Hepatitis B: diagnosis

Diagnosis of hepatitis B is based on the analysis of cumulative clinical and laboratory data.

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

Clinical diagnosis of hepatitis B

From clinical symptoms, the gradual onset of the disease occurs at normal or subfebrile body temperature, the predominance of infectious asthenia in the form of general lethargy, weakness, muscle or joint pain, the appearance of skin rashes. A relatively long pre-zhelthus period and a lack of improvement in well-being or even worsening with the appearance of jaundice are important. All these clinical symptoms can be attributed to the category of suggestive ones, since their presence is not necessary for hepatitis B and, in addition, it is possible for other viral hepatitis. The basic diagnostic features include the appearance of a marked hepatolienal syndrome in the patient, the establishment of the fact of gradually progressive jaundice. Only with hepatitis B there is an increase in icteric staining of the skin and visible mucous for 5-7 days or more. Following this, one can usually see the so-called "jaundice plateau", when it remains intense without a tendency to rapidly decrease for another 1-2 weeks. You can observe a similar dynamics of liver size, less often - the spleen. The intensity of urine color and fecal discolouration strictly repeats the jaundice severity curve and is in direct correlation with the level of blood content of the conjugated bilirubin fraction.

[8], [9], [10], [11], [12], [13],

Epidemiological diagnosis of hepatitis B

From the epidemiological data for the diagnosis of hepatitis B, indications of the transferred operations, the presence of blood transfusions, injections and other manipulations associated with disruption of the integrity of the skin or mucous membranes 3 to 6 months before the disease, as well as close contact with a patient with chronic hepatitis B or a carrier HBV.

Noting the great importance of the anamnestic data on the presence of parenteral manipulations for the diagnosis of hepatitis B, it is necessary nevertheless to caution against their reassessment. According to our clinic, about a quarter of the patients with hepatitis B in history do not manage to note any parenteral manipulations at all. Infection in these cases occurs in close contact with the virus carrier through latent microtrauma. Especially often this way of transmission of the hepatitis B virus is realized in families or in closed children's institutions, and foci of hepatitis B diseases can be observed. They are treated as a focal point of hepatitis A when examined superficially and only the results of testing the marker spectrum make it possible to correctly diagnose.

[14], [15], [16], [17], [18], [19],

Biochemical criteria for diagnosis of hepatitis B

The nature of biochemical shifts in the blood as a whole reflects the peculiar dynamics of the clinical course of the disease, which is manifested by pronounced and prolonged hyperbilirubinemia due to an increase in serum levels of predominantly conjugated bilirubin, a persistent increase in hepatic cell enzyme activity (ALT, ACT, F-1-FA, etc. .), the phenomena of disproteinemia due to lowering albumins and increasing globulin fractions, a decrease in the content of coagulation factors (prothrombin, fibrinogen, proconvertin, etc.). But these indicators do not differ by strict specificity. Similar biochemical parameters in the blood serum can be in other etiologic forms of viral hepatitis. The peculiarity of them with hepatitis B is that they are sharp-cut, and most importantly, they are detected for a long time, which is not typical for hepatitis A. The exception is a timole sample, the indices of which are almost always low when hepatitis B, other viral hepatitis, they are 3-4 times higher than normal. Therefore, biochemical indicators should be considered as leading indications for the diagnosis of hepatitis B, they are important for the group characteristics of hepatitis B and can not be used to establish an etiological diagnosis.

[20], [21], [22], [23],

Specific criteria for diagnosis of hepatitis B

They are based on the determination in the blood serum of hepatitis B virus antigens (HBsAg, HBeAg) and antibodies to them (anti-HBc, anti-HBe, anti-HBs).

The surface antigen of the hepatitis B virus (HBsAg) serves as the main marker of hepatitis B. It is recorded in the blood long before the appearance of clinical signs of the disease, is constantly found in the pre-jaundice and icteric period. In acute disease, HBsAg disappears from the blood by the end of the first month after the onset of jaundice. More prolonged detection of HBsAg in serum indicates a prolonged or chronic course of the disease. Concentration of HBsAg in the blood is subject to wide fluctuations, but nevertheless, the inverse relationship with the severity of the disease is revealed, that is, the harder the pathological process, the lower the concentration of this antigen in the blood.

