Fulminant hepatic failure

　　1. Causes of Onset

　　The causes of fulminant hepatic failure are diverse, and can be classified into infectious, toxic, metabolic, infiltrative, autoimmune, ischemic, radiation injury, and idiopathic according to the pathogen.

　　1. Infectious viral infections, especially viral hepatitis, are the most common causes of fulminant hepatic failure in China, with other viruses occasionally discovered.

　　(1) Hepatitis Viruses: There are currently 7 types of hepatitis viruses discovered, namely hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), hepatitis E virus (HEV), hepatitis G virus (HGV, also known as GBV-C), and TTV (TT is the abbreviation of the patient's name in whom the virus was first discovered). HAV infection rarely causes fulminant liver failure, with a risk of about 0.01% to 0.1%. In 1988, there was an outbreak of hepatitis A in Shanghai, China, with more than 300,000 cases reported, and only 25 cases of death among those infected with HAV alone. However, the risk of fulminant liver failure increases significantly when hepatitis A is combined with other chronic hepatitis, especially when combined with chronic active hepatitis B, chronic hepatitis C, or liver cirrhosis, but the prognosis is good for those carrying HBsAg and having hepatitis A. The main cause of fulminant liver failure is the infection of HBV alone or simultaneous infection with HDV. When a G to A point mutation occurs at position 1896 of the pre-C region of HBV, the codon TGG, which originally represented tryptophan, becomes a stop codon TAG, leading to the interruption of the synthesis of the pre-C protein, HBeAg becomes negative, and this mutation strain can cause fulminant hepatitis B with negative HBeAg. Fulminant hepatitis B with positive HBeAg is caused by the wild-type strain. HDV is a defective virus that requires the surface antigen HBsAg of HBV as its viral coat, so HDV infection can be simultaneous with HBV or superimposed infection in chronic HBV carriers, and the risk of fulminant liver failure in HDV carriers is much higher than that in HBV carriers alone. HBV chronic carriers can also develop fulminant liver failure after infection with HDV. The role of HCV in causing fulminant liver failure is not yet clear, and in Japan and other Asian regions, HCV infection may be one of the main causes of fulminant liver failure. Vento et al. in Italy followed up 163 cases of chronic hepatitis B with negative serum hepatitis A antibodies and 432 cases of chronic hepatitis C for 7 years. Among them, 10 cases of chronic hepatitis B and 17 cases of chronic hepatitis C had simultaneous infection with hepatitis A. Among all 77 cases of chronic hepatitis with simultaneous hepatitis A infection, 7 cases of chronic hepatitis C with simultaneous hepatitis A infection developed fulminant liver failure, while no cases of fulminant liver failure occurred among those with chronic hepatitis B and simultaneous hepatitis A infection. In the epidemic areas of hepatitis E, HEV infection can cause fulminant liver failure, with a risk of up to 20% to 40% in pregnant women, especially in the third trimester. In non-pregnant women, HEV infection can also lead to fulminant liver failure. A study in Germany confirmed that among 22 cases of fulminant liver failure, 11 had positive serum GBV-C/HGVRNA.In 7 cases of fulminant hepatitis B, 6 cases were GBV-C/HGVRNA positive, in 10 cases of fulminant non-A and non-E hepatitis, 5 cases were GBV-C/HGVRNA positive, and other authors have also found GBV-C/HGV in a small number of fulminant liver failure patients. According to the analysis of 22 papers reported globally in 1998 by Hadziyannis, the infection rate of GBV-C/HGV in unexplained fulminant liver failure was 20%, but the infection rate of GBV-C/HGV was similar or higher in fulminant hepatitis B, C, and D, so it is inferred that the appearance of GBV-C/HGV in fulminant liver failure is a secondary infection or concurrent infection, rather than the cause of fulminant liver failure. The positive rate of TTVDNA in unexplained fulminant liver failure patients is 19% to 27%, and it can be detected at the onset of the disease, so it cannot be excluded as a cause of fulminant liver failure.

　　(2) Other viral infections: Immunosuppression, immunosuppression, neonates, and AIDS patients infected with other viruses can also lead to fulminant liver failure. For example, herpes simplex virus infection, especially disseminated infection in neonates and immunocompromised individuals, can lead to fatal fulminant liver failure. AIDS patients and immunosuppressed patients infected with varicella-zoster virus can cause varicella hepatitis and fulminant liver failure. There have been 16 reported cases of fulminant liver failure caused by Epstein-Barr virus infection, and immunocompetent individuals can also occur, with a mortality rate as high as 87%. Other viruses such as cytomegalovirus and paramyxovirus infections can also lead to fulminant liver failure.

　　2. Toxicity

　　(1) Idiosyncratic drug reactions: Many drugs can cause fulminant liver failure, among which common drugs include anesthetics such as halothane, isoflurane, methoxyflurane, chloroform, antituberculosis drugs such as isoniazid and rifampicin, antidepressants such as phenelzine and phenytoin sodium, cocaine, chlorpromazine, anticoagulants such as dicoumarol, sulfonamide drugs such as salicylate azosulfapyridine, non-steroidal androgen receptor antagonists Bicalutamide, alcoholism treatment drug disulfiram, recreational drug 'ecstasy', antihypertensive drug hydralazine, antiepileptic drug valproic acid, as well as antithyroid drugs, non-steroidal anti-inflammatory drugs, amphotericin B, methyldopa, cyclophosphamide, 5-fluorouracil, 6-mercaptopurine, sedatives, and others.

