Pediatric liver cirrhosis

　　1. Etiology

　　Infection is the main cause of pediatric liver cirrhosis, and congenital bile duct obstruction, congenital metabolic defects, and hereditary diseases are also relatively common causes of pediatric liver cirrhosis:

　　1. Infection:

　　Viral hepatitis (hepatitis B, hepatitis C, hepatitis D, hepatitis G, cytomegalovirus hepatitis), rubella virus, herpes simplex virus, varicella virus; congenital syphilis; parasitic diseases (Schistosoma japonicum, liver flukes, toxoplasmosis) and others.

　　2. Congenital genetic metabolic abnormalities:

　　Wilson's disease, glycogen storage disease type IV, galactosemia, α1-antitrypsin deficiency, congenital tyrosinemia (congenitaltyrosinosis), hereditary fructose intolerance, Fanconi syndrome (Fanconisyndrome), cystic fibrosis (mucoviscidosis), β-lipoproteinemia, hereditary hemorrhagic telangiectasia (Osler-Weber disease), hemochromatosis (hemochromatosis) [Idiopathic hereditary hemochromatosis (IHC), neonatal hemochromatosis (NHC), secondary hemochromatosis], peroxisomal disorders (peroxisomal disorders, PD) [Brain-liver-kidney syndrome, also known as Zellweger syndrome, biliary hypoplasia with trihydroxycoprostanic acidemia (THCA)].

　　3. Acquired metabolic abnormalities:

　　Alcohol intoxication, nutritional, toxic (neonatal infection intoxication, toxins, drugs).

　　4. Immune abnormalities:

　　Autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), pediatric primary sclerosing cholangitis (PSC).

　　5. Liver and bile duct cystic diseases:

　　(cystic diseases of the biliary tract and liver) congenital hepatic fibrosis (congenital hepatic fibrosis, CHF), congenital bile duct dilatation disease (Caroli disease), congenital choledochal cyst.

　　6. Congestive liver cirrhosis:

　　Budd-Chiari syndrome, chronic constrictive pericarditis.

　　7. Cryptogenic cirrhosis:

　　Indian childhood cirrhosis (Indian childhood cirrhosis, ICC), familial cirrhosis (familial cirrhosis, also known as Alper's disease).

　　2. Pathogenesis

　　1. Pathogenesis

　　(1) Infection: after the liver is infected by viruses, bacteria, fungi, and parasites, it gradually progresses to liver cirrhosis. In children, it is common to be hepatitis B or C viral hepatitis (Table 1); post-necrotic liver cirrhosis after acute severe hepatitis; newborns due to incomplete immune function, infection hepatitis presents an subclinical process, prone to develop into chronic hepatitis or liver cirrhosis; intrauterine infection with cytomegalovirus, rubella virus, herpes simplex virus, congenital syphilis are easy to invade the liver, develop into chronic hepatitis and liver cirrhosis; parasitic diseases such as schistosomiasis in the late stage, clonorchiasis, toxoplasmosis, and malaria; bacterial toxic hepatitis is less likely to develop into liver cirrhosis, but staphylococcal sepsis or infants under 1 year of age with malnutrition or viral hepatitis are prone to cause liver cirrhosis.

　　(2) Hereditary or congenital metabolic defects: mainly due to the deficiency of certain enzymes, causing the accumulation of esters, amino acids, fats, or trace elements such as copper and iron in the liver, leading to liver cirrhosis. Common conditions include Wilson's disease, alpha-1 antitrypsin deficiency, phenylketonuria, galactosemia, glycogen storage disease type IV, hereditary fructose intolerance, Fanconi syndrome, Gaucher's disease, etc. The late stage progression of hemochromatosis (hemachromatosis) to liver cirrhosis is rare; Zellweger syndrome (encephalomyocardiosis) is a rare autosomal recessive genetic disease caused by defects in peroxisome development or the lack of function of a certain enzyme in peroxisomes. It is mainly manifested by liver cirrhosis, renal cysts, muscle weakness, seizures, special facial features, and congenital eye diseases such as glaucoma and cataracts, accompanied by abnormal iron metabolism.

　　(3) Poison and drug intoxication: such as arsenic, phosphorus, bismuth, chloroform, isoniazid, cinchophen, poisonous mushrooms, etc.