HBeAg (an antigen associated with a nuclear, cow antigen) is usually detected using highly sensitive methods - radioimmunoassay and ELISA. In the blood serum, it begins to appear almost simultaneously with the surface antigen in the middle of the incubation period. The maximum concentration is determined by the end of the incubation period and in the pre-egg period. With the appearance of jaundice, the concentration of HBeAg in the blood rapidly decreases, and in most patients it will no longer be found in free circulation for the 2-3 weeks from the onset of the disease and, usually 1-3 weeks before the disappearance of HBsAg. Detection of HBeAg in free circulation always indicates active replication of the hepatitis B virus (replicative phase of the infectious process) and can be interpreted as evidence of high blood infectivity. It has been established that the risk of infection through blood preparations containing HBeAg is many times greater than if seroconversion occurred and anti-HBe appeared, regardless of the persistence of high concentrations of HBsAg. It is also known that transplacental transmission of the hepatitis B virus occurs almost exclusively if there is HBeAg in the blood of the mother. Prolonged detection of HBeAg in serum indicates the formation of prolonged or chronic hepatitis B

Anti-HBe are detected in the blood serum with acute hepatitis B in almost 100% of cases. Usually, antibodies appear 1-2 weeks after the disappearance of HBeAg. According to the research, in the first week of the disease they appear in 73% of cases, after 30-50 days - in 100% of cases. After hepatitis B, anti-HBe is detected in blood in low titres for a long time.

HBcAg in the blood in free circulation is not detected by highly sensitive methods, which is explained by the extremely rapid appearance of antibodies to the nuclear antigen in the blood due to its high immunogenicity.

HBcAg is found in the nuclei of hepatocytes in the morphological study of liver biopsy and on autopsy using special methodical techniques (immunofluorescence, etc.).

Anti-HBc are detected in the blood in all patients with acute hepatitis B, but the greatest diagnostic value is the detection of antibodies of IgM class. Anti-HBcAg IgM are found in the pre-jaundice and throughout the icteric period, as well as in the period of convalescence. The titer of anti-HBc IgM begins to decrease as the active replication of the virus is completed. The complete disappearance of anti-HBcAg IgM from circulation usually occurs a few months after the completion of the acute phase of the disease, which indicates a complete clinical recovery.

According to the research, detection of anti-HBs should be considered the most consistent and reliable laboratory sign of acute hepatitis B. High titers of anti-HBc IgM are observed in all patients, regardless of the severity of the disease, at the earliest and throughout the acute phase, including in cases where HBsAg was not detected due to a drop in its concentration, for example, fulminant hepatitis or late admission to hospital. Detection of anti-HBc IgM in these cases was practically the only informative test that confirmed hepatitis B. On the other hand, the absence of anti-HBc IgM in patients with clinical signs of acute hepatitis reliably excludes the HBV virus etiology of the disease.

Particularly informative is the definition of anti-HBc IgM in cases of mixed-hepatitis, or when hepatitis A, hepatitis D is deposited on the chronic carrier of HBV. The detection of HBsAg in these cases would seem to confirm the presence of hepatitis B, but the negative results of the anti-HBc assay make it possible to unequivocally interpret such cases as the layering of another viral hepatitis on chronic HB carrier, and vice versa, the detection of anti-HBc IgM, HBsAg indicates active current hepatitis B

The determination of anti-HBc or total anti-HBc does not substantially supplement the diagnostic information, but given that anti-HBc IgG after hepatitis B is evidently retained for life, their determination can be used as a reliable test for retrospective diagnosis of hepatitis B or detection of the immunological layer, including collective immunity.

The DNA of the virus in the serum is detected by the PCR method. The advantage of this study is that it makes it possible to detect in the blood directly the viral genome itself, rather than its partial antigens, and therefore this technique has become widespread. DNA of the virus can be detected in 100% of cases in the early period of hepatitis B, which allows us to recommend this method for the diagnosis of acute hepatitis B and especially to evaluate the effectiveness of antiviral therapy.

The detection of viral DIC polymerase indicates active replication of the hepatitis B virus. But in the blood, it circulates for a short time, even before the first signs of the disease develop, and therefore this test can not be recommended for the diagnosis of hepatitis B.