　　(2) Toxic Reactions: Acetaminophen (paracetamol) is one of the most common drugs and the main cause of fulminant liver failure in Western and European countries. Under conditions of malnutrition or hunger, the liver glutathione decreases, the sensitivity to the drug increases, and even therapeutic doses of acetaminophen can cause fulminant liver failure. There are also other drugs such as phenacetin and salicylates. Certain chemical toxins and natural toxins can also cause fulminant liver failure, the former including carbon tetrachloride, galactosamine, alcohol, tetracycline, phosphorus, etc., and the latter including certain herbs and poisonous mushrooms (such as Agaricus, Amanita phalloides, Enoki mushrooms, etc.), aflatoxin, bacterial toxins, etc.

　　3, Metabolic:The most common metabolic disease causing fulminant liver failure is Wilson's disease, also known as hepatolenticular degeneration, which can be accompanied by hemolytic anemia or hemolytic crisis, cornea may have Kayser-Fleischer ring, serum transaminase and alkaline phosphatase levels are relatively low, and sometimes there may be blurred vision and cholelithiasis.

　　4, Infiltrative:Including fatty infiltration and tumor infiltration, both of which can lead to the occurrence of fulminant liver failure. Fatty liver infiltration includes acute fatty liver of pregnancy, Reye's syndrome, etc., where a large number of fat droplets occupy most of the volume of liver cells, preventing liver cells from functioning normally. The use of valproic acid or intravenous administration of high-dose tetracycline can also cause similar lesions. Liver tumor infiltration leading to fulminant liver failure is an uncommon manifestation, which can be caused by primary or metastatic liver tumors, including melanoma, malignant lymphoma, small cell lung cancer, urinary tract epithelial cancer, etc. Sometimes, the tumor can spread widely to the liver sinusoids, but no metastatic nodules can be found in the liver, and the clinical manifestation is fulminant liver failure.

　　5, Autoimmune:Autoimmune liver disease refers to a series of immune diseases that affect the liver. This includes autoimmune hepatitis, autoimmune cholangitis, and post-liver transplantation autoimmune hepatitis. Clinical examination may show positive for smooth muscle antibodies, antinuclear antibodies, and liver-kidney microsome antibodies. The first two are mainly due to genetic abnormalities that are prone to produce autoimmune reactions, and the liver autoantigen peptides are recognized by T lymphocytes, resulting in autoimmune injury against the liver. The pathogenesis of post-liver transplantation autoimmune hepatitis is still unclear. A rheumatoid disease called Still's disease, which usually occurs in adults, can sometimes affect the liver and lead to fulminant liver failure.

　　6, Ischemic:Vascular factors rarely cause fulminant liver failure. Liver ischemia can be caused by systemic hemodynamic changes (such as cardiogenic shock, heat stroke, and recurrent arrhythmias, etc.) or local hemodynamic disorders (such as acute prehepatic venous obstruction).

　　7, Radiation injury:Fulminant liver failure caused by radiation injury is not common. Acute radiation sickness or large-dose radiotherapy of the liver locally can also sometimes cause fulminant liver failure.

　　8, Others:Hepatitis B virus carriers may experience deterioration of liver function when treated with interferons and immunosuppressive drugs, which can sometimes lead to fulminant liver failure. In addition, about 1/3 of patients with fulminant liver failure have unknown etiology, and it is generally believed that the etiology of these patients is related to hepatitis viruses, which can be collectively referred to as non-A-G hepatitis.

　　Two, Pathogenesis

　　The pathogenesis of fulminant hepatic failure varies with the etiology. In China, viral hepatitis is the most common cause of fulminant hepatic failure, among which the pathogenesis of hepatitis B is the most extensively studied. It is currently believed that cytotoxic T lymphocytes (cytotoxic T lymphocyte, CTL) are the main effector cells leading to widespread necrosis of hepatocytes. CTL cells attack hepatocytes infected with HBV through a dual recognition mechanism, restricted by the major histocompatibility complex (major histocompatibility complex, MHC) -Ⅰ. The membrane of the attacked hepatocytes needs to express both the HBV membrane antigen HBcAg and MHC-Ⅰ simultaneously, and CTL must also recognize both antigens to bind to target cells and release perforin and other lymphokines to attack and dissolve target cells; CTL cells also have lymphocyte function-associated antigen-1 (lymphocyte function-associated antigen-1, LFA-1) on their surface, and there exists an LFA-1 ligand-intercellular adhesion molecule-1 (intercellular adhesion molecule-1, ICAM-1) on the hepatocyte membrane, allowing hepatocytes to attract CTL cells expressing LFA-1 and make them adhere to hepatocytes, promoting dual recognition between CTL and hepatocytes and enhancing the toxic response of CTL to hepatocytes; the hepatocyte membrane also contains Fas antigen, which can interact with the Fas ligand on the CTL membrane, induce apoptosis of hepatocytes; when the liver is subjected to the above immune injury, its detoxification function is impaired, and endotoxemia is prone to occur, leading to the release of various cytokines by the mononuclear-macrophage system both inside and outside the liver, exacerbating liver damage, among which the most important is tumor necrosis factor (tumor necrosis factor-α, TNF). TNF can bind to the TNF receptor expressed on the hepatocyte membrane, activate proteases and phospholipase A2, induce the production of free radicals, leading to membrane structural damage and DNA breakage, and can also bind to receptors on the sinus endothelial cell membrane, damage sinus endothelial cells, promote the deposition of fibrin and the formation of microthrombi in the sinusoid, causing microcirculatory disorders in hepatocytes and cell necrosis. TNF-? can also induce nitric oxide damage to hepatocytes, and HBV infection can promote the sensitivity of hepatocytes to TNF; in addition, the mutation in the HBV pre-C region interrupts the synthesis of HBeAg, and HBeAg disappears from the serum. Since HBeAg and the CTL target antigen HBcAg expressed on the hepatocyte membrane have cross-reactivity with CTL, the interference and inhibitory effect of HBeAg in the serum on CTL disappear, allowing more CTL to attack HBcAg-positive hepatocytes, leading to the death of a large number of hepatocytes. The pathogenesis of fulminant hepatic failure caused by HCV infection is similar to that caused by HBV infection. The pathogenesis of hepatitis A is also mainly immune reaction, and in the early stage, due to the massive proliferation of HAV in hepatocytes and the toxic effect of CTL cells, liver cell damage occurs together.In the late stage of the disease, the expression of MHC-Ⅰ on the membrane of infected liver cells induced by endogenous gamma interferon promotes the function of CTL, kills liver cells, and clears HAV. The co-infection of HDV and HBV is prone to massive liver necrosis, which may be due to the combined action of the direct pathogenicity of HDV to liver cells and immune pathogenic damage of the body. The liver cell damage caused by HEV infection may be due to cell-mediated immune response. The reason why pregnant women infected with HEV are prone to fulminant liver failure may be related to low levels of serum immunoglobulins or increased sensitivity and reactivity to HEV. The pathogenesis of fulminant liver failure caused by GBV-C/HGV and TTV is still unclear.

