Hepatitis B: diagnosis

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

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Clinical diagnostics of hepatitis B

Of the clinical symptoms, the following are significant: gradual onset of the disease with normal or subfebrile body temperature, prevalence of infectious asthenia in the form of general lethargy, weakness, muscle or joint pain, appearance of skin rashes. Of significance are a relatively long pre-icteric period and lack of improvement in well-being or even deterioration with the appearance of jaundice. All these clinical symptoms can be classified as suggestive, since their presence is not necessary for hepatitis B and, in addition, is possible with other viral hepatitis. The supporting diagnostic signs include the appearance of pronounced hepatosplenic syndrome in the patient, the establishment of the fact of gradually progressing jaundice. Only with hepatitis B is there an increase in the yellowish staining of the skin and visible mucous membranes 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 quickly decrease for another 1-2 weeks. Similar dynamics of liver size can be observed, less often - spleen. The intensity of urine coloring and feces discoloration strictly repeats the curve of jaundice severity and is in direct correlation with the level of conjugated bilirubin fraction in the blood.

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Epidemiological diagnostics of hepatitis B

Of the epidemiological data for the diagnosis of hepatitis B, indications of previous surgeries, the presence of blood transfusions, injections and other manipulations associated with a violation of the integrity of the skin or mucous membranes 3-6 months before the disease, as well as close contact with a patient with chronic hepatitis B or an HBV carrier are important.

Noting the great importance of anamnestic data on the presence of parenteral manipulations for the diagnosis of hepatitis B, it is necessary to warn against their overestimation. According to our clinic, in about a quarter of the observed patients with hepatitis B, no parenteral manipulations can be noted in the anamnesis at all. In these cases, infection occurs during close contact with the virus carrier through hidden microtraumas. This route of transmission of the hepatitis B virus is especially common in families or closed children's institutions, and focality of hepatitis B diseases can be observed. When superficially examined, they are often interpreted as foci of hepatitis A, and only the results of the study of the marker spectrum allow us to make a correct diagnosis.

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Biochemical criteria for the diagnosis of hepatitis B

The nature of biochemical changes in the blood generally reflects the peculiar dynamics of the clinical course of the disease, which is manifested by pronounced and prolonged hyperbilirubinemia due to an increase in the content of predominantly conjugated bilirubin in the blood serum, a persistent increase in the activity of hepatocellular enzymes (ALT, AST, F-1-FA, etc.), dysproteinemia due to a decrease in albumins and an increase in globulin fractions, a decrease in the content of blood coagulation factors (prothrombin, fibrinogen, proconvertin, etc.). But these indicators are not strictly specific. Similar biochemical indicators in the blood serum may also be present in other etiologic forms of viral hepatitis. Their peculiarity in hepatitis B is only that they are sharply expressed, and most importantly, they are detected for a long time, which is not typical for hepatitis A. The exception is only the thymol test, the indicators of which in hepatitis B are almost always low, while in other viral hepatitis they are 3-4 times higher than normal. Consequently, biochemical indicators should be considered as suggestive signs when diagnosing hepatitis B, they are important for the group characteristics of hepatitis B and cannot be used to establish an etiological diagnosis.

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Specific diagnostic criteria for hepatitis B

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

The hepatitis B virus surface antigen (HBsAg) is the main marker of hepatitis B. It is registered in the blood long before the clinical signs of the disease appear, and is constantly detected in the pre-icteric and icteric periods. In the acute course of the disease, HBsAg disappears from the blood by the end of the first month from the onset of jaundice. A longer detection of HBsAg in the blood serum indicates a protracted or chronic course of the disease. The concentration of HBsAg in the blood is subject to wide fluctuations, but an inverse relationship with the severity of the disease is still revealed, i.e. the more severe the pathological process, the lower the concentration of this antigen in the blood.

