Neonatal hepatitis syndrome

Introduction to neonatal hepatitis syndrome Hepatitis syndrome (newborn) is caused by a variety of causes, the main pathological changes are a neonatal disease formed by non-specific multinucleated giant cells. It is characterized by obstructive jaundice, hepatosplenomegaly and abnormal liver function, and elevated combined and unconjugated bilirubin in the late neonatal period. Most cases are caused by intrapartum or postpartum infection. It usually occurs about 1 month after birth. Broadly speaking, it includes hepatocyte-derived intrahepatic cholestasis, such as infections, metabolic diseases, familial cholestasis, chromosomal abnormalities, and idiopathic neonatal hepatitis. In a narrow sense, it is limited to the liver caused by infection. Cellular inflammation. basic knowledge Sickness ratio: 1%-2% Susceptible population: newborn Mode of transmission: mother-to-child transmission Complications: rickets, hepatic encephalopathy

Causes of neonatal hepatitis syndrome

(1) Causes of the disease

Infection factor (45%):

It can be caused by hepatitis A, hepatitis B virus, herpes simplex virus, rubella virus, etc., as well as toxic hepatitis caused by bacterial infection. It may also be caused by Toxoplasma gondii, Treponema pallidum and the like.

Bile excretion disorder (30%):

It can be caused by dysplasia of the bile duct inside and outside the liver, thick bile, liver or biliary mass. Non-specific multinucleated giant cell formation, cholestasis, inflammatory cell infiltration in the liver interstitial and portal vein, the degree is related to the severity of the disease, light liver lobular structure is normal, severe disorder can be disordered, hepatocyte punctate or flaky necrosis , Koch's cells and small bile duct hyperplasia, there may be fibrosis around the portal vein of the chronic disease, and the affected cells of the giant cell inclusion body disease are characterized by the owl-like intranuclear inclusion body.

Family genetic metabolic deficiency disease (15%):

Including galactosemia, fructose intolerance, glycogen accumulation disease and the like.

(two) pathogenesis

1. Infectious hepatitis: Mostly referred to as intrauterine infection of hepatitis, the significance of perinatal infection is particularly important, especially TORCH infections, namely T:toxoplasma, Toxoplasma gondii, R:rubella virus, rubella virus, C:cytomegalic Virus, CMV, cytomegalovirus, H:herpes simplex virus, HSV, herpes simplex virus, O:other, other infections, Chinese scholars have proved through extensive research that CMV is the first in the pathogen of this syndrome, and found CMV The infection may develop into a bile duct atresia and is closely related to the common bile duct cyst.

2. Congenital biliary atresia or cholestasis: including congenital intrahepatic and extrahepatic bile duct atresia, cholestasis caused by different causes (mainly cholestasis after hemolysis, etc.).

3. Hepatic damage caused by congenital genetic metabolic diseases: sugar (mainly galactose and fructose), abnormal metabolism of amino acids and bilirubin can be the etiology of this syndrome, in the case of metabolic abnormalities, Defects of 1 antitrypsin (1-AT) are important causes of primary chronic intrahepatic cholestasis in infants and young children, such as galactosemia caused by deficiency of 1-fluorogalactosyluriatransferase (UGUT), phosphoric acid Fructose aldolase (FPA) deficiency leads to fructose intolerance, glucose-6-phosphate kinase deficiency leads to glycogen storage disease, etc., and a representative disease of abnormal amino acid metabolism is hereditary tyrosinemia type I, based on gallbladder Diseases with abnormal acid metabolism include idiopathic obstructive biliary disease and familial progressive intrahepatic cholestasis syndrome (Byler disease).

Often multiple factors cause disease, infection, congenital hepatobiliary abnormalities and congenital metabolic abnormalities are confused with this syndrome.