　　Direct hepatotoxic drugs can directly damage liver cells, or after transformation by liver cells, their intermediate products have hepatotoxicity. These substances combine with glutathione in the liver to detoxify, and when the glutathione in liver cells is exhausted, liver cell poisoning and necrosis occur; some drugs act as haptens and combine with proteins in the body to form complete antigens, causing immune reactions that result in liver damage. Direct hepatotoxic drugs such as acetaminophen have obvious hepatotoxicity in their intermediate metabolites. In cases of overdose or fasting, the glutathione in the liver is exhausted, leading to liver cell poisoning and death, triggering liver failure. The liver damage caused by such drugs has a clear dose-effect relationship. Specific drugs do not have a clear dose-effect relationship, such as isoniazid, which forms isonicotinic acid and acetylhydrazine through acetylation in the liver. Acetylhydrazine can bind to macromolecules in liver cells and cause cell death. The exact mechanism is not clear and may be related to immune injury caused by the drug as a hapten, or may be related to the intermediate metabolites of the drug, or may be related to the state of the body.

　　Wilson's disease is an autosomal recessive genetic disease, in which the patient's intestines absorb an excessive amount of copper, while the liver can only synthesize a very small amount of ceruloplasmin. The serum copper level increases directly, leading to excessive copper deposition in tissues, causing liver, brain, and kidney tissue damage as well as the formation of the K-F ring in the cornea. The mechanism by which tumor cell infiltration in the liver leads to fulminant liver failure is still waiting for further study. Some researchers have found that in such patients, the necrosis of liver cells is more severe than that of tumor cells, and it is closely related to the degree of invasion of the tumor into the liver sinusoids. Therefore, it is believed that hypoxic necrosis of liver cells is one of the causes of fulminant liver failure caused by tumor liver metastasis. In addition, fulminant liver failure often has endotoxemia, and endotoxins can increase the activity of thymus and activation-regulated chemokine (thymus and activation-regulated chemokine, TARC) in the liver, which has a chemotactic effect on CD4+ helper T cells, causing an increase in the infiltration of CD4+ helper T cells into the liver parenchyma, further aggravating liver cell necrosis.

　　Traditionally, the pathological basis of fulminant hepatic failure was considered to be massive liver necrosis, but recent research has confirmed that the liver pathological changes in fulminant hepatic failure show obvious diversity. Clinically diagnosed as fulminant hepatic failure, the pathological manifestations can be divided into 3 types: massive liver necrosis, submassive liver necrosis, and liver cirrhosis. The massive liver necrosis type shows a significant reduction in liver size, with the capsule showing wrinkles, the liver parenchyma showing patchy coloration, and irregular residual liver tissue can be seen in the cut surface; under the microscope, the disappearance of hepatic cells within the lobules, collapse of the reticular framework, and occasionally narrow liver parenchyma and a small amount of edematous and deformed liver cells around the portal areas and around the liver lobules with bile stasis can be seen, with sparse chronic inflammatory cells, hypertrophied Kupffer cells, and macrophages in the sinusoids, and varying degrees of bile duct hyperplasia in the portal areas. The submassive liver necrosis type shows a lesser degree of liver atrophy, with a fused necrotic area of 30% to 90% in the cut surface, forming varying degrees of submassive liver necrosis; under the microscope, widespread swelling of hepatic cells, common pseudo-acinar transformation, and significant bile stasis can be seen, and giant cell transformation can sometimes be observed, with general hyperplasia of small bile ducts in the portal areas, inflammatory cell infiltration, and sometimes bile ductitis reactions. The liver cirrhosis type shows typical liver cirrhosis features in appearance and cut surface, and under the microscope, varying degrees of inflammatory reactions are shown on the basis of liver cirrhosis.