HBeAg (antigen associated with the nuclear, core antigen) is usually detected using highly sensitive methods - radioimmunoassay and ELISA. It begins to be detected in the blood serum 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-icteric period. With the onset of jaundice, the concentration of HBeAg in the blood quickly decreases, and in most patients it can no longer be detected in free circulation on the 2-3rd week from the onset of the disease and, as a rule, 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 infectivity of the blood. It has been established that the risk of infection through blood products containing HBeAg is many times greater than in the case where seroconversion has occurred and anti-HBe has appeared, regardless of the persistence of a high concentration of HBsAg. It is also known that transplacental transmission of the hepatitis B virus occurs almost exclusively in the presence of HBeAg in the mother's blood. Long-term detection of HBeAg in the blood serum indicates the development of protracted or chronic hepatitis B.

Anti-HBe are detected in the blood serum in acute hepatitis B in almost 100% of cases. Usually, antibodies appear 1-2 weeks after the disappearance of HBeAg. According to 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 are detected in the blood in low titers 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 detected in the nuclei of hepatocytes during morphological examination of liver biopsies and at autopsy using special methodological techniques (immunofluorescence, etc.).

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

According to research data, detection of anti-HBc should be considered the most constant 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, in the earliest stages and throughout the acute phase, including in cases where HBsAg was not detected due to a drop in its concentration, for example, in fulminant hepatitis or late admission of the patient to hospital. Detection of anti-HBc IgM in these cases was virtually the only informative test confirming hepatitis B. On the other hand, the absence of anti-HBc IgM in patients with clinical signs of acute hepatitis reliably excludes the HB viral etiology of the disease.

Determination of anti-HBc IgM is especially informative in cases of mixed hepatitis or superimposition of hepatitis A, hepatitis D on chronic HBV carriage. Detection of HBsAg in these cases would seem to confirm the presence of hepatitis B, but negative results of the analysis for anti-HBc allow such cases to be unambiguously interpreted as superimposition of another viral hepatitis on chronic HB carriage, and vice versa, detection of anti-HBc IgM, regardless of the presence of HBsAg, indicates active hepatitis B.

Determination of anti-HBc or total anti-HBc does not significantly add to the diagnostic information, but given that anti-HBc IgG after hepatitis B apparently persists 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.

Viral DNA in blood serum is detected by PCR. The advantage of this study is that it allows detecting the viral genome itself in the blood, rather than its private antigens, and therefore this method has become widespread. Viral DNA can be detected in 100% of cases in the early period of hepatitis B, which allows recommending this method for diagnosing acute hepatitis B and especially for assessing the effectiveness of antiviral therapy.

Detection of viral DIC polymerase indicates active replication of the hepatitis B virus, but it circulates in the blood for a short time, even before the development of the first signs of the disease, and therefore this test cannot be recommended for the diagnosis of hepatitis B.

In conclusion, it can be said that at present the most informative methods of specific diagnostics of acute hepatitis B are the determination of HBsAg, anti-HBc IgM and HBV DNA in the blood serum. The determination of other viral antigens and antibodies is of auxiliary importance.

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

Acute cyclic hepatitis

Serological marker	Period of illness
	Peak (2-4 weeks)	Early convalescence (1-3 months)	Late convalescence (3-6 months)
HBsAg	+	+/-	-
Anti-HBc IgM	+	+	-
Anti-HBc IgG	-/+	+	+
Anti-HBs	-	-/+	+
HBeAg	+	+/-	-
Anti-NVE	-	-/+	+

As can be seen from the presented data, each period of acute hepatitis B is characterized by 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 must first be differentiated from other viral hepatitis: A, C, E, D.

The clinical criteria for viral hepatitis presented in the table should be considered indicative, since on their basis it is possible to identify the characteristics of viral hepatitis only through group analysis, whereas a final etiological diagnosis can only be made by determining specific markers in the blood serum.