Neonatal hepatitis syndrome prevention

The disease is caused by intrauterine infection of rubella virus, cytomegalovirus, herpes simplex virus, toxoplasma, etc. during pregnancy, and is transmitted directly to the fetus by the mother, and the mother may not develop the disease. The mother has hepatitis B and has a history of intrauterine infection, and the incidence of neonatal is high. The key to the prevention of this disease is to avoid infection and hepatitis in various diseases during pregnancy, which can reduce the incidence of this disease. The prognosis is better, 60% to 70% can be cured. Less conversion to cirrhosis or death. The curative effect of this disease is not satisfactory, and some patients have a tendency to develop chronic hepatitis and cirrhosis, so it should be diagnosed and treated early.

Neonatal hepatitis syndrome complications Complications, hepatic encephalopathy

The course of migration often falls behind, can occur rickets, enamel dysplasia, etc., development to severe cirrhosis, portal hypertension, hepatic encephalopathy, hyperbilirubinemia, gastrointestinal bleeding, septic cirrhosis , liver failure and so on.

Symptoms of neonatal hepatitis syndrome Common symptoms Large hepatocyte necrosis Hairy hereditary fructose intolerance Hepatosplenomegaly Anorexia jaundice Anuria diarrhea Sleepiness toxemia

1. General performance characteristics

(1) Astragalus: the most prominent manifestation of neonatal hepatitis. Most of the children are treated with jaundice. The onset of neonatal hepatitis is often slow and insidious. Most children develop neonatal jaundice in the first week after birth and last for 2 weeks. At the above time, or after the physiological jaundice subsided, the jaundice appeared again. Most of the children had jaundice after 1 month of treatment.

(2) Hepatosplenomegaly: liver and spleen can be touched, the liver is generally moderately enlarged, the liver is enlarged, the palpation is smooth, the edge is slightly blunt, the spleen is not enlarged, and the mild disease is gradually improved after general treatment. The stool first turns yellow, the skin and sclera jaundice gradually subsides, the liver shrinks to the normal range, and the growth and development are also good, the whole course of disease is 4 to 6 weeks.

(3) Stool: The color of stool is normal at birth, and then gradually turns into pale yellow or grayish white stool, which is often not continuous, sometimes with a little yellowish or green stool.

(4) Urine: combined with bilirubin can be discharged from the urine, most of the children have a strong tea-like urination, can be dyed yellow diapers.

(5) Others: often accompanied by a little vomiting, anorexia, weight loss and so on.

Some of the sick children develop slowly due to the disease, generally no fever, anorexia, vomiting, etc., and the yellow color of the jaundice and stools have not caught the attention of parents until the full moon or later, and then gradually developed into heavy, and also started from the beginning. Severe symptoms of severe symptoms, severe jaundice is becoming more and more serious, the stool is terracotta color, the liver is enlarged (up to 5 to 7 cm under the ribs), the quality is hard, the spleen is also enlarged (up to 6 to 7 cm under the rib), and the abdominal wall venous anger Zhang, ascites sign, perineal and lower extremity edema, can progress to hepatic encephalopathy, etc.; or major bleeding, sepsis and other complications and death.

2. Common causes of clinical features

Clinical features of several pathogen-induced neonatal hepatitis syndrome:

(1) Neonatal hepatitis B: The distribution of hepatitis B surface antigen (HBsAg)-positive population has a family aggregation phenomenon, which is related to its horizontal and vertical transmission. The study indicates that chronic HBsAg carries The mothers have a high incidence of HBsAg in their newborn babies; these babies develop a lower rate of chronic carriers of HBsAg (approximately 16%) and believe that infants infected during the neonatal period can actively eliminate the hepatitis B virus.

1 The factors that affect the mother's infection of children may be:

A. The higher the maternal complement titer, the higher the positive rate of HBsAg in infants, and the positive rate of HBsAg in infants born to maternal complement titer of 1:64 is as high as 90%.

B. The mother with hepatitis B and HBsAg carriers within 2 months after delivery or 2 months after delivery is more likely to infect the offspring than the asymptomatic carriers. The former infection rate is 56.5%, and the latter is 5%.