　　(4) Immune abnormalities: French scholars Vajro et al. conducted a prospective study on 92 cases of pediatric chronic hepatitis, including 46 cases of hepatitis B and 46 cases of autoimmune hepatitis. The former developed liver cirrhosis in 32%, while the latter in 89%. It can be seen that in France, autoimmune hepatitis accounts for the first place in the etiology of post-hepatitis liver cirrhosis in children.

　　(5) Liver and bile duct cystic diseases: A group of congenital liver fibrosis and bile duct cystic disease. Congenital hepatic fibrosis (CHF) is an autosomal recessive genetic disease with unknown etiology, about 40% are siblings. The 302 Hospital of the People's Liberation Army has treated siblings with CHF. The diagnosis mainly relies on liver biopsy. The genetic pattern of Caroli's disease is the same as CHF, and the diagnosis is mainly based on ultrasound, CT, and sometimes endoscopic retrograde cholangiopancreatography (ERCP). Congenital choledochal cysts are detailed in biliary diseases.

　　(6) Congestive cirrhosis: It is caused by long-term liver congestion due to venous vascular malformations, thrombosis, chronic congestive heart failure, and chronic constrictive pericarditis, leading to cirrhosis.

　　(7) Other causes: It is not uncommon to have undetermined etiology. Biliary cirrhosis in Indian children mainly occurs in India and its neighboring regions, and there are also reports from West Africa and Central America. It often occurs between 1 and 3 years of age, with liver enlargement as the initial manifestation. Other symptoms include fever, anorexia, and jaundice. Most cases progress rapidly to cirrhosis and liver failure. The cause of this disease is unclear.

　　2. Pathological changes:The characteristics of cirrhosis are the hyperplasia of connective tissue, degeneration of a large number of liver cells or liver lobules, followed by fibrous tissue hyperplasia replacing normal liver tissue. If the lesion involves several adjacent lobules, the lobular structure becomes disordered, and the framework collapses. Due to the contraction of fibrous tissue and the compression of regenerative nodules, the blood flow within the liver is obstructed, leading to portal hypertension. The disease progresses, forming collateral circulation. Generally, it is divided into portal, postnecrotic, and biliary cirrhosis. In the late stage, it is often mixed type.

　　(1) Portal cirrhosis: Less common in children than in adults, it is due to chronic hepatitis or liver congestion. In the early stage, the liver is often enlarged, and in the later stage, it shrinks, becoming hard. The surface is irregular, showing granular or nodular appearance. Histologically, there is liver cell degeneration or necrosis, normal lobular structure destruction, and regenerative nodules of varying sizes. Fibrous tissue hyperplasia around the nodules and portal areas is widespread, with varying degrees of inflammatory cell infiltration and bile duct hyperplasia. The liver vascular network is compressed and displaced.

　　(2) Postnecrotic cirrhosis: It often occurs several months after acute severe hepatitis or toxic hepatitis, with the liver shrinking, becoming hard, and the liver parenchyma often showing large areas of necrosis, affecting one or more lobules. The reticular framework collapses, connective tissue hyperplasia forms wider fibrous bundles. Liver cells near the necrotic area regenerate, forming nodules of varying sizes. Larger nodules often contain normal liver lobules. In the fibrous tissue, there is significant infiltration of inflammatory cells and hyperplasia of bile ducts.

　　(3) Biliary cirrhosis: In children, it is mostly secondary, and its pathological changes are mainly obvious bile stasis in the liver cells and small bile ducts, with hyperplasia of connective tissue in the portal areas, which may include new bile ducts and inflammatory cell infiltration. The small bile ducts in the liver are dilated, with bile stasis and cholestasis formation. The hyperplastic connective tissue grows between and within lobules, and the liver cells show no obvious regeneration.

　　1. Upper gastrointestinal bleeding is caused by portal hypertension accompanied by varices and abnormal coagulation mechanism, with vomiting blood, hematochezia, and gastrointestinal hemorrhage being common causes of death that can easily trigger hepatic encephalopathy.

　　2. Hepatic encephalopathy.

　　3. Secondary infection is mainly caused by bacterial infection or fungal infection, which can also occur, especially in the biliary tract.

　　4. Portal vein thrombosis is not common in children, and thrombosis forms slowly, with no obvious clinical symptoms. If it occurs suddenly, it can cause severe abdominal pain, hematochezia, and even shock.