Objective difficulties often arise in the differential diagnosis of hepatitis B with other diseases, the list of which is determined by the patient's age, severity and phase of the pathological process. For example, in the pre-icteric period, hepatitis B most often has to be differentiated from acute respiratory viral diseases, biliary tract lesions, food poisoning, acute intestinal infections, various surgical pathologies of the abdominal organs, etc. In general, the differential diagnostic criteria in these cases are not much different from those for hepatitis A. The same can be said about the differential diagnosis of hepatitis B in the icteric period. The main circle of diseases with which hepatitis B most often has to be differentiated at the height of the disease is almost the same as with hepatitis A. Among the so-called suprahepatic jaundices, these are various protracted forms of hereditary and acquired hemolytic anemias occurring with cholestasis syndrome; Among hepatic or parenchymatous jaundices - a large group of hereditary pigment hepatoses (Gilbert's, Dubin-Johnson, Rotor syndromes); various infectious diseases accompanied by damage to the liver parenchyma (infectious mononucleosis, icteric forms of leptospirosis, intestinal yersiniosis and pseudotuberculosis, visceral forms of herpes infection, opisthorchiasis, etc.), as well as toxic and drug-induced liver damage, etc. Great difficulties in conducting differential diagnostics can also arise when distinguishing hepatitis B from subhepatic jaundice caused by blockage of the common bile duct by a tumor, cyst or stone in cholelithiasis. The general principles of differential diagnostics in all these cases are also fully described above.

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

The basis for differential diagnostics in such cases should be the results of laboratory research methods and careful consideration of the general symptoms characteristic of these diseases. However, in a number of cases it is possible to identify fairly characteristic clinical and biochemical features of liver damage in individual nosological forms.

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

Great difficulties may arise in differentiating acute hepatitis B from an exacerbation of chronic hepatitis or liver cirrhosis, especially if the latter were latent and were not diagnosed in a timely manner. The studies conducted at our department have shown that almost all so-called icteric exacerbations of chronic hepatitis are nothing more than the result of superimposition of acute hepatitis A or D on chronic hepatitis B. In these cases, the disease usually manifests itself with a rise in body temperature, the appearance of intoxication symptoms, jaundice, hepatomegaly, an increase in the level of conjugated bilirubin in the blood serum and the activity of hepatocellular enzymes, which would seem to give grounds for diagnosing acute hepatitis B. However, when observing these patients dynamically, it turns out that after the disappearance of the clinical symptoms of the acute phase of the disease, the child retains hepatosplenic syndrome, minor persistent hyperfermentemia and HBcAg is detected, while antibodies to the cow coma antigen of the IgM class are not detected or are in a low titer without significant fluctuations. Of decisive importance for diagnosis is the detection of specific IgM antibodies to the hepatitis A or D virus in the blood serum, which allows for the diagnosis of viral hepatitis A or D in these cases in a patient with chronic HBV infection.

Liver lesions that occur in patients with congenital metabolic anomalies (tyrosinosis, glycogenosis, hemochromatosis, lipoidosis, etc.) often have to be differentiated from chronic, if not acute, hepatitis B.

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Liver damage due to helminthic invasions

In opisthorchiasis and other helminthic invasions, liver damage may only vaguely resemble acute hepatitis B. Common symptoms of these diseases may include jaundice, liver enlargement, arthralgia, increased body temperature, and dyspeptic symptoms. However, unlike hepatitis B, in opisthorchiasis, for example, body temperature and intoxication symptoms persist for a long time, reaching their maximum severity not in the initial pre-icteric period, as is usually the case with viral hepatitis, but in the icteric period. In this case, severe liver pain upon palpation is very characteristic; enzyme activity in the blood serum often remains within normal limits or is slightly elevated. The peripheral blood picture is of important differential diagnostic significance. Leukocytosis, eosinophilia, and a moderate increase in ESR are usually observed in opisthorchiasis.

In children in the first year of life, acute hepatitis B must be differentiated from septic liver damage, biliary atresia, congenital hepatitis caused by cygomegalovirus, listeria, as well as prolonged physiological jaundice, carotene jaundice, toxic hepatitis, congenital liver fibrosis, alpha-1-antitrypein deficiency and many other congenital metabolic liver diseases.