C. Children born to antigen carriers, if they have been HBsAg-positive, the likelihood of HBsAg-positive babies being born in the future is high, with a positive rate of 72%, and vice versa 10.2%.

De antigen is considered to be an important factor for vertical transmission. The positive rate of HBsAg in infants born with e antigen positive is extremely high. For example, maternal anti-e antibody positive and e antigen negative, infant HBsAg is almost negative, which is also different. View.

2 Clinical manifestations: Most HBsAg-infected infants have a subclinical process, no jaundice, only mild liver damage, except for persistent HBsAg-positive and aminotransferase, no other signs, liver is rare, aminotransferase fluctuations It can be extended for 1 to 2 years, often developing into chronic HBsAg carrying status, and a small number of people with jaundice recover rapidly. HBsAg is negative in the 6th to 9th month after the disease, and HBsAb appears, indicating neonatal hepatitis B. Similar to adults.

A small number can be manifested as fulminant or severe disease, the condition is critical, from the appearance of jaundice to acute liver failure for an average of 10 days (2 to 15 days), common hepatic encephalopathy, hemorrhage, blood ammonia up to 10mg / L or more (normal The value is 0.9 ~ 1.5mg / L), the short-term prognosis is very poor, the mortality rate is about 60%, the cause of death is mostly sepsis, pulmonary hemorrhage, hepatic encephalopathy with sepsis, etc., but its long-term prognosis is better, survivors Liver tissue recovered well.

(2) congenital cytomegalic inclusion hepatitis: CMV is a herpesvirus genus, which is one of the main pathogens of neonatal hepatitis syndrome.

Clinical manifestations of intrauterine infection, clinical symptoms appear in the neonatal period, manifested as prominent jaundice, hepatosplenomegaly and other symptoms of hepatitis, the infection at birth, the clinical manifestations of hepatitis generally appear in the postnatal 4 About a month, a small number of symptoms of respiratory infection, anemia, thrombocytopenia and mononucleosis, brain damage can be manifested as microcephaly, epilepsy, deafness, mental retardation, choroiditis.

(3) Listeriosis of the newborn: Listeria is a Gram-negative bacillus, infection mostly occurs in newborns, immunodeficiency patients, pregnant or puerperal women, especially newborns The infection is most common.

1 mode of transmission: the way newborns get this disease is as follows:

A. When the mother has bacteremia, the bacteria can enter the fetal circulation through the placenta and umbilical vein.

B. A mother's vaginal or endometrial infection causes an amnion infection, or when the fetus passes through the birth canal, inhaled or swallowed infected amniotic fluid.

C. Listeria can be present in the female vagina, male urethra for a long time without symptoms, and the newborn can get infection from the surrounding environment after birth.

2 clinical manifestations: fetal or neonatal granuloma or cell necrosis of multiple organs, with liver damage as a prominent symptom, manifested as jaundice, hepatosplenomegaly and other clinical manifestations, the mortality rate can be as high as 40% to 50% Premature infants can reach 73%, often with sepsis, the most common clinical type of neonatal infection, more than immediately or within a few days after birth, the mother has a history of perinatal fever, manifested as postnatal fever, vomiting, antifeeding , diarrhea, lethargy, jaundice, hepatosplenomegaly, sometimes conjunctivitis, rash, severe body temperature does not rise, respiratory distress, cyanosis, apnea or spontaneous breathing after birth, and symptoms of myocarditis and meningitis, smear Listeria monocytogenes, peripheral white blood cells increased, cerebrospinal fluid for meningitis.

(4) 1-antitrypsin deficiency: 1 anti-trypsin deficiency (1-AT) deficiency is an autosomal recessive genetic defect, the main manifestations of liver and lung damage, Most of the symptoms of liver disease and emphysema appear after birth, the onset age is different, the first time can appear jaundice on the first day of birth, the clinical features of cholestasis can not be distinguished from congenital bile duct atresia, biliary stasis about a few months later Progressive cirrhosis occurs, some children die in infancy, some have ascites in school age, esophageal varices, and cirrhosis occurs in late puberty.