In conclusion, it can be said that currently the most informative methods for the specific diagnosis of acute hepatitis B are the determination of serum HBsAg, anti-HBc IgM and HBV DNA. The determination of other viral antigens and antibodies has an auxiliary significance.

The most characteristic marker spectra for acute hepatitis B are given in the table.

Acute cyclic hepatitis

Serological marker	Disease Period
	High time (2-4 weeks)	Early convalescence (1 -3 months)	Late convalescence (3-6 months)
HBsAg	+	+/-	-
Anti-HBc IgM	+	+	-
Anti-HBc IgG	- / +	+	+
Anti-HBs	-	- / +	+
HBeAg	+	+/-	-
Anti-HBe	-	- / +	+

As can be seen from the presented data, for each period the hepatitis B acute has its own serological marker spectrum, on the basis of which it is possible to accurately diagnose this disease, determine the phase of the pathological process and predict the outcome.

Differential diagnosis of hepatitis B

Acute hepatitis B in the first place must be differentiated with other viral hepatitis: A, C, E, D.

The clinical criteria for viral hepatitis presented in the table should be considered indicative, since they can be used to identify the characteristics of viral hepatitis only in case of group analysis, whereas the final etiologic diagnosis can be made only when specific markers are detected in the blood serum.

Objective difficulties often arise in the differential diagnosis of hepatitis B with other diseases, whose list is determined by the age of the patient, the severity and the phase of the pathological process. For example, in the pre-hectic period, hepatitis B is most often differentiated from acute respiratory viral diseases, lesions of the bile ducts , food poisoning, acute intestinal infections, various surgical pathologies of the abdominal cavity organs, etc. In general, the differentials In reality, the diagnostic criteria in these cases differ little from those in hepatitis A. The same can be said for the differential diagnosis of hepatitis B in the icteric period. The main abnormality of diseases with which one often differentiates hepatitis B at the height of the diseases, is almost the same as in hepatitis A. Among the so-called superhepatic jaundice are various protracted forms of hereditary and acquired hemolytic anemia occurring with cholestasis syndrome; among hepatic or parenchymal jaundice - a large group of hereditary pigmentary hepatoses (syndromes Gilbert, Dabin-Johnson, Rotor); various infectious diseases accompanied by damage to the liver parenchyma (infectious mononucleosis, icteric forms of leptospirosis, intestinal yersiniosis and pseudotuberculosis, visceral forms of herpetic infection, opisthorchiasis, etc.), as well as toxic and medicamentous liver lesions, etc. Great difficulties in conducting differential diagnostics may arise and when distinguishing hepatitis B from subhepatic jaundice that have arisen on the ground of blockage of the common bile duct by a tumor, cyst or stone with gallstone Handy. The general principles of differential diagnosis in all these cases are also fully described above.

Noting the similarity of differential diagnostic criteria for hepatitis A and B, it is nevertheless necessary to pay attention to their originality, which basically reflects the features of the course of the pathological process in these hepatitis. The essence of the difference is that hepatitis A is always an acute, cyclically occurring benign infection, and with this hepatitis there is no need to conduct differential diagnosis with numerous chronic liver diseases. With hepatitis B, due to the fact that the pathological process often has a prolonged course, it becomes necessary to exclude other long-term liver diseases (opisthorchiasis, blood diseases, hereditary congenital metabolic abnormalities, drug-induced hepatitis, etc.).

The basis for differential diagnosis in such cases should be based on the results of laboratory research methods and careful consideration of the common symptoms inherent in these diseases. However, in a number of cases it is possible to identify and sufficiently characteristic clinical and biochemical features of the liver lesions in individual nosological forms.

