Neonatal hepatitis

　　First, etiology

　　Neonatal hepatitis occurs within a month of birth, so infection may occur in utero. Most of it is caused by viruses, common pathogens include: hepatitis viruses (including HAV, HBV, HCV, HDV, HEV), cytomegalic inclusion virus (CMV), herpesvirus, rubella virus, coxsackievirus, ECHO virus, adenovirus, and EB virus, as well as syphilis spirochete, tuberculosis bacillus, rat toxoplasma, and various pathogenic bacteria and other pathogens. Bacterial infections such as group B streptococcus, listeria, staphylococcus aureus, Escherichia coli can cause liver lesions. So far, there are still many unknown causes of neonatal hepatitis. Hepatitis B virus infection is quite common in Asia and often occurs in the early neonatal period, but it does not cause neonatal cholestasis. Most of them are asymptomatic and the liver function is normal within a year, although severe acute or fulminant hepatitis B can occur in infancy, these children do not show liver dysfunction or jaundice within the first two months after birth. CMV is the most common pathogen in neonatal hepatitis, often appearing early symptoms.

　　Although there are many causes, the main pathological change is the formation of non-specific multinucleated giant cells. Bile stasis, liver interstitium, and portal area have infiltration of inflammatory cells, the degree of which is related to the severity of the disease. In mild cases, the lobular structure of the liver is normal, while in severe cases, it may be disordered, with dot-like or patchy necrosis of liver cells, hyperplasia of Kupffer cells and small bile ducts, and fibrosis around the portal area in long-standing cases. The characteristic of giant cell inclusion disease is the owl's eye-like nuclear inclusions in the affected cells.

　　Second, pathogenesis

　　1. Infectious hepatitis

　　Mostly refers to intrauterine infection of hepatitis, the significance of perinatal infection is particularly important, especially for TORCH infections (TORCH infections), namely T: toxoplasma, toxoplasma; R: rubella virus, rubella virus; C: cytomegalicvirus, CMV, cytomegalovirus; H: herpes simplex virus, HSV, herpes simplex virus; O: other, other infections. Chinese scholars have proven through a large amount of in-depth research that CMV is the leading pathogen in this syndrome, and it has been found that CMV infection may develop into biliary atresia, and it is closely related to choledochal cysts.

　　2. Congenital bile duct atresia or cholestasis

　　Including congenital intrahepatic and extrahepatic bile duct atresia, cholestasis caused by different reasons (mainly post-hemolytic cholestasis syndrome, etc.).

　　3. Liver damage caused by congenital hereditary metabolic diseases

　　Abnormal metabolism of sugar (mainly galactose and fructose), amino acids, and bilirubin can all be the etiological basis of this syndrome. Among those with metabolic abnormalities as the cause, α1-antitrypsin (α1-AT) deficiency is an important cause of primary chronic intrahepatic cholestasis in infants and young children. Other conditions such as galactosemia caused by the lack of 1-phosphogalactosyltransferase (UGUT), fructose intolerance caused by fructose-1-phosphate aldolase (FPA) deficiency, glycogen storage disease caused by glucose-6-phosphate kinase deficiency, and the representative disease of amino acid metabolism abnormality is hereditary tyrosinemia type I. Diseases based on bile acid metabolism abnormality include idiopathic obstructive biliary disease and familial progressive intrahepatic cholestasis syndrome (Byler disease) and others.

　　Various factors often act together to cause the disease, including infection, congenital biliary abnormalities, and congenital metabolic abnormalities, which are mixed in this syndrome.

　　The course of the disease often leads to growth retardation, and rickets, enamel hypoplasia, and other conditions may occur. Severe cases may present with liver cirrhosis, portal hypertension, hepatic encephalopathy, hyperbilirubinemia, massive gastrointestinal bleeding, septicemia liver cirrhosis, and liver failure.

　　1. Rickets, also known as rickets, is more common in infancy and is a disease caused by vitamin D deficiency, leading to disorders of calcium and phosphorus metabolism in the body, resulting in poor bone calcification. Rickets develops slowly and is not easy to attract attention. Rickets reduces the resistance of children, making them prone to diseases such as pneumonia and diarrhea, affecting the growth and development of children.