Because 1-AT can not basically pass through the placenta, so the fetal period has been affected, its birth weight is often low, emphysema usually occurs around 30 years old, biochemical examination such as 1 globulin quantification <2g / L, can be used as 1-AT Lack of initial diagnosis, indirect quantitative determination of 1-AT by inhibiting trypsin activity. Normally, 1.1 mg of trypsin is inhibited by 1 ml of normal human serum, which is trypsin inhibition capacity (TIC), ie The normal value of TIC is 1~2mg/ml. If it is less than this value, it can be diagnosed.

(5) bile duct atresia:

1 blocking can be divided into:

A. The hepatic duct, gallbladder, and common bile duct are completely locked.

B. Only the gallbladder effusion, the remaining bile ducts are locked.

C. Liver tube atresia, gallbladder and duodenum.

D. The extrahepatic bile duct is normal and the intrahepatic bile duct is locked.

E. The hepatic duct and gallbladder are normal, and the common bile duct is locked.

F. Gallbladder and common bile duct atresia.

G. The hepatic duct and gallbladder are normal, and the remaining extrahepatic bile ducts are atresia.

2 Common symptoms and laboratory tests are as follows:

A. No jaundice at birth, meconium color is normal, jaundice appears in 1 to 2 weeks and gradually worsens. In severe cases, tears and saliva are yellow.

B. The liver is obviously enlarged, and ascites may occur in the late stage, sometimes touching the spleen.

C. At the beginning, the nutritional status is good, but gradually weak, euphemistic, may have nosebleeds, and other vitamin deficiency.

D. Dark urine, contains a lot of bilirubin, but no urinary bilirubin.

E. The stool is grayish white. In severe cases, the intestinal mucosal epithelial cells can exude bilirubin, making the surface of the stool yellow, while the middle is still white.

F. Increased serum conjugated bilirubin, the total amount of bilirubin often exceeds 171mol/L (10mg/dl), but the unconjugated bilirubin does not increase or only slightly increases, so it does not cause bilirubin encephalopathy, bile duct atresia 3 After a month, the liver begins to harden. From 6 months to 2 years old, it often kills due to liver failure. Therefore, it should be operated within 2 months after the diagnosis is clear. Since the development of liver transplantation technology, the prognosis of bile duct atresia has been greatly improved. .

Examination of neonatal hepatitis syndrome

Medical examination

Hepatosplenomegaly, dark urine, stool from yellow to light yellow, may also be white.

Laboratory inspection

1. Blood, urinary bilirubin: total bilirubin is generally lower than 171mol/L (10mg/dl), combined with bilirubin and unconjugated bilirubin, the former is the main, early changes in flocculation turbidity test Not obvious, urinary bile positive, urinary bilirubin can be positive or negative according to the degree of biliary obstruction.

2. Enzymatic changes: The elevation of alanine aminotransferase (ALT) is different. The lower one can only be slightly higher than the normal value. The higher one can be >200U. After most clinical improvement, ALT decreases, and some children have clinical improvement. It is higher than the original and then falls.

3. Determination of alpha-fetoprotein: normal newborn alpha-fetoprotein is positive, about 1 month after birth, it is negative, if using quantitative method, it is still above normal value, newborn infant hepatitis is full moon alpha-fetoprotein still Positive (may be the role of new liver cells), and can last for 5 to 6 months, if observed by quantitative methods, it can be seen as the disease improves, if the alpha-fetoprotein does not decline, clinical Symptoms may be severely damaged by the liver and may not be regenerated.

4. Etiology detection: specimen smear of meconium, external auditory canal, conjunctiva, nasopharynx or amniotic fluid, Gram staining for bacteria, blood hepatitis B virus marker, CMV, herpes simplex, rubella, Toxoplasma antibody (IgG) Compared with IgM) and serum after 2 weeks, others such as urine bacterial culture, CMV culture, and mother "TORCH" antibody test.