　　It is noteworthy that the distribution of liver necrosis areas in patients with fulminant hepatic failure and the degree of necrosis in each liver lobe show a highly heterogeneous pattern. The results of liver biopsy at different sites can be completely different, therefore, the value of liver biopsy for diagnosis and prognosis assessment is limited; patients with fulminant hepatic failure showing the same clinical manifestations may have completely different liver tissue pathological manifestations; the number of remaining liver cells may not necessarily determine the survival rate; in addition, fulminant hepatic failure can also occur on the basis of liver cirrhosis.

　　1. Hepatic encephalopathy

　　The pathogenesis of hepatic encephalopathy has not been fully elucidated to date. The related theories include ammonia poisoning, imbalance in the ratio of branched-chain amino acids to aromatic amino acids, the theory of false neurotransmitters, γ-aminobutyric acid theory, and the increase of other neurotoxic substances such as thiol compounds, short-chain fatty acids, glutamine, and α-ketoglutaric acid, which are all related to the occurrence of hepatic encephalopathy. Late-stage hepatic failure can lead to hepatic encephalopathy. Patients with extensive porto-caval collateral circulation or porto-caval shunt surgery may develop hepatic encephalopathy if they consume too much protein or have upper gastrointestinal bleeding.

　　The early symptoms of hepatic encephalopathy include changes in personality, elation or depression, decline in intelligence, changes in sleep habits, and inappropriate behavior, with the most characteristic neurological sign being flapping tremor. In the late stage, coma or delirium may occur. According to clinical manifestations, hepatic encephalopathy can be divided into 4 stages:

　　1、前驱期（Ⅰ期）：轻度性格和行为改变，如沉默、淡漠或兴奋、欣快常无或仅有轻微的神经体征。

　　2、昏迷前期（Ⅱ期）：轻微精神错乱、行为反常、计算、定向及理解力减退。神经体征明显，如反射亢进、肌张力增强、病理反射阳性。出现肝臭和（或）扑翼样震颤。

　　3、昏睡期（Ⅲ期）：以昏睡或浅昏迷为主，各种神经体征持续或加重。少数有极度精神或运动性兴奋。

　　4、昏迷期（Ⅳ期）：呈昏迷状态，对各种刺激均不起反应。

　　二、脑水肿

　　暴发性肝衰竭发生脑水肿的机制尚未完全明了，可能是血管性及脑细胞毒性共同作用的结果，与血-脑屏障的崩解，脑细胞线粒体功能受损，脑细胞膜Na-K-ATP酶受抑制，胆汁酸-内毒素-氨的协同作用，致渗透性氨基酸-牛磺酸/谷氨酰胺在星形胶质细胞内堆集，脑渗透压调节功能受损，细胞外间隙扩大，脑血管内微血栓形成及脑血管对二氧化碳的反应性丧失导致脑阻力血管扩张，脑血流的自动调节功能丧失有关。脑水肿发生后患者昏迷加深，有呕吐、血压升高、视盘水肿等颅内压增高的表现，可有瞳孔扩大、固定及呼吸变慢、心动过缓、锥体束征阳性、踝阵挛，严重者可形成脑疝，如形成中脑幕疝，可出现陈-斯（Cheyne-Stokes）氏呼吸、瞳孔缩小、眼睛向上方凝视及性格改变，如形成大脑中叶勾突幕疝，可出现意识丧失、瞳孔散大固定、半身瘫痪等，如形成小脑扁桃体枕骨大孔疝，可导致意识丧失、呼吸不规则甚至暂停，如不及时治疗可迅速死亡。

　　三、继发感染

　　由于机体免疫功能的减退及侵入性诊疗操作和广谱抗生素的应用等因素，使暴发性肝衰竭患者易于产生继发感染。常见的继发感染包括肺部感染、败血症、尿路感染、胆道及肠道感染、真菌感染等。病原菌以G菌为主，最多见的为金黄色葡萄球菌，其次为表皮葡萄球菌，其他还有肠道菌及厌氧菌等，真菌感染则是导致患者死亡的主要原因之一。患者可出现发热、外周血白细胞计数升高、中性粒细胞分类增加、核左移、病情急剧恶化，并可出现各系统感染的相应症状。

　　四、原发性腹膜炎

　　暴发性肝衰竭发生原发性腹膜炎的原因可能与肠原性细菌易位（translocation）通过胃肠屏障进入血流及机体与腹腔抵抗力下降有关。有资料表明腹水蛋白10g/L者的10倍。原发性腹膜炎的临床特点包括：

　　1. Acute onset without perforation of hollow viscera.

　　2. Fever, usually persistent low fever, but may also have remittent high fever and chills.

　　3. Abdominal pain may occur, bowel sounds may be reduced, and there may also be muscle tension and rebound pain, but most are mild.

　　4. Rapid increase in abdominal fluid, poor diuretic effect.

　　5. The abdominal fluid is yellowish and turbid, Rivalta test positive, the leukocyte count in abdominal fluid >0.5×10^9/L, neutrophil count >50%, or polymorphonuclear leukocyte count >0.25×10^9/L is of diagnostic significance. Abdominal fluid culture should be performed by bedside inoculation of 10ml into blood culture bottles to increase the positivity rate.

　　6. The positivity rate of blood culture is 40% to 60%, and urine culture also has a certain positivity rate.

　　7. Elevated peripheral blood leukocyte count, increased neutrophil count, but the leukocyte count may not increase in patients with pre-existing splenic hyperfunction.