Liver damage in sepsis

In sepsis, liver damage usually occurs secondarily, against the background of a pronounced septic process and a severe general condition of the patient. Biochemical analysis reveals a discrepancy between the high content of conjugated bilirubin and the low activity of hepatocellular enzymes. The peripheral blood picture is of decisive importance for the diagnosis: leukocytosis with a neutrophilic shift, increased ESR in the case of septic hepatitis and a normal picture in hepatitis B.

Atresia of extrahepatic bile ducts

The main symptoms of extrahepatic duct atresia are discolored stool, dark urine, and jaundice, which appear immediately after birth (complete atresia) or during the first month of life (partial atresia). Regardless of the time of appearance, jaundice gradually increases, and eventually the skin takes on a saffron color, and later - a greenish-dirty color due to the conversion of bilirubin in the skin to biliverdin, feces are constantly acholic, stercobilin is not detected in it, urine is intensely colored due to an increase in bile pigment, while the reaction to urobilin is always negative. The liver gradually increases in size, its soft consistency is maintained during the first 1-2 months, then a gradual compaction of the organ is detected, and at the age of 4-6 months the liver becomes dense and even hard due to the developing biliary cirrhosis. The spleen is usually not enlarged during the first weeks of life, but as liver cirrhosis develops and portal hypertension forms, splenomegaly appears. The general condition of children does not suffer in the first months of life. However, later (usually in the 3rd-4th month of life), children become lethargic, gain weight poorly, their symptoms of portal hypertension increase (varicose veins on the anterior abdominal wall, ascites), the volume of the abdomen increases due to hepatosplenomegaly and flatulence. In the terminal phase of the disease, hemorrhagic syndrome appears in the form of hemorrhages in the skin and mucous membranes, bloody vomiting and bloody stool are possible. Without surgical intervention, children die in the 7th-9th month of life from progressive liver failure due to secondary biliary cirrhosis of the liver.

In the blood serum of patients with extrahepatic biliary atresia, attention is drawn to the high content of conjugated bilirubin, total cholesterol, significantly increased activity of alkaline phosphatase, y-glutamyl transpeptidase, 5-nucleotidase and other enzymes excreted by the liver, while the activity of hepatocellular enzymes (AJIT, ACT, F-1-FA, glutamate dehydrogenase, urocaninase, etc.) remains within normal limits during the first months of life and is moderately increased in the final stages of the disease. With biliary atresia, the thymol test indicators and prothrombin content remain normal, there is no dysthyroteinemia,

Other methods of examination for diagnosing atresia of the extrahepatic and intrahepatic bile ducts include retrograde cholangiopancreatography, which allows filling the bile ducts with a radiopaque substance and thus determining their patency; scintigraphic examination with rose Bengal, which allows establishing the complete absence of bile passage into the duodenum with complete obstruction or absence of extrahepatic bile ducts; direct laparoscopy, which allows viewing the gallbladder and extrahepatic bile ducts, as well as assessing the appearance of the liver. Additional information on the condition of the bile ducts can be obtained from ultrasound and CT of the liver.

To exclude atresia of the intrahepatic bile ducts, histological examination of liver tissue obtained by puncture or surgical biopsy is of decisive importance, allowing to reveal a decrease or absence of interlobular bile ducts, as well as the presence of portal fibrosis of varying degrees of severity or inflammatory infiltration of the portal spaces and giant cells in the parenchyma.

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Bile thickening syndrome

Mechanical jaundice syndrome may occur due to thickening of bile in children with prolonged physiological jaundice or hemolytic jaundice, as well as due to compression of the common bile duct by enlarged lymph nodes, a tumor or a cyst of the common bile duct. In all these cases, clinical symptoms associated with a decrease or complete cessation of bile outflow appear: progressive jaundice due to an increase in conjugated bilirubin, discoloration of feces, dark urine, itchy skin, an increase in the blood level of cholesterol, bile acids, beta-lipoproteins. high activity of alkaline phosphatase with low activity of liver cell enzymes, etc. Ultrasound, as well as CT and negative results of determining markers of HBV infection can be of decisive importance for the diagnosis.