Auxiliary inspection

Hepatobiliary ultrasound images, biliary scintigraphy, duodenal fluid color analysis and nuclide counting were performed simultaneously with biliary scintigraphy in children with pale yellow or earthy feces.

Diagnosis and diagnosis of neonatal hepatitis syndrome

diagnosis

The diagnosis of neonatal hepatitis syndrome is difficult. It can only be ruled out from common diseases according to the history and physical signs. In the 2 months after birth, the incidence of jaundice is manifested as intrahepatic cholestatic hepatitis, and the stool color is gray. Dark urine, lasting more than 1 month, and the cause can be diagnosed as a narrow neonatal hepatitis syndrome. For neonatal hepatitis, if the cause is clear, the corresponding name can be given, such as neonatal cytomegalovirus hepatitis. , newborn hepatitis B and so on.

Galactosemia-induced liver injury can occur in the neonatal period, but it is easy to be diagnosed because it is easily covered by other clinical symptoms. Therefore, when a liver injury of unknown cause is found in the neonatal period, the disease should be considered. Liver damage occurs after feeding fructose-rich foods to infants, and hereditary fructose intolerance should be considered.

Laboratory examination: neonatal alpha-fetoprotein should be negative after full moon and the patient can continue to increase, which indicates that the liver cells are damaged and the regeneration is increased, usually reaching a peak around 1 week after the peak of transaminase, and serum alkaline phosphatase is normal.

Differential diagnosis

Of particular importance in the differential diagnosis of the cause is the need to identify hepatitis and extrahepatic bile duct atresia as early as possible, extracorporeal bile duct atresia (EHBA) is a congenital dysplasia, manifested as symptoms of progressive biliary obstruction, direct bilirubin, Cholesterol, -glutamylaminotransferase, etc., increased the need for radionuclide scanning, laparoscopic and liver biopsy, etc., due to the disparity between hepatitis and EHBA treatment principles, the former is mainly based on internal medicine, while the latter must strive for 3 Surgical treatment within a month.

The identification of neonatal hepatitis syndrome and bile duct atresia is difficult. A large number of studies have proved that the identification of the two should be carried out from the following aspects.

1. Time of appearance of jaundice: After physiological jaundice, jaundice continues to deepen, and the possibility of atresia is greater; if physiological jaundice is clearly resolved and recurrent jaundice, hepatitis is more likely.

2. Color of stool: whitening after birth, no yellow stool has been seen since birth, considering atresia or intrauterine hepatitis; it is clear that there is a high possibility of hepatitis in yellow stool, but there is indeed a child with bile duct atresia in early postnatal period Have had yellow stools.

3. Birth weight: The birth weight of intrauterine hepatitis is low, and it can also be a small sample. The appetite is also poor after birth. The intrauterine growth of children with bile duct atresia is normal, and the appetite is good at the beginning of life.

4. Changes in bilirubin: direct bilirubin increased in the early stage of the disease, and dynamic observation continued to increase. Bilateral phase appeared after prolonged period of time. This pattern indicates that the atresia may be caused. The early stage of the disease or the age of the child is still small, but total The bilirubin is very high, and the dynamic observation is fluctuating, and hepatitis can be considered more.

5. Glutamic-pyruvic transaminase (GPT, now known as "alanine aminotransferase", alanine aminotransferase, ALT) is elevated: higher in the early course of the disease, suggesting hepatitis; long course Those with elevated ALT only suggest that the liver cells are damaged and have no differential value.

6. Alpha-fetoprotein (AFP) is elevated: alpha-fetoprotein is produced by newborn hepatocytes. In theory, AFP is positive for hepatitis and negative for atresia. Some people think that when the child is born 1 to 4 months, AFP>35g/ml prompts. Hepatitis, atresia <10g/ml, but some cases have crossovers, so the actual value is not large.

