tricarboxylic acid cycle (Krebs cycle) is carried out. 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 body's acetylating capacity can be judged by the percentage of acetylated sulfonamides excreted in daily urine after a load of white streptocide at a dose of 0.1-0.3 g per dose. The intensity of acetylation processes of sulfonamides directly depends on the biological activity of acetylation processes in the body. Therefore, by determining the percentage of acetylated sulfonamides, one can indirectly judge the cytobiochemical processes occurring in liver cells.

In healthy people, the ability to acetylate is on average 52.5±0.93%. In viral hepatitis, the ability to acetylate at the height of the disease is significantly reduced: in a mild form - to 44±1.38%, in a moderate form - to 38±1.25, and in a severe form - to 30.6+3.33%.

Of the other indicators of interstitial metabolism related to the assessment of the functional state of the liver, and therefore to the assessment of the severity of the disease, attention should be paid to the determination of the content of pyruvic and lactic acids, which, as is known, play a major role in the processes of breakdown and synthesis of carbohydrates. The dynamics of average pyruvate values is inversely related to its ability to acetylate sulfonamides. In a mild form, the concentration of pyruvate exceeds normal values by 2 times, in a moderate form - by 2.5, and in a severe form - by 4 times.

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

The course of the disease is cyclical. The duration of the icteric period is on average 7-10 days. Normalization of the liver size occurs on the 25th-35th day. About the same time, its functional state is completely restored. Only in 5% of patients the disease takes a protracted course.

Differential diagnosis of hepatitis A

In the pre-icteric period of hepatitis A, in 70-90% of cases, the diagnosis of ARVI is erroneously made. The difficulties of diagnosis are that in the initial period of hepatitis A, slight hyperemia of the mucous membrane of the oropharynx or nasal congestion is sometimes detected. However, it should be taken into account that catarrhal phenomena (cough, runny nose) are not typical for hepatitis A, and if they do occur, they are usually caused by residual effects of ARVI or are a consequence of the combined course of hepatitis A and ARVI. The dynamics of the disease are important for differential diagnosis. In patients with hepatitis A, when the body temperature drops, symptoms of intoxication may persist. Dyspeptic disorders (nausea, vomiting) persist, abdominal pain often appears, the liver enlarges, which is not typical for respiratory viral infections.

Diagnostic errors may occur when differentiating hepatitis A from intestinal infections, acute appendicitis, helminthic invasion, mesadenitis, etc. Analysis of diagnostic errors convinces us that objective difficulties exist only on the 1-2nd day from the onset of the disease, when there are no characteristic signs of the above diseases and hepatitis A. Unlike intestinal infection, vomiting with hepatitis A is not frequent, loose stools in the pre-icteric period are extremely rare, whereas acute intestinal infection is characterized by the appearance of frequent loose stools with pathological impurities after vomiting. An objective examination reveals rumbling and pain along the intestines; if pain is noted with hepatitis A, it is exclusively associated with the liver area.

With 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-icteric period with hepatitis A almost never lasts more than 7 days, more often it lasts 3-5 days.

Some patients with hepatitis A may have quite severe pain in the prodromal period, and in some cases they are taken for acute appendicitis, acute pancreatitis or other diseases of the abdominal organs. With hepatitis A, abdominal palpation is usually painless, the abdomen is soft, and there is pain in the liver area. There is no tension in the rectus abdominis muscles or symptoms of peritoneal irritation, even in cases of severe abdominal pain. It is important to consider that the pain syndrome in hepatitis A occurs due to acute swelling of the liver, and it is always possible to detect its sharp enlargement and pain during palpation, whereas with acute appendicitis, pain is usually localized in the right iliac region, and with acute pancreatitis, pain is determined in the projection of the pancreas. In differential diagnostics of hepatitis A with surgical diseases of the abdominal organs, it is important to take into account the nature of the temperature reaction, pulse rate, condition of the tongue and especially the nature of changes in the peripheral blood - with hepatitis A there is a tendency to leukopenia and lymphocytosis, while with acute appendicitis, pancreatitis and other surgical pathology, leukocytosis of a neutrophilic nature is noted. In addition, with hepatitis A, in the case of a correctly collected anamnesis, it is almost always possible to identify disturbances in the patient's condition several days before the onset of abdominal pain - an increase in body temperature, poor appetite, malaise - in contrast to acute abdomen, in which the disease occurs acutely and abdominal pain serves as the first signs of the disease.