　　5. Hepatorenal syndrome occurs in late liver cirrhosis due to liver failure, reduced renal blood flow, and hypokalemia, leading to secondary renal failure, i.e., hepatorenal syndrome. Children may have oliguria or anuria, general edema, and azotemia.

　　First, portal cirrhosis

　　The onset process is relatively slow and can潜伏 for several years.

　　Second, postnecrotic liver cirrhosis

　　Once this type of liver cirrhosis occurs, its development is relatively rapid, not easily compensated, and often leads to liver failure and death due to secondary infection in a short period of time. In cases with slower progression, symptoms and signs of liver cirrhosis can gradually appear, but most children often present with liver failure as the earliest manifestation, with jaundice and gastrointestinal symptoms, which are easily misdiagnosed as acute hepatitis. The Pathology Department of Beijing Children's Hospital reported 14 cases of postnecrotic liver cirrhosis, with most cases from the onset of symptoms to death being 2 to 3 months, the shortest being 11 days, and the longest two cases were half a year and 2 years and 3 months respectively. The speed of liver cirrhosis development is directly related to the age of the child, with neonatal and infantile hepatitis developing rapidly. Pathological data show that neonatal hepatitis can develop into liver cirrhosis, and most die within 1 to 6 months.

　　Third, biliary cirrhosis

　　It can be divided into 2 types:

　　1. Primary: There are special clinical manifestations, most of which have fever, fatigue, decreased appetite, and upper abdominal discomfort. Due to cholangitis, early manifestations include obstructive jaundice, pruritus, deep yellow urine, diarrhea, whitish or light-colored stools, significant liver enlargement, and in cases with long-term jaundice, there may be a tendency to hemorrhage and skin jaundice. Laboratory tests mainly show the manifestations of obstructive jaundice. The course is benign and can last for several years, ultimately deteriorating due to liver cirrhosis, liver failure, and gastrointestinal bleeding. The relationship between this disease and hepatitis virus is not yet clear, and it may also be related to autoimmune disease.

　　2. Secondary: During childhood, the main cause of liver cirrhosis is secondary to extrahepatic biliary obstruction, with clinical manifestations of obstructive jaundice, which is very similar to primary cases, but the prognosis and treatment are completely different. Therefore, it is necessary to make a distinction and avoid incorrect surgery.

　　Infection is the main cause of pediatric liver cirrhosis. Strengthening prenatal care, preventing various infectious diseases during pregnancy, especially hepatitis B virus, cytomegalovirus, rubella virus, herpes simplex virus, congenital syphilis, and other infections, is necessary to prevent liver damage in children and the occurrence of this disease. There are hundreds of drugs and toxins that can cause damage to liver cells, so it is necessary to avoid long-term and large-scale contact to prevent the occurrence of this disease. At the same time, rational feeding, balanced diet, and doing well in various postnatal preventive vaccination work, as well as cultivating good hygiene habits, preventing various chronic inflammatory bowel diseases, and so on are important.

　　1, Ultrasound examination

　　Although B-ultrasound often cannot accurately measure the size of the liver or spleen, nor can it diagnose the hardness of the liver, it can assess the diameter and tortuosity of the portal vein, and is helpful for detecting small amounts of ascites and whether the kidney structure is abnormal. Doppler ultrasound examination shows that the formation of collateral blood vessels around the portal vein is a sign of extrahepatic portal vein obstruction. Normally, respiration has a regulatory effect on portal vein blood flow. If this sign disappears, it suggests portal hypertension, but the appearance of this sign cannot absolutely exclude portal hypertension.

　　2, Esophageal X-ray barium meal examination

　　Esophageal X-ray barium meal examination can show the presence and degree of esophageal varices. The varices are often located in the lower two-thirds of the esophagus, showing shadows of barium filling defects. When varices are severe and widespread, they may resemble several intertwined earthworms. The degree of varices is not related to the etiology or the age of the child. Generally speaking, thicker barium is better than thinner barium for imaging, but sometimes it is necessary to use both thick and thin barium to make the delicate esophageal mucosal patterns more clearly visible. In adults, the sensitivity of barium meal examination for detecting esophageal varices is about 70%. In recent years, due to the widespread application of endoscopy, this technique has been rarely used for the examination of esophageal varices, and its value for detecting active upper gastrointestinal bleeding is extremely limited.