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Toxic liver damage

When using various drugs [chlorpromazine (chlorpromazine), atofan, metatestosterone, halothane (fluorothane), etc.] clinical symptoms and biochemical changes in the serum may appear, as in acute hepatitis B. However, the occurrence of jaundice against the background of treatment with hepatotoxic drugs, the absence of a pre-icteric period, a torpid course of jaundice (type) cholestasis without pronounced hyperenzymemia, dysproteinemia and the disappearance of jaundice after discontinuation of the drug suggest drug-induced liver damage. In these cases, a morphological study of liver tissue obtained by intravital puncture biopsy reveals a picture of fatty hepatosis.

Congenital or neonatal hepatitis

Cytomegalovirus, listerellosis and other hepatitis usually manifest themselves immediately after the birth of the child. There is no pre-icteric period in these cases. The condition of children is severe: hypotrophy, mottled skin, general cyanosis; jaundice is moderate, feces are partially discolored, urine is saturated. Body temperature is usually elevated, but may be normal. Pronounced hepatosplenic syndrome, hemorrhagic manifestations in the form of skin rashes, subcutaneous hemorrhages, gastric bleeding are characteristic. The course of the disease is long, torpid. Children remain lethargic for a long time, gain weight poorly; jaundice is observed for more than a month. The liver and spleen remain enlarged for many months. Biochemical studies are of secondary importance for the differential diagnosis of hepatitis B with congenital hepatitis.

Congenital hepatitis is indicated by an unfavorable obstetric history 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, gastrointestinal tract, etc.). Specific research methods can be of decisive importance for establishing the diagnosis of congenital hepatitis: detection of DNA and RNA of pathogens by PCR, detection of IgM antibodies to cytomegalovirus, listerellosis pathogens by enzyme immunoassay, or detection of an increase in the titer of total antibodies in the complement fixation reaction (CFR). PH GA, etc.

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α1-antitrypsin deficiency

The disease usually manifests itself in the first 2 months of life with jaundice, discolored feces, dark urine, and an enlarged liver. There are no symptoms of intoxication, and the jaundice is congestive, which suggests atresia of the extrahepatic bile ducts, but not hepatitis B. In the blood serum with a1-antitrypsin deficiency, the content of exclusively conjugated bilirubin and total cholesterol is increased, the activity of alkaline phosphatase and other enzymes excreted by the liver may be high, while the activity of hepatocellular enzymes remains within normal limits for a long time. Histological examination of liver puncture often reveals a picture of ductular hypoplasia, sometimes prolonged neonatal cholestasis or cirrhosis of the liver. Very characteristic is the detection of SHI K-positive bodies located inside many hepatocytes, which are accumulations of a1-antitrypsin. In the case of a cirrhotic process, portal fibrosis and fine-nodular regeneration are detected in combination with ductular hypoplasia.

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Congenital liver fibrosis

This is a severe congenital disease characterized by the proliferation of connective tissue along the portal tracts, the presence of multiple bile microcysts and hypoplasia of the intrahepatic branches 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 chest 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 liver tests remain almost normal. When contrasting the bile ducts, an increase in their caliber can be seen. Diagnostics is significantly simplified if concomitant polycystic kidney disease is detected. The results of a puncture biopsy of the liver are of decisive importance for the day of diagnosis of congenital liver fibrosis. Histological examination reveals a sharp expansion of the portal tracts, containing powerful layers of mature connective tissue with many small cystically dilated bile ducts, and signs of hypoplasia of the branches of the portal vein.

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Carotene jaundice

It occurs as a result of excessive consumption of carrot juice, tangerines and other orange-colored fruits and vegetables. Unlike hepatitis B, carotene jaundice is characterized by uneven coloring of the skin: more intense on the palms, feet, ears, around the mouth, near the nose, and a complete absence of yellowness of the sclera. The general condition of the children is not disturbed, functional liver tests are not changed.

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Reye's syndrome

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