Of the laboratory methods in the pre-icteric period, biochemical tests are of great importance, and first of all, enzymatic tests. An increase in the activity of the enzymes ALT, F-1-FA and other indicators is observed even before the first clinical symptoms of hepatitis A appear, whereas in 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 indicator, 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 accurate diagnosis of hepatitis A, the determination of specific markers of the disease is used - detection of anti-HAV class IgM in the blood serum.

In differential diagnostics of hepatitis A in the icteric period, it seems important to answer the question at the first stage: what type of jaundice (suprahepatic, hepatic, subhepatic) do we have to deal with in each specific case. Identifying the type of jaundice by the location of the primary disorder of pigment metabolism is very arbitrary, but such an approach significantly facilitates a targeted examination of the patient, serves as a justification for the need for differentiated therapy.

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Suprahepatic jaundice

They arise as a result of increased hemolysis of erythrocytes and excessive formation of unconjugated bilirubin under conditions of decreased functional activity of the liver. This type of jaundice occurs in hereditary and acquired hemolytic anemias, various intoxications, massive hemorrhages, etc. Spherocytic hemolytic anemia, erythrocyte enzymopathy and other rare forms of anemia caused by hemoglobin pathology are sometimes mistaken for viral hepatitis. Diagnostic errors in these cases are primarily associated with underestimation of anamnestic data indicating the familial nature of the disease, as well as with incorrect interpretation of clinical manifestations and the course of the disease. In differential diagnostics, one should keep in mind the long-term wave-like course of hemolytic anemia from an early age, and an objective examination always reveals more or less pronounced anemia and, most importantly, a significant increase in the size of the spleen; the liver may also be enlarged, but moderately, jaundice may be weak even during a crisis. Urine often remains light or changes slightly due to an increase in the amount of urobilin, bilirubin is not detected in the urine. In the blood serum, the content of exclusively unconjugated bilirubin is increased. Other biochemical parameters (enzyme activity, thymol test level) are not changed. The color of feces in hemolytic anemia, in contrast to viral hepatitis, is dark brown due to a large amount of stercobilinogen. The diagnosis of hemolytic anemia is confirmed by changes in the blood: decreased hemoglobin and erythrocyte content, microspherocytosis, reticulocytosis and decreased osmotic resistance of erythrocytes to hypotonic sodium chloride solutions.

In typical cases, differential diagnostics of hereditary spherocytic anemia with hepatitis A does not present major difficulties. Difficulties may arise in cases where, with long-term hemolytic anemia, the level of conjugated bilirubin in the blood begins to increase and abdominal pain appears, while pigment stones may form in the bile ducts or gall bladder due to excess bilirubin, causing clinical manifestations of mechanical jaundice and calculous cholecystitis.

To a large extent, hepatitis A may resemble hemolytic jaundice of autoimmune genesis, accompanied by high temperature, headache, moderate jaundice and hyperbilirubinemia. Diagnosis in these cases is based on the presence of rapidly developing anemia, not characteristic of hepatitis A, as well as on the discrepancy between mild jaundice and severe intoxication. Of the laboratory indicators, autoimmune anemia is characterized by leukocytosis, reticulocytosis and increased ESR, while the indicators of functional liver tests are slightly changed. The diagnosis of autoimmune hemolytic anemia is confirmed by the detection of anti-erythrocyte antibodies using the direct and indirect Coombs reaction, and the diagnosis of hepatitis A is confirmed by the presence of specific antibodies - anti-HAV class IgM.

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

Liver jaundice

Liver jaundices are heterogeneous in their mechanism of origin; they may arise as a result of impaired function of bilirubin uptake, conjugation or excretion by liver cells. In cases where the function of bilirubin uptake is predominantly impaired, unconjugated bilirubin accumulates in the blood serum, and a picture characteristic of Gilbert's syndrome appears; with impaired conjugation (glucuronidation) of bilirubin, Crigler-Pajar syndrome occurs, and with impaired excretion of conjugated bilirubin, a picture of Dubin-Johnson or Rotor syndromes appears.