　　3, Gastroscopy

　　Gastroscopy can directly observe the presence and degree of esophageal varices. Currently, endoscopic examination for all pediatric age groups is feasible and safe, and it is the most accurate and sensitive method to confirm the presence of esophageal varices. For children with upper gastrointestinal bleeding, once the condition is stable, immediate gastroscopy should be performed to quickly determine the bleeding site, the nature of the lesion, and to perform endoscopic hemostasis treatment as soon as possible. Gastroscopy can also be performed for asymptomatic or stable children to predict the risk of variceal bleeding and to choose the timing of prophylactic sclerotherapy.

　　4, Selective superior mesenteric artery angiography

　　After inserting a catheter through the femoral artery, selective superior mesenteric artery angiography is performed. Normally, the portal vein can be visualized within 10 to 20 seconds. When portal vein thrombosis occurs, the portal vein cannot be filled. In patients with cavernous angioma-like variations, many small collateral blood vessels can be seen around the occluded portal vein. Possible vascular images may also include: retrograde portal vein blood flow, esophageal varices, and other interportal shunts.

　　It is advisable to eat high-protein, high-sugar, high-vitamin, low-fat, and easily digestible foods such as lean meat, fish, eggs, vegetables, and fruits; appropriately limit the intake of animal fats and oils such as lard.

　　First, supportive treatment

　　1, Pay attention to adequate rest, and in the later stage, bed rest is required.

　　2, Consume high-calorie, high-sugar, moderate-protein, and a variety of vitamins (especially B-group vitamins and A, D, K, and C are more important), easily digestible and non-irritating foods.

　　3. Choose appropriate liver-protecting drugs, with a variety of drugs not to be excessive, especially avoiding drugs that are toxic to the liver, such as phenobarbital, chlorpromazine, tetracycline, isoniazid, and others.

　　Secondly, treat the primary disease

　　1. Primary Disease

　　For active liver cirrhosis caused by viral hepatitis, autoimmune hepatitis (AIH), and other causes, corresponding etiological and pathogenic treatments such as antiviral therapy should be actively carried out during the active compensatory period. The active lesions of hepatitis or progressive liver necrosis should mainly control their development and make them static.

　　2. Drug Treatment

　　Prednisone can be taken orally, and the dose can be reduced after the hepatitis is controlled, and maintenance can be given. At the same time, azathioprine or immunostimulants can be given.

　　3. Treatment of Complications

　　(1) Ascites:

　　① Limit sodium and water intake, with sodium salt limited to less than 0.5g per day, and water intake limited to less than 1L per day.

　　② In necessary cases, blood, plasma, or human serum albumin can be transfused, and appropriate diuretics should be used. Protein in ascites can be applied by autologous reinfusion, and for large amounts of ascites, abdominal fluid ultrafiltration and reinfusion treatment can be used.

　　③ If ineffective, switch to furosemide. However, diuretics should not be used in the case of hepatic encephalopathy to avoid water and electrolyte disorders. Hormones have a certain effect on biliary cirrhosis.

　　(2) Gastrointestinal bleeding:

　　In addition to fasting and injecting vitamin K1, somatostatin can be administered. In cases of massive hemorrhage, whole blood can be infused to replenish blood volume and plasma albumin. In patients with a large spleen and good liver function, splenectomy can be performed.

　　(3) Hepatic Encephalopathy:

　　The treatment of hepatic encephalopathy is comprehensive and multi-link.

　　(4) Hepatorenal Syndrome:

　　Eliminate the causes of renal failure, maintain the balance of intake and output, appropriately and reasonably expand the volume therapy, abdominal fluid filtration and concentration reinfusion, dialysis therapy, and surgical portocaval shunt surgery.

　　3. Liver Transplantation (Liver Transplantation)

　　Artificial liver is an effective method for completely treating liver cirrhosis, especially for liver cirrhosis caused by metabolic liver disease and abnormal development of intrahepatic bile ducts. Due to the limitations of donors, it cannot be carried out on a large scale yet.

　　4. Antifibrotic Treatment

　　Antifibrotic drugs such as colchicine (Colchicine), penicillamine (Penicillamine), gamma interferon, and traditional Chinese medicine preparations can be selected according to the condition.