　　5. Hepatorenal syndrome

　　Hepatorenal syndrome occurs after severe liver cell necrosis, leading to portal hypertension, increased peripheral vasodilatory substances, decreased peripheral vascular resistance, and relative reduction in effective blood volume, resulting in increased activity of the renin-angiotensin-aldosterone system, sympathetic nervous system, and increased secretion of antidiuretic hormone, producing ascites and edema as well as renal vascular constriction, exceeding the compensatory function of renal function, leading to functional renal insufficiency. Hepatorenal syndrome in patients with fulminant hepatic failure is often acute, occurring in patients with severe liver dysfunction and ascites, or in patients with hepatic encephalopathy, bacterial infection, or bleeding, manifested by oliguria or anuria, rapid increase in plasma urea nitrogen and creatinine levels, normal or slightly abnormal urine routine examination, urine/plasma osmolality ratio >1.0, urine sodium concentration of 30, often accompanied by ascites, dilute hyponatremia, hypotension, and jaundice, and no sustained improvement can be obtained after volume expansion treatment.

　　6. Upper gastrointestinal bleeding

　　Patients with fulminant hepatic failure have obvious coagulation mechanism disorders, plus the formation of portal hypertension, reduced inactivation of substances such as gastrin and histamine by the liver leading to increased gastric acid secretion, endotoxemia, and other factors, which are highly susceptible to upper gastrointestinal bleeding. The most common cause of upper gastrointestinal bleeding in patients with fulminant hepatic failure is acute diffuse gastric mucosal erosion, while bleeding from esophageal varices rupture is less common. Bleeding is often sudden, with no obvious prodromal signs, and a few patients may have frequent hiccups, manifesting as sudden vomiting of a large amount of fresh blood, with a rapid drop in blood pressure and entering a shock state. After bleeding, the patient's pre-existing liver damage is further exacerbated, jaundice progresses, prothrombin time is further prolonged, and severe complications such as hepatic encephalopathy, hepatorenal syndrome, or primary peritonitis may occur within a few days. Upper gastrointestinal bleeding is the most common fatal complication of fulminant hepatic failure and is also the cause of other severe complications.

　　7. Coagulation dysfunction

　　The causes of coagulation dysfunction in fulminant hepatic failure are related to the following factors:

　　1. Decreased production or excessive consumption of coagulation factors.

　　2. Thrombocytopenia and dysfunction.

　　3. Disseminated intravascular coagulation (DIC).

　　4. Abnormalities of the anticoagulation system in the blood.

　　5. Formation of ineffective abnormal fibrinogen.

　　6. Abnormalities of vitamin K-dependent coagulation factors.

　　The incidence of bleeding in fulminant hepatic failure reaches 73%, of which severe bleeding is 30%. The most common site of bleeding is the gastrointestinal tract, other sites include the nasopharynx, lung, retroperitoneum, kidney, injection sites, etc. Intracranial hemorrhage is rare but severe. DIC causes widespread microthrombosis in capillaries and small blood vessels, leading to excessive consumption of coagulation factors and platelets, followed by secondary fibrinolysis, resulting in more severe bleeding. Clinical manifestations include widespread bleeding of the skin and mucous membranes, and can cause circulatory failure and dysfunction of important organs such as the kidney and brain, accelerating death.

　　Eighth, respiratory failure and hepatopulmonary syndrome

　　About 30% of patients with fulminant hepatic failure develop adult respiratory distress syndrome (ARDS), with symptoms such as tachypnea, tachycardia, cyanosis, irritability, and progressive worsening. The respiratory rate can exceed 35 times/min, and sputum resembling blood may occur. Routine oxygen therapy is difficult to alleviate. Early cardiopulmonary examination may show no abnormalities, but as the condition progresses, moist? sounds and wheezing sounds as well as inspiratory crackling sounds can be heard. In the later stage, signs of lung consolidation may appear. X-ray examination may show no abnormalities or mild increase in pulmonary markings in the early stage, while patchy or large areas of shadow may appear in the middle and late stages, even presenting as 'white lung'. Blood gas analysis shows a decrease in arterial oxygen partial pressure

　　Hepatopulmonary syndrome is a concept proposed in the past 10 years, referring to severe hypoxemia caused by pulmonary arteriovenous shunting and arterial oxygenation dysfunction due to pulmonary vascular dilation caused by the basic lesions of the liver. The cause may be due to the reduced inactivation of pulmonary vascular dilating substances in the liver, leading to increased intracellular cAMP and cGMP levels, resulting in the loss of pulmonary vascular hypoxia contraction function and dilation. Clinically, there are symptoms such as cyanosis, clubbing, portal hypertension, and hyperdynamic circulation. Orthodeoxidation (orthodeoxidation) may occur (referring to a decrease in PaO2 by more than 10% when the patient changes from a supine position to an upright position) and platypnea (referring to shortness of breath when the patient changes from a supine position to an upright position, which is relieved when lying down). Blood gas analysis is characterized by a decrease in PaO2, with mild cases where PaO2 can also be normal, but a significant increase in the alveolar-arterial oxygen pressure difference >2.0 kPa. Chest X-rays may be normal or nodular due to increased interstitial density, and contrast-enhanced echocardiography can detect pulmonary arteriovenous dilation. A whole-body scan with 99technetium-macroaggregated albumin can detect the presence of extrapulmonary organs.