　　2. Dental enamel hypoplasia is a defect left during the development and calcification of teeth, which can only be discovered after eruption, so it is meaningless to supplement vitamin D after discovery. Attention should be paid to the health care of pregnant women and the prevention of acute febrile diseases in infants and young children.

　　3. Liver cirrhosis (hepaticsclerosis) is a common chronic progressive liver disease in clinical practice, which is a diffuse liver damage formed by the long-term or repeated action of one or more etiologies. Pathologically, there are extensive liver cell necrosis, nodular regeneration of residual liver cells, proliferation of connective tissue and formation of fibrous septa, leading to the destruction of the lobular structure and the formation of pseudo-lobules. The liver gradually deforms and hardens, leading to liver cirrhosis.

　　4. Portal hypertension (portalhypertension) is a syndrome caused by persistent elevation of portal vein pressure, the vast majority of patients are caused by liver cirrhosis, a few patients are secondary to portal vein trunk or hepatic vein obstruction, and some unknown factors.

　　5. Hepatic encephalopathy (hepaticencephalopathy, HE) also known as hepatic coma, is a comprehensive syndrome of central nervous system dysfunction caused by severe liver disease, based on metabolic disorders. The main clinical manifestations are disturbance of consciousness, abnormal behavior, and coma. There are acute and chronic encephalopathy.

　　6. Jaundice (jaundice) is a common symptom and sign, which occurs due to the increase of bilirubin concentration in the serum caused by the disturbance of bilirubin metabolism. Clinically, it is manifested as the yellowing of the sclera, mucosa, skin, and other tissues. Because the sclera contains more elastic protein (elastin) and has a strong affinity for bilirubin, the yellowing of the sclera is often noticed before the mucosa and skin. When the total bilirubin in the serum is between 17.1-34.2 μmol/L, and jaundice is not visible to the naked eye, it is called concealed jaundice or subclinical jaundice.

　　7. Sepsis (sepsis) refers to a systemic inflammatory response syndrome caused by infection, which is confirmed by clinical evidence of the presence of bacteria or highly suspicious infection foci. Although sepsis is caused by infection, once it occurs, its development follows its own pathological process and规律, so in essence, sepsis is the body's response to infectious factors.

　　1. General characteristics of clinical manifestations

　　1. Jaundice

　　It is the most prominent manifestation of neonatal hepatitis. Most children seek medical attention due to jaundice. Neonatal hepatitis often starts slowly and insidiously, with most children showing neonatal jaundice in the first week after birth, which lasts for more than 2 weeks, or reappears after the physiological jaundice subsides. Most children have their jaundice resolved after 1 month of treatment.

　　2. Liver and spleen enlargement

　　The liver and spleen can be palpated, the liver is generally moderately enlarged, smooth to the touch, with slightly blunt edges, and the spleen is not significantly enlarged. Mild cases improve gradually after general treatment, the stool turns yellow first, the jaundice of the skin and conjunctiva gradually subsides, the liver returns to normal size, growth and development are also good, and the whole course lasts for 4-6 weeks.

　　3. Stool

　　The color of the stool at birth is normal, and it gradually turns into light yellow or grayish white stool, which is often not persistent, and sometimes there is a little light yellow or green stool.

　　4. Urine

　　Conjugated bilirubin can be excreted in urine, most children have tea-colored urine, which can stain diapers.

　　5. Other

　　It is often accompanied by slight vomiting, anorexia, and no weight gain.

　　Some children with slow disease progression generally do not have symptoms such as fever, anorexia, vomiting, and the yellowing and lightening of stool color do not attract the attention of parents either. It is not until the full month or later that it is discovered, and it gradually develops into a severe condition. Some may present with severe symptoms from the beginning. Severe cases may have increasingly severe jaundice, clay-colored stools, liver enlargement (up to 5-7 cm below the ribs), slightly hard texture, spleen enlargement (up to 6-7 cm below the ribs), distension of abdominal wall veins, signs of ascites, perineal and lower limb edema, which can develop into hepatic encephalopathy, and so on; or die from complications such as massive hemorrhage and sepsis.

　　Second, common etiological clinical characteristics

　　Clinical characteristics of neonatal hepatitis syndrome caused by several pathogens:

　　1. Neonatal hepatitis B

　　The distribution of the population with HBsAg positivity in hepatitis B has a family aggregation phenomenon, which is related to its horizontal and vertical transmission. Studies indicate that chronic HBsAg carriers have a high incidence of HBsAg in their newborns; the ratio of these infants to become chronic HBsAg carriers is relatively low (about 16%), and it is believed that infants infected during the neonatal period can actively eliminate the hepatitis B virus.