Patients with Gilbert's syndrome are most often mistakenly admitted to the hepatitis department, and difficulties in differential diagnosis are possible when jaundice as a manifestation of functional hyperbilirubinemia occurs against the background of some disease: acute respiratory viral infection, acute intestinal infection, etc. In this case, symptoms such as fever, nausea, vomiting, preceding the appearance of jaundice, create a picture of the pre-icteric period of viral hepatitis and seem to demonstrate the cyclical nature of the disease. Contact with a patient with hepatitis A especially complicates the diagnosis. For the diagnosis of functional hyperbilirubinemia, anamnesis data on the familial nature of jaundice are of significant importance. Hyperbilirubinemia has a wave-like course, with periods of increased jaundice coinciding with various stress conditions: physical exertion, acute respiratory viral infection, etc. The final diagnosis is made after a laboratory test. In functional hyperbilirubinemia, the content of unconjugated bilirubin in the blood serum is increased, the activity of hepatocellular enzymes remains within normal values. It is much more difficult to establish the correct diagnosis in cases where, 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 had an increased content of the conjugated fraction, but the bilirubin indicator did not exceed 25% (in viral hepatitis it is 3-5 times higher), and the activity of hepatocellular enzymes (APT, AST, F-1-FA, etc.) did not change significantly.

In rare cases, objective difficulties arise in the differential diagnosis of hepatitis A with Dubin-Johnson and Rotor syndromes, in which pigment metabolism disorder occurs at the stage of bilirubin excretion by hepatocytes, and therefore, in the blood serum, as in hepatitis A, the level of the conjugated fraction of bilirubin increases predominantly, darkening of urine and discoloration of feces are observed. However, unlike hepatitis A, in these pigment hepatoses, jaundice appears against the background of normal temperature, is not accompanied by symptoms of intoxication. The liver is not significantly enlarged. The activity of liver enzymes and the thymol test indicators remain within the normal range.

Angiocholecystitis and angiohepatocholecystitis

Sometimes it is necessary to differentiate hepatitis A from angiocholecystitis or angiohepatocholecystitis, which may have mild icterus and a short-term change in urine color. Unlike hepatitis A, with angiohepatocholecystitis, the most common complaints are paroxysmal or aching abdominal pain, especially in the right hypochondrium, nausea, periodically recurring vomiting, poor appetite, intolerance to certain types of food, especially fatty foods. Such patients often have prolonged subfebrile temperature, transient joint pain, often a tendency to constipation, and sometimes periodic loose stools. Angiocholecystitis may have an acute onset, with an increase in body temperature, vomiting, and paroxysmal abdominal pain. An objective examination often reveals a slightly enlarged liver, soreness and muscle tension upon palpation in the right hypochondrium. There may be mild icterus or subicterus of the sclera. There is no pronounced icterus of the skin in angiocholecystitis and angiohepatocholecystitis, the spleen is usually not palpable. Changes in the color of urine and feces are inconstant and short-lived. During laboratory testing, the level of bilirubin in the blood is usually not elevated or is slightly elevated due to the conjugated fraction. The activity of liver-specific enzymes may be slightly elevated only in individual patients. In these rare cases, it is especially important to correctly assess the clinical course of the disease: the absence of a pre-icteric period, the duration of subjective complaints without significant dynamics of clinical symptoms, pain in the projection of the gallbladder, the duration of fever, etc. Mucus, bacteria or lamblia are found in the bile obtained during duodenal intubation, and ultrasound reveals signs of inflammation: thickened walls of the gallbladder, stagnation and impaired evacuation of bile. In the peripheral blood; moderate leukocytosis, neutrophilia, increased ESR, which, in combination with clinical manifestations, helps to establish the diagnosis of angiocholecystitis.

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

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Yersiniosis

It is especially difficult to differentiate hepatitis A from yersiniosis, which occurs with liver damage. In these cases, the disease, as with hepatitis A, can manifest itself with a rise in body temperature, symptoms of intoxication, abdominal pain, an increase in the size of the liver, spleen, and changes in the color of urine and feces. In the blood serum with yersiniosis, an increase in the bilirubin level and high activity of hepatocellular enzymes are noted, which makes these diseases clinically very similar. However, unlike hepatitis A, with the liver form of yersiniosis, a prolonged fever is more often observed, in some patients, a small-point rash appears on the skin against a hyperemic background, mainly in the groin folds, around the joints, on the hands and feet. White dermographism is characteristic, sometimes arthralgia, catarrhal phenomena are common, injection of scleral vessels, short-term bowel disorder. Laboratory research methods are of decisive importance for the diagnosis. In yersiniosis, moderate leukocytosis, neutrophilia, and elevated ESR are constantly detected in the peripheral blood, and a relatively low thymol test value is found in a biochemical study, which is completely uncharacteristic of hepatitis A. In rare cases, differential diagnosis is possible only based on the results of a specific study for hepatitis A and yersiniosis.