7.131I rose red excretion test: intravenous injection of 131I-labeled rose red, most of which pass through the bile duct into the intestine, a small part of which is excreted by the kidney, so if the amount of 131I is <5% in the stool for 3 consecutive days, consider the bile duct obstruction, the lower the value The greater the possibility of occlusion; if >5%, the hepatitis is considered more, but in fact there is a crossover phenomenon between the two, and in practice, the stool must not be mixed into the urine, which is difficult for a baby girl.

8.99mTc () radionuclide examination: labeling various iminoacetic acid (IDA) derivatives with hepatobiliary scintigraphy with 99mTc has specific value for extrahepatic bile duct atresia, and the coincidence rate for the diagnosis of bile duct atresia and neonatal hepatitis can be as high as 85.7%, its sensitivity is higher than the 131I rose red excretion test. 99mTc-IDA imaging agent has rapid passage through the liver, high concentration in bile, can still be visualized in the bile duct system of high bilirubin level, and can obtain bile duct function status. The advantages of kinetics and morphological data are that hepatocyte clearance index (HCI) is above grade 2, 95% of children have radioactivity in the intestine, and the hepatobiliary transit time is extended to 2-8 hours, of which 99mTc is labeled. Isopropyl IDA and ortho-isopropyl IDA are most suitable for neonatal applications.

9. Cholangiography: Whether oral or venography, normal infants are not developed, may be related to poor liver concentrating ability, so laparoscopic cholecystography is performed abroad, that is, when exploratory laparotomy, the gallbladder is first searched, and then the contrast agent is injected from the gallbladder. Take a picture and observe the condition of the extrahepatic bile duct.

10. Liver biopsy: Liver biopsy has certain identification value, but some cases have atypical changes, so a single liver biopsy data cannot be used as the basis for diagnosis.

11. Dynamic observation of serum bile acid after phenobarbital or cholestyramine: It has been reported that phenobarbital can reduce the concentration of serum bile salts and bilirubin in some infants with intrahepatic cholestasis, cholestyramine In the intestinal tract combined with goose cholic acid, the ratio of serum cholate to goose bile acid increased in children with primary hepatic cytopathy, and the above effects were not observed in children with bile duct atresia.

12. Observation of duodenal juice: the method is to insert a opaque catheter (No 8 France) into children with high-binding bilirubin, and insert it into the second and third segments of the duodenum under fluoroscopy. Then do not eat in the first 24h, give 2ml of boiled water, drip into the catheter for 30 to 60min, to ensure that the catheter can continue to drain from the duodenum, concentrate 1 tube every 2h, visually observe 6 tubes (ie 12h) If there is no bilirubin, give the test children glucose electrolyte solution 60ml, once every 2 hours, a total of 6 times, continue to collect duodenal juice for observation, check the day to give intravenous rehydration, if the duodenum is found Bile, transfer surgery for cholangiography, liver biopsy, hepatic portal-intestinal anastomosis, if bile juice is found in the duodenal juice, liver percutaneous puncture after removal of metabolic defects, some scholars have found typical hepatitis children, The duodenal juice is first white mucus, secreted for 4 to 8 hours, then yellowed for about 2 hours, then turned into a non-pigmented liquid for about several hours, and then there is biliary pigment discharge.

13. Low-density lipoprotein-X (LP-X): Infants with bile duct atresia, even if the age is small, LP-X is positive, but the number of children with hepatitis increases with age, and the positive rate increases. The trend, but there are also overlapping phenomena.

14. Hormone therapy test: Prednisone was observed for 3 to 6 weeks. The majority of children with hepatitis showed yellowing of stool in 3 weeks, and jaundice subsided. A small number of hepatitis was effective for 6 weeks. If it is invalid for 6 weeks, laparotomy can be considered. However, it is often impossible to operate because of cirrhosis for more than 3 months.

15. Exploratory laparotomy: Individual cases of congenital biliary atresia cannot be ruled out 2 months after birth. It is necessary to consider laparoscopic cholangiography. In general, the identification of the two is difficult, and their performance often has crossover and lack of specificity. Its identification points.

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