　　(1) Factors that may affect the infection of offspring by the mother include:

　　① The higher the complement value of the mother, the higher the positivity rate of HBsAg in the infant. For mothers with a complement value of 1:64, the positivity rate of HBsAg in the infants they give birth to is as high as 90%.

　　② Mothers who have hepatitis B with HBsAg carriage during the later stages of pregnancy or within 2 months after delivery are more likely to infect their offspring than asymptomatic carriers. The infection rate of the former is 56.5%, while that of the latter is 5%.

　　③ Children born to antigen carriers, if they have already had a positive HBsAg, the possibility of the next born infant having a positive HBsAg is very high, with a positivity rate of 72%, while the reverse is 10.2%.

　　④ The e antigen is considered an important factor in vertical transmission. Infants born to e antigen-positive individuals have a very high rate of HBsAg positivity. If the mother has a positive anti-e antibody but a negative e antigen, the infant's HBsAg is almost always negative. There are also different opinions on this matter.

　　(2) Clinical manifestations: Most infants infected with HBsAg show an asymptomatic process, without jaundice, and only mild liver function damage. Apart from persistent HBsAg positivity and elevated aminotransferases, there are no other signs. Liver enlargement is rare, aminotransferases fluctuate, and the condition may persist for 1-2 years, often developing into a chronic HBsAg carrier state. A few infants with jaundice recover quickly, with HBsAg turning negative between the 6th and 9th month after the disease, and HBsAb appearing, indicating that neonatal hepatitis B is similar to that in adults.

　　A few cases may present with fulminant or severe disease, with a critical condition. The average time from the onset of jaundice to acute liver failure is 10 days (2-15 days), common symptoms include hepatic encephalopathy, hemorrhage, and blood ammonia levels reaching above 10mg/L (normal range 0.9-1.5mg/L). The prognosis in the recent period is extremely poor, with a mortality rate of about 60%, and the main causes of death are sepsis, pulmonary hemorrhage, hepatic encephalopathy with sepsis, etc. However, the long-term prognosis is relatively good, and the liver tissue of survivors recovers well.

　　2. Congenital cytomegalovirus hepatitis

　　CMV belongs to the Herpesviridae family and is one of the main pathogens of neonatal hepatitis syndrome.

　　Clinical characteristics of intrauterine infected individuals include the onset of clinical symptoms during the neonatal period, characterized by prominent jaundice, hepatosplenomegaly, and symptoms of hepatitis. Infected individuals at birth generally show clinical manifestations of hepatitis around 4 months after birth, with a few also presenting with respiratory tract infection symptoms, anemia, thrombocytopenia, and monocytosis. Brain damage can manifest as microcephaly, epilepsy, deafness, intellectual disability, and choroiditis.

　　3. Neonatal Listeriosis

　　Listeria is a Gram-negative bacillus, which often causes infection in neonates, immunodeficient patients, pregnant or postpartum women, etc., especially neonates are most common.

　　(1) Modes of transmission: The ways in which neonates acquire this disease are as follows:

　　① When the mother has bacteremia, bacteria can enter the fetal circulation through the placenta and umbilical vein.

　　② Maternal vaginal or endometrial infection can cause amniotic infection, or the fetus can inhale or ingest contaminated amniotic fluid when passing through the birth canal.

　　③ Listeria can exist in the female vagina and male urethra for a long time without producing symptoms, and neonates can acquire infection from the surrounding environment after birth.

　　(2) Clinical manifestations: Granuloma or necrosis of multiple organs in the fetus or neonate, with liver damage as the prominent symptom, presenting with jaundice, enlargement of the liver and spleen, and the mortality rate can be as high as 40% to 50%, and up to 73% in premature infants. It often occurs as sepsis, the most common clinical type of neonatal infection, occurring immediately or within a few days after birth. The mother often has a history of perinatal fever, presenting as fever, vomiting, refusal to eat, diarrhea, drowsiness, jaundice, enlargement of the liver and spleen, and sometimes conjunctivitis, rash. In severe cases, the body temperature may drop, respiratory distress, cyanosis, apnea, or no spontaneous respiration after birth, with symptoms of myocarditis and meningitis. The smear can show Listeria, peripheral blood routine shows an increase in white blood cells, and cerebrospinal fluid shows the symptoms of meningitis.