　　Ninth, hypoproteinemia

　　Due to massive liver cell necrosis during fulminant hepatic failure, the synthesis function of albumin fails. Since the half-life of albumin in the body is 13 days, if the patient recovers or dies within 2 weeks, the serum albumin level can remain normal or at the original level. If the course of the disease exceeds 2 weeks, due to the gradual decomposition of albumin in the body and the minimal synthesis of albumin by the liver, hypoproteinemia may occur.

　　Tenth, cardiovascular and hemodynamic abnormalities

　　The cardiovascular system complications during fulminant liver failure mainly include intrinsic heart damage, hyperdynamic circulation, and acute portal hypertension. The intrinsic heart damage may be mainly due to the invasion of the virus into the heart and the obstruction of the coagulation mechanism leading to hemorrhagic damage to the heart, which is manifested as arrhythmias and changes in the electrocardiogram, such as bradycardia, ventricular escape, atrioventricular block, and ST-T changes. The mechanism of hyperdynamic circulation is not yet clear and may be related to the increase of vasodilatory substances in the circulation, widespread shunting of blood flow, and increased production of nitric oxide. The clinical manifestations include warm skin, prominent capillary pulsation at the fingertips, large pulse, hypotension, and shortening of the circulatory time. This hyperdynamic circulation, combined with pulmonary shunting leading to insufficient oxygenation, is极易引起组织缺氧，加重各脏器的损害。Acute portal hypertension is due to the collapse of hepatic sinus due to widespread liver cell necrosis, the narrowing of hepatic sinus due to liver cell edema, reducing the intraluminal space of the liver blood vessels, and the obstruction of hepatic blood circulation. In addition, hyperdynamic circulation increases the blood flow of portal vein, causing portal vein pressure to exceed 1.33 kPa (10 mmHg), forming acute portal hypertension. Acute portal hypertension is often lower in pressure than chronic portal hypertension.

　　Eleven, hypoglycemia, electrolyte and water balance disorders, and acid-base imbalances

　　About 40% of patients with fulminant liver failure have severe hypoglycemia, the pathogenesis of which includes impaired gluconeogenesis, reduced insulin inactivation, reduced glycogen reserve in liver cells, and impaired glycogen mobilization, which is common in children. Hypoglycemia can appear rapidly and is often misdiagnosed as hepatic encephalopathy, and can also exacerbate hepatic encephalopathy and cerebral edema. Generally speaking, liver failure patients should be supplemented with at least 300g of glucose per day. When blood glucose levels fall below 3.5 mmol/L, 50% glucose 50-100ml should be administered intravenously immediately, and as much as possible, use hypertonic (30% to 50%) glucose solution to reduce water intake.

　　Due to the effects of the renin-angiotensin-aldosterone system and antidiuretic hormone, among others, the reabsorption of sodium by the kidneys increases during liver failure. However, due to severe water retention, patients often experience dilute hyponatremia with unclear clinical manifestations; in the early stage of liver failure, patients often also suffer from hypokalemia, and in the later stage, refractory hyperkalemia appears due to renal dysfunction. In addition, due to reasons such as vomiting and the use of potent diuretics, hypochloremia can worsen metabolic alkalosis, induce hepatic encephalopathy, and hypocalcemia and hypomagnesemia can also be seen. Various acid-base imbalances can occur during liver failure, the most common being respiratory alkalosis, followed by metabolic alkalosis or the combination of respiratory alkalosis and metabolic alkalosis. In the late stage, respiratory alkalosis combined with metabolic alkalosis and metabolic acidosis can occur. Generally speaking, in the early stage of liver failure, due to hypoxemia, hyperammonemia, hypokalemia, anemia, and other reasons, the respiratory center is stimulated to cause excessive ventilation, leading to respiratory alkalosis. With the progression of the disease, the exacerbation of hypokalemia, excessive alkaline supplementation, and the use of sodium glutamate and other alkaline deaminating drugs can lead to the combined occurrence of respiratory alkalosis and metabolic alkalosis on the basis of respiratory alkalosis. In the late stage of the disease, due to the accumulation of acid caused by the combined complications of infection, liver-kidney syndrome, hemorrhage, shock, and hypoxia, metabolic acidosis can occur on the basis of hyperalkalemia + metabolic alkalosis.

　　Twelfth, acute pancreatitis

　　In the autopsy of patients with fulminant hepatic failure, it was found that about 1/3 had concurrent hemorrhagic necrotizing pancreatitis, the mechanism of which is unknown. Some people have calculated that the incidence of acute pancreatitis in patients with fulminant hepatic failure reaches 23% to 33%. Due to the patient's coma, pre-death diagnosis is extremely difficult, and once it occurs, it is sufficient to be fatal. Regular detection of blood amylase in patients with fulminant hepatic failure may help with diagnosis, but only 1/3 of patients have elevated amylase levels.

　　1. Manifestations of the primary disease:Depending on the etiology, there may be related clinical manifestations, such as liver facies, liver palms, and skin vascular spider angiomata in fulminant hepatic failure occurring on the basis of chronic liver disease or liver cirrhosis, corresponding toxic manifestations in those caused by intoxication, corneal K-F rings in those caused by Wilson's disease, and primary tumor manifestations in those caused by tumor infiltration.