Leptospirosis

The icteric form of leptospirosis (icterohemorrhagic leptospirosis) differs from hepatitis A by its summer seasonality, rapid onset of the disease with a sharp rise in body temperature, chills, and severe headache. Muscle pain is characteristic, especially in the calf and occipital muscles, puffiness and hyperemia of the face, injection of the scleral vessels, skin rashes and hemorrhages, and herpetic eruptions. At the height of intoxication, kidney damage is detected, manifested by decreased diuresis, proteinuria, hematuria, and cylindruria. Jaundice of the mucous membranes and skin usually appears on the 3rd-5th day of the disease and can be mild or moderate. With the appearance of jaundice, the symptoms of intoxication persist, which is not typical for hepatitis A. The disease is characterized by symptoms of damage to the central nervous system: confusion, delirium, agitation, meningeal phenomena, which is completely uncharacteristic for hepatitis A. With leptospirosis, high leukocytosis, neutrophilia, increased ESR are detected in the peripheral blood, anemia, thrombocytopenia, eosinopenia are possible. Biochemical studies in the blood show an increased content of both conjugated and unconjugated fractions of bilirubin, the activity of liver-cell enzymes does not increase sharply, the thymol test indicators often remain within the normal range.

Infectious mononucleosis

Infectious mononucleosis can resemble hepatitis A only if it is accompanied by jaundice. Such forms of infectious mononucleosis are rare - 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 liver enlargement. Jaundice is usually mild in intensity and does not dominate the clinical picture of the disease. Infectious mononucleosis is especially characterized by damage to the lymphoid ring of the oropharynx, enlargement of the cervical lymph nodes, and enlargement of the spleen. Characteristic changes in the peripheral blood are of great diagnostic importance: leukocytosis, lymphocytosis, monocytosis, and especially the appearance of a large number of atypical mononuclear cells. These cells are often detected in the first days of the disease or at its height, 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 - beginning of the 2nd week. In 40% of cases, they are detected in the blood for a month or longer. In biochemical tests for infectious mononucleosis, a moderate increase in the activity of ALT, AST, F-1-FA is noted. However, unlike hepatitis A, these changes are inconstant and weakly expressed, more characteristic are an increase in the level of excretory enzymes - ALT, ALP, GGT, as well as dysproteinemia. In doubtful cases, specific research methods are used to establish a diagnosis.

Subhepatic jaundice

Objective difficulties may arise in the differential diagnosis of hepatitis A with subhepatic jaundices, which occur due to mechanical obstruction of the normal outflow of bile. Bile outflow may be obstructed by tumors of the hepatopancreatoduodenal zone, cysts of the common bile duct, stones in the bile duct, etc. Diagnostic errors in these cases usually occur only in the early stages of the disease and are often due to underestimation of anamnestic data (the appearance of jaundice as the first symptom of the disease in the absence of intoxication symptoms, paroxysmal abdominal pain, and intermittent jaundice). Pain is especially severe in jaundices of calculous genesis. In patients with mechanical jaundice of tumor genesis, pain syndrome may be completely absent. Differential diagnostics in these cases can be difficult, especially if jaundice appears after a short-term rise in body temperature. All subhepatic jaundices are characterized by a protracted course and occur with more or less pronounced symptoms of cholestasis; congestive nature of jaundice, itchy skin, traces of scratching. During an objective examination of such patients, one can detect Ortner's symptoms, Murphy's symptoms (in cholelithiasis), and Courvoisier's symptom (in a tumor process). The degree of liver enlargement has no differential diagnostic value, but still, with jaundice associated with a tumor process, we sometimes noted an asymmetrical enlargement of the liver and tuberosity on palpation. With blockage of the common bile duct by a stone, pain syndrome is almost always determined in the projection of the gallbladder, but not in the projection of the edge of the liver. An increase in the size of the spleen is generally not characteristic of mechanical jaundice.

Of the laboratory data, high activity of liver-excreted enzymes in the blood serum is especially typical for subhepatic jaundice: SF, LAP, GGT, 5-nucleotidase, while the activity of liver-cell enzymes (ALT, AST, F-1-FA, etc.) remains normal or slightly elevated in the first days of the disease. With mechanical jaundice, the level of conjugated (direct) bilirubin in the blood is elevated for a long time, high levels of total cholesterol and beta-lipoproteins are detected, which also indicates the prevalence of cholestasis syndrome in the genesis of jaundice.

Changes in the peripheral blood are inconstant, but with mechanical jaundice, moderate leukocytosis, neutrophilia, band shift, and increased ESR are often observed, which is not observed in viral hepatitis.

Often, special research methods are of decisive importance in the diagnosis of hepatitis A: ultrasound, endoscopy, radiography, scintigraphy, laparoscopy, etc., as well as negative test results for specific markers of viral hepatitis.