　　4. α1-antitrypsin deficiency

　　Congenital α1-antitrypsin (α1-AT) deficiency is an autosomal recessive genetic defect. The main manifestations of the affected children are liver and lung damage, and symptoms such as liver disease and emphysema often appear after birth. The onset age varies, with jaundice appearing as early as the first day of life. The clinical characteristics of bile stasis cannot be distinguished from congenital bile duct atresia. After about a few months of bile stasis, progressive liver cirrhosis appears. Some children die in infancy, some develop ascites, esophageal varices in the school age period, and some develop liver cirrhosis symptoms late in adolescence.

　　Neonatal hepatitis is often caused by maternal intrauterine infection with rubella virus, cytomegalovirus, simplex virus, toxoplasma, etc. during pregnancy, which is directly transmitted to the fetus by the mother, and the mother may not be ill. The incidence of neonatal hepatitis is high in mothers with hepatitis B and a history of intrauterine infection. The key to preventing this disease is to avoid various diseases and hepatitis during pregnancy, which can reduce the incidence of the disease. The prognosis is relatively good, with 60% to 70% curable. There are fewer cases of liver cirrhosis or death. The therapeutic effect of this disease is not satisfactory, and some patients have a tendency to develop chronic hepatitis or liver cirrhosis, so early diagnosis and treatment are necessary.

　　1. Laboratory examination

　　1. Blood and urine bilirubin

　　Total bilirubin is generally below 171μmol/L (10mg/dl), with both conjugated and unconjugated bilirubin elevated, with the former being the main cause. The flocculent turbidity test shows no early changes, and urobilinogen is positive. Urobilin is positive or negative according to the degree of bile duct blockage.

　　2. Enzymatic changes

　　The degree of increase in alanine aminotransferase (ALT) varies, the lower ones may only slightly exceed the normal value, and the higher ones may be >200U. Most cases show a decrease in ALT after clinical improvement, while some children show clinical improvement and ALT increases compared to the original, and then decreases.

　　3. Alpha-fetoprotein measurement

　　Normal neonatal alpha-fetoprotein is positive, it turns negative after about 1 month after birth, if quantitative method is used, it is still above the normal value, neonatal hepatitis infants are still positive for alpha-fetoprotein at one month (may be the effect of new liver cells), and it can last for 5-6 months. If it is observed dynamically with quantitative method, it can be seen that it decreases with the improvement of the condition. If alpha-fetoprotein does not decrease, and clinical symptoms improve, it may indicate severe liver damage that can no longer regenerate, showing severe condition.

　　4. Pathogen detection

　　Obtain specimens from the meconium, external auditory canal, conjunctiva, nasopharynx, or amniotic fluid of the child, make smears, Gram stain for bacteria, hepatitis B virus markers, CMV, herpes simplex, rubella, toxoplasma IgG and IgM antibodies, and serum contrast 2 weeks later. Other tests include urine bacterial culture, CMV culture, and maternal 'TORCH' antibody test, etc.

　　Second, auxiliary examination

　　Liver and gallbladder ultrasound imaging, bile duct scintigraphy, duodenal fluid color analysis and radioactive counting, and synchronous bile duct scintigraphy for children with pale yellow or earth-colored feces.

　　1. Pay attention to nutritional balance.

　　2. Ensure the daily supply of carbohydrates for fasting individuals, glucose can be administered at a rate of 8-12mg/(kg·min).

　　3. Provide an appropriate amount of protein, do not overload.

　　4. Decreased fat supply, reduced bile salts in the intestines affect the decomposition and absorption of fats in food, and also promote the synthesis of cholesterol in the liver and small intestine.

　　5. Intramuscular injection of vitamins A, K, D, and E.

　　For general cases of neonatal hepatitis, traditional Chinese medicine can be used to clear heat, promote diuresis, and relieve jaundice, such as Yinchen Hāo decoction. The traditional Chinese medicine Yinchen Sanhuang decoction can be taken for a long time, and for severe cases, injections can be used, once or twice a day. For those with clear etiology, treatment should be targeted at the etiology.