　　2. Manifestations of liver function failure:Jaundice deepens rapidly in a short period of time, accompanied by明显升高 of serum transaminases, significant prolongation of prothrombin time, and significant decrease in activity; In the early stage of the course, there may be low fever, and if the low fever persists, it indicates sepsis or persistent liver cell necrosis; The overall condition is extremely poor, such as poor appetite, extreme fatigue, restlessness, and so on; There are persistent hiccups, nausea, vomiting, and obvious abdominal distension; There is a significant tendency to bleed, which may appear subcutaneous petechiae, ecchymosis, which is more obvious at the injection site, and may have gingival hemorrhage, nosebleed, and in severe cases, upper gastrointestinal bleeding; Ascites appears rapidly, and those with a course of more than 2 weeks generally have ascites and hypoalbuminemia; The liver tends to shrink progressively during physical examination; Liver odor may appear; Manifestations of hepatic encephalopathy may appear, such as changes in personality, reversal of diurnal rhythm, repetition of speech, excessive excitement, peculiar behavior, urinating anywhere, etc., and in severe cases, there may be consciousness disorders; Other neurological and psychiatric abnormalities may include increased muscle tone, positive pyramidal tract signs, patellar and/or ankle clonus, disorientation, and calculation disorders; There may also be tachycardia and hypotension.

　　3. Manifestations of complications:The clinical manifestations of fulminant hepatic failure are variable due to the diversity of its complications.

　　In China, 85% to 90% of fulminant hepatic failure is caused by fulminant viral hepatitis. In Europe and America, except for the UK, the situation is similar. In the UK, drug intoxication accounts for about 50%. In a group of 188 cases of fulminant hepatitis (acute severe hepatitis) in the United States in 1979, hepatitis B accounted for 50%, hepatitis C accounted for 34%, hepatitis A accounted for 2%, and mixed infection of hepatitis A and B accounted for 2%. According to a group of data from China, among 121 cases of fulminant hepatitis confirmed by pathology, hepatitis A accounted for 0.8%, hepatitis B accounted for 81.8%, hepatitis C accounted for 14.9%, and mixed infection of hepatitis A and B accounted for 2.5%. It can be seen that in China, the vast majority of cases are caused by hepatitis B. However, the situation in Japan is different. According to the report of Yssutoshi et al., hepatitis C virus infection accounts for 63% (17/27) of fulminant hepatitis, therefore, fulminant hepatic failure caused by hepatitis C should not be ignored.

　　Recent research believes that HBV infection can directly cause fulminant hepatic failure and can also develop from asymptomatic chronic carriers. The mutations in the HBV infection group are closely related to the occurrence of fulminant hepatic failure, often being the pre-C mutation of HBV-DNA, producing a stop codon, stopping the production of HBeAg. The absence of HBeAg can increase the host's immune response to infected liver cells and cause fulminant hepatic failure. In addition, in many patients with only HBsAg positive in serological markers, serological examination has confirmed the presence of HDV infection in the development of FHF, indicating that this viral infection is also prone to cause fulminant liver injury.

　　1. Biochemical examination:

　　1. Liver function test:Serum bilirubin levels are often significantly elevated, and some patients may show a rapid increase. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are significantly elevated, and ALT/AST

　　2. Blood ammonia detection:It is still one of the important indicators reflecting hepatic encephalopathy and should be checked regularly.

　　3. Renal function examination:It can reflect the degree of kidney damage. Since urea is synthesized in the liver, in cases of severe liver injury, blood urea nitrogen may not increase, and blood creatinine levels can better reflect kidney function.

　　4. Electrolyte measurement:It helps detect electrolyte disorder in a timely manner.

　　5. Blood gas analysis:It can detect acid-base imbalance and hypoxemia early, facilitating timely treatment.

　　6. Alpha-fetoprotein measurement:In the later stage of the disease, if it increases, it indicates the regeneration of liver cells.

　　7. Measurement of serum cholesterol and cholesterol esters:Cholesterol in patients with fulminant hepatic failure is significantly reduced, and in severe cases, it may even drop to an undetectable level. Cholesterol esters are often lower than 40% of total cholesterol.

　　8. Blood glucose measurement:It can detect hypoglycemia in a timely manner.

　　9. Gc protein measurement:Gc protein is an alpha globulin synthesized by the liver, one of whose main functions is to clear actin released by necrotic liver cells. During fulminant hepatic failure, Gc protein is significantly reduced, and if it is below 100mg/L, it indicates poor prognosis.

　　10. Others:Regular measurement of amylase can help detect pancreatitis in a timely manner. Blood amino acid analysis can detect the decrease in the ratio of branched-chain amino acids to aromatic amino acids in a timely manner, which should be corrected in time to prevent and treat hepatic encephalopathy.

　　2. Hematology examination:

　　1. Routine blood test:The speed of hemoglobin decrease can be used to judge the degree of hemorrhage and the effectiveness of hemostatic treatment. White blood cell count and classification often significantly increase during fulminant hepatic failure, and platelet examination is also helpful for the judgment of the condition.

　　2, Prothrombin time and activity:is the most valuable indicator reflecting the degree of liver damage. In severe liver cell damage, the coagulation factors in the blood decrease rapidly, causing prolonged prothrombin time and decreased activity.

　　3, Detection of coagulation factors:If coagulation factor V

　　4, Other:DIC-related examinations can be performed if necessary.