For example, in diseases of the blood system (acute leukemia, lymphogranulomatosis), liver damage in connection with leukemia infiltration is manifested mainly by a significant increase in the organ (the lower edge of the liver protrudes 3-5 cm below the costal arch), a non-persistent increase in serum activity of the hepatic- cellular enzymes (ALT, ACT, etc.) and the content of conjugated bilirubin. The thymol test is usually normal or slightly elevated, the cholesterol, beta-lipoproteins, gamma globulin content moderately increases. Unlike hepatitis B, liver damage in diseases of the blood system often occurs against a background of persistent increase in body temperature and is accompanied by a pronounced increase in the spleen, an increase in peripheral lymph nodes, rapidly progressing anemia, and characteristic hematological changes. It is also important to note that the specific liver damage in diseases of the blood system appears to be extremely rare. In any case, according to our clinic, among the 233 children with hemoblastosis (including acute leukemia - 78, lymphogranulomatosis - 101, lymphosarcoma - 54) liver damage was noted in 84, and all were documented hepatitis B or C. Isolated lesions the liver due to leukemoid infiltration or toxic hepatitis in connection with the treatment with cytostatics was not observed in any case.

Great difficulties can arise when differentiating acute hepatitis B with exacerbation of chronic hepatitis or cirrhosis of the liver, especially if the latter were latent and not timely diagnosed. Studies conducted at our department have shown that almost all of the jaundiced exacerbations of chronic hepatitis are nothing more than the result of lamination to chronic hepatitis B of acute hepatitis A or D. The disease in these cases usually manifests as a rise in body temperature, the appearance of symptoms of intoxication, jaundice, hepatomegaly, increased serum level of conjugated bilirubin and the activity of hepatic cell enzymes, which would seem to give grounds for diagnosing acute hepatitis B. One When observing these patients in dynamics, it turns out that after the disappearance of the clinical symptoms of the acute phase of the disease, the child retains hepatolienal syndrome, a slight persistent hyperfermentemia, and HBcAg is detected, whereas antibodies to the cow to whom the IgM antigen are not detected or are in low titer without significant fluctuations . Critical for diagnostics is the detection in the serum of specific IgM antibodies to the hepatitis A or D virus, which allows to diagnose in these cases viral hepatitis A or D in a patient with chronic HBV infection.

Liver disorders that occur in patients with congenital anomalies of metabolism (tyrosinosis, glycogenosis, hemochromatosis, lipoidosis, etc.) often have to be differentiated from chronic, with acute hepatitis B.

[24], [25], [26], [27], [28], [29], [30], [31]

The defeat of the liver in helminthic invasions

With opisthorchiasis and other helminthic invasions, liver damage can only remotely resemble acute hepatitis B. Common symptoms in these diseases may be jaundice, an increase in the liver, arthralgia, an increase in body temperature, and dyspeptic phenomena. However, unlike hepatitis B. With opisthorchiasis, for example, body temperature and symptoms of intoxication persist for a long time, reaching maximum severity not in the initial pre-zheltushnom period, as is usually the case with viral hepatitis, and in the icteric period. In this case, the sharp pain of the liver is palpable; the activity of enzymes in serum often remains within normal limits or slightly increased. An important differential diagnostic value is the picture of peripheral blood. With opisthorchiasis, leukocytosis, eosinophilia, and a moderate increase in ESR are usually observed.

In children of the first year of life, acute hepatitis B must be differentiated from septic liver damage, biliary atresia, congenital hepatitis caused by cigomegalovirus, listeria, and with prolonged physiological jaundice, carotid jaundice, toxic hepatitis, congenital liver fibrosis, alpha-1 antitrapein insufficiency and many other congenital metabolic diseases of the liver.

Liver involvement with sepsis

In sepsis, liver damage usually occurs again, against the background of a pronounced septic process and a severe general condition of the patient. In biochemical analysis, there is a discrepancy between a high content of conjugated bilirubin and a low activity of hepatic cell enzymes. A critical picture for the diagnosis is the picture of peripheral blood, leukocytosis with neutrophil shift increased ESR in the case of septic hepatitis and normal carcinoma in hepatitis B.

Atresia of extrahepatic bile ducts

The main symptoms of atresia of the extrahepatic ducts are discoloration of the feces, dark urine and jaundice that appear immediately after the birth of the child (complete atresia) or during the first month of life (partial atresia). Regardless of the timing of the onset, jaundice gradually builds up, and eventually the skin becomes saffron, and subsequently - greenish-dirty due to the transformation of bilirubin in the skin into biliverdin, the feces are constantly acholiculous, the stercobilin is not detected in it, urine is intense is colored due to the increase in the bile pigment, whereas the reaction to urobilin is always negative. The liver gradually increases, its soft consistency persists for the first 1-2 months, "then a gradual consolidation of the organ is found, and at the age of 4-6 months the liver becomes dense and even hard due to the formation of biliary cirrhosis. The spleen during the first weeks of life is usually not increased, but with the development of cirrhosis and the formation of portal hypertension, splenomegaly appears. The general state of children does not suffer in the first months of life. However, in the future (usually at the 3-4th month of life) children become lethargic, poorly added to the mass, they have symptoms of portal hypertension (vein dilatation in the anterior abdominal wall, ascites) increases the volume of the stomach due to hepatosplenomegaly and flatulence. In the terminal phase of the disease, hemorrhagic syndrome occurs in the form of hemorrhages to the skin and mucous membranes, bloody vomiting and a stool with blood are possible. Without surgery, children die on the 7th-9th month of life from progressive liver failure due to secondary biliary cirrhosis.

The high content of conjugated bilirubin, total cholesterol, significantly increased activity of alkaline phosphatase, y-glutamyltranspeptidase, 5-nucleotidase and other liver-excreted enzymes attract attention in patients with atresia of extrahepatic biliary tracts, whereas the activity of hepatic cell enzymes (AJIT, ACT, F-1-FA, glutamate dehydrogenase, urokinanase, etc.) remains within normal limits during the first months of life and is moderately elevated in the final stages of the disease. At the atresia of the biliary tract, the indices of the thymol test, the prothrombin content, there is no dysirotheinemia,

Among other research methods for the diagnosis of atresia of extrahepatic and peritoneal bile ducts, retrograde cholangiopancreatography is important, during which it is possible to fill the radiopaque substance with bile ducts and thereby determine their patency; scintigraphic examination with Bengal pink, allowing to establish complete absence of bile passage into the duodenum with complete obstruction or absence of extrahepatic bile ducts; direct laparoscopy, allowing to see the gallbladder and extrahepatic bile ducts, as well as assess the appearance of the liver. Additional information on the state of the biliary tract can be obtained with ultrasound and CT of the liver.

The day of elimination of atresia of intrahepatic bile ducts is crucial to histological examination of liver tissue obtained with puncture or surgical biopsy, which allows to detect the decrease or absence of interlobular biliary tracts, as well as the presence of portal fibrosis of different degrees or inflammatory infiltration of portal spaces and giant cells in the parenchyma.

[32], [33], [34], [35], [36], [37], [38], [39]

Bile-thickening syndrome

The syndrome of mechanical jaundice can occur when the bile is thickened in children with prolonged physiological jaundice or hemolytic jaundice, and also by compressing the common bile duct with enlarged lymph nodes, a tumor or a cyst of the common bile duct. In all these cases, there are clinical symptoms associated with a decrease or complete cessation of bile flow: progressive jaundice due to increased conjugated bilirubin, fecal discoloration, dark urine, skin itching, an increase in blood levels of cholesterol, bile acids, beta-lipoproteins. High activity of alkaline phosphatase at low liver enzyme activity, etc. The diagnostic day may be crucial for ultrasound, as well as for CT and negative results for the detection of markers of HBV infection

[40], [41], [42], [43], [44]

Toxic liver disease

With the use of various drugs [chlorpromazine (aminazine), atophane, metatestosterone, halothane (fluorothane), etc.], clinical symptoms and biochemical shifts in the serum may appear, as in acute hepatitis B. Olnako the appearance of jaundice in the context of treatment with hepatotoxic drugs, the absence pre-zheltushnogo period, torpid jaundice during the type) cholestasis without severe hyperfermentemia, dysproteinemia and the disappearance of jaundice after drug discontinuation allow us to assume the medicated period ix liver. In a morphological study of liver tissue obtained by intravital puncture biopsy, in these cases a picture of fatty hepatosis is found.

Congenital or neonatal hepatitis

Cytomegalovirus, leafy and other hepatitis, as a rule, appear immediately after the birth of the child. Pre-zheltushnogo period in these cases does not happen. The condition of children is severe: hypotrophy, marbling of the skin, general cyanosis; jaundice is moderately expressed, the feces are partially discolored, urine is saturated. Body temperature is usually elevated, but can be normal. Characteristic hepatolyenal syndrome, hemorrhagic manifestations in the form of rashes on the skin, subcutaneous hemorrhages, gastric bleeding. The course of the disease is long, torpid. Children for a long time remain sluggish, poorly added to the masses; jaundice has been observed for more than a month. For many months, the liver and spleen remain enlarged. For differential diagnosis of hepatitis B with congenital hepatitis, biochemical studies are of secondary importance.

Congenital hepatitis is confirmed by an unfavorable obstetrical anamnesis of the mother, as well as a combination of symptoms of liver damage with other manifestations of intrauterine infection (malformations of the central nervous system, heart, kidneys, lung damage., GIT, etc.). The detection of DNA and RNA pathogens by PCR, the detection of IgM antibodies against cytomegalic agents, leaferelease using enzyme immunoassay, or the detection of a rise in the titer of common antibodies in the complement fixation reaction (RBC) may be crucial for the diagnosis of congenital hepatitis. PH GA, etc.

[45], [46], [47], [48], [49], [50], [51], [52], [53], [54]

Deficiency of a1-antitrypsin

The disease usually manifests itself in the first 2 months of life with jaundice, discoloration of feces, darkening of urine, enlargement of the liver. Symptoms of intoxication are absent, and jaundice is stagnant, suggesting atresia of extrahepatic bile ducts, but not hepatitis B. In serum with a deficiency of a-antitrypsin, the content of exclusively conjugated bilirubin, total cholesterol is increased, there are high rates of activity of alkaline phosphatase and other excreted by the liver enzymes, whereas the activity of hepatic cell enzymes remains within the normal range for a long time. Histological examination of liver punctata often reveals a picture of duktular hypoplasia, sometimes prolonged neonatal cholestasis or cirrhosis of the liver. Very characteristic is the detection of III-K-positive cells located inside many hepatocytes, which are clusters of a1-antitrypsin. With cirrhotogenic orientation of the process, portal fibrosis, small-scale regeneration in combination with the phenomena of ductular hypoplasia are revealed.

[55], [56], [57], [58], [59], [60], [61]

Congenital fibrosis of the liver

This is a serious congenital disease, characterized by proliferation of connective tissue along the portal tracts, the presence in them of a multitude of biliary microcysts and the phenomena of hypoplasia of the intrahepatic branching of the portal vein. Clinically, the disease is manifested by an increase in the volume of the abdomen, an increase in the pattern of the venous network on the abdominal and thoracic walls, a sharp increase and compaction of the liver, spleen, bleeding from varicose veins of the esophagus and stomach. Children lag behind in physical development. At the same time, functional tests of the liver remain almost normal. When contrasting the biliary tract, one can see an increase in their caliber. Diagnosis is greatly simplified if concomitant polycystic kidney is detected. The decisive significance of the day of diagnosis of congenital liver fibrosis is the results of a puncture liver biopsy. Histological examination reveals a sharp widening of the portal tracts, containing powerful layers of mature connective tissue with many small, cystically dilated bile ducts, and hypoplasia of portal portal veins.

[62], [63], [64], [65]

Carotenic jaundice

It arises from excessive consumption of carrot juice, mandarins and other fruits and vegetables, painted in orange. Unlike hepatitis B, with carotid jaundice, uneven coloring of the skin is noted: more intense on the palms. Feet, auricles, around the mouth, near the nose, and complete absence of icteric sclera. The general condition of children is not violated, functional tests of the liver are not changed.

[66], [67], [68], [69],

Reye's syndrome

Malignant form of hepatitis B with fulminant course sometimes has to be differentiated with Ree's syndrome, in which a coma occurs due to the steatosis of the liver, leading to severe disturbances in the metabolism of ammonia. Unlike hepatitis B, jaundice is weak or absent in Reye's syndrome, or absent, leading symptoms are hepatomegaly, hemorrhagic manifestations, repeated vomiting, convulsions, loss of consciousness and coma. Of the biochemical changes, hyperammonemia, hypertransaminase, hypoglycemia are most common, sometimes the content of conjugated bilirubin is increased, metabolic acidosis or respiratory alkalosis is often found, violations in the hemostatic system are characteristic. A histological examination of liver tissue reveals a picture of massive fatty hepatosis without signs of inflammatory infiltration and without necrosis phenomena of liver parenchyma.