　　Three: Microbiological and immunological examination

　　1, Examination related to viral hepatitis:Including the detection of anti-HAV-IgM, HBsAg, anti-HBs, HBeAg, anti-HBe, anti-HBc, anti-HBc-IgM, HBV-DNA, DNA polymerase, anti-HCV, HCV-RNA, HDV-RNA, anti-HEV, GBV-C/HGV-RNA, TTV-RNA, and the detection of antibodies against cytomegalovirus and E-B virus.

　　2, Bacteriological examination:According to the need, blood culture, urine culture, stool culture, sputum culture, and ascites culture should be performed. Emphasis should be placed on bedside inoculation with blood culture bottles for ascites culture, and fungal smear microscopy and culture should be performed if necessary.

　　3, Endotoxin detection:The limulus test can be performed.

　　4, Immunological examination:The detection of autoantibodies includes antinuclear antibodies, antismooth muscle antibodies, antimitochondrial antibodies, etc., as well as the detection of serum total complement and complement C3, and the detection of circulating immune complexes.

　　Four: B-type ultrasonic examination:Observe the size of the liver and exclude bile duct obstruction and gallbladder disease.

　　Five: Electroencephalogram waveform:Consistent with clinical practice, the amplitude increases and the frequency slows down with the severity of the disease. It is divided into A to F six levels, with A level being normal electroencephalogram, the patient is conscious, and B to D levels have increased amplitude and slowed frequency, with the patient being confused (B level), rigid (C level), and comatose (D level). The D level presents with a triphasic wave of hepatic encephalopathy, which is a high-voltage, slower diffused triphasic wave. The E level has reduced amplitude and unchanged frequency, with the patient in deep coma. The F level has complete cessation of electroencephalographic activity.

　　Six: Intensive care:It can detect arrhythmia, changes in blood potassium, and breathing, as well as abnormal blood pressure in a timely manner.

　　Seven: CT:It can observe the changes in liver size and make comparisons before and after, and also observe the condition of brain edema.

　　Eight: Magnetic resonance examination:Magnetic resonance spectroscopy (magnetic resonance spectroscopy) determines the concentration of lactate in the brain, and an increased lactate level in the brain suggests a poor prognosis.

　　Nine: Liver nuclear scan:After injection of 99mTc-labeled galactosyl diethylenetriamine pentaacetic acid human serum albumin (99mTc-GSA), computer acquisition of gamma camera is performed to observe the binding of 99mTc-GSA to the liver receptors, which is helpful in judging the reserve of liver function and prognosis.

　　10. Epidural intracranial pressure monitoring:It is generally recommended to install it when the encephalopathy is Ⅲ-Ⅳ grade, used for monitoring intracranial pressure, and after treatment, the intracranial pressure should be lower than 2.7kPa (20mmHg).

　　Dietary care:The patient's intestinal peristalsis recovered on the second day after surgery, and was advised to try drinking water. Gradually transition from liquid food to normal food according to the condition, and maintain a certain amount of calories each day. Instruct the family to provide a diet high in protein, carbohydrates, and fiber, with low residue and low fat, and adopt a method of eating small meals frequently and drinking plenty of water.

　　1. Basic supportive treatment:Patients with fulminant liver failure should ensure adequate energy intake, ensuring that daily calorie intake reaches more than 2000kcal to reduce protein catabolism in the body. Each day should be infused with 10% glucose 1500-2000ml intravenously. The appropriate use of fat emulsion can improve the patient's negative nitrogen balance, but it should be infused slowly, and 500ml of 10% fat emulsion can be infused over a period of not less than 4 hours. Fresh plasma, human serum albumin, or whole blood should be infused once a day or every 2-3 days according to the situation. Since the administration of blood products may cause the aggravation of hepatitis B virus (HBV) and hepatitis C virus (HCV) and other hepatitis viruses, strict screening of blood products should be carried out. When encephalopathy occurs, the intake of protein in the diet should be controlled at less than 40g/d. Potassium magnesium aspartate has the effects of promoting liver cell metabolism, improving liver function, reducing bilirubin, and maintaining electrolyte balance, and can be infused slowly intravenously by adding 10-20ml to 250-500ml of 5%-10% glucose. Glycyrrhizin类药物 such as Qiangliyin, glycyrrhizin disodium (Ganlixin), and glycyrrhizin/ glycine/L-cysteine (compound glycyrrhizin) can inhibit liver inflammation, which may reduce liver cell necrosis and alleviate the condition. Prostaglandin E1 can dilate liver blood vessels, improve liver blood circulation and liver function, but its efficacy has not been universally recognized. Some people believe that the drug is ineffective after 10 days of onset. N-acetylcysteine is a non-toxic glutathione precursor that can increase ornithine cyclase activity, increase tissue oxygen utilization, reduce the occurrence of multiple organ failure, and improve survival rate, and is often used for fulminant liver failure caused by Wilson's disease. The growth factor for liver cells has a very high plasma content in patients with fulminant liver failure, but the expression of its receptor c-met is significantly reduced, so the supplementation of exogenous growth factor for liver cells may be ineffective.

　　The effect of glucagon/insulin therapy on promoting liver cell regeneration has not been universally recognized. Early application of prednisolone (Prednisolone) and azathioprine for autoimmune hepatitis seems effective, but the treatment effect of immunosuppression is very poor when fulminant liver failure occurs, and liver transplantation is the only effective treatment method. The efficacy of other immunosuppressants or immunomodulators such as cyclosporine, tacrolimus, or ursodeoxycholic acid needs further confirmation. Recently, some people have reported that ciprofloxacin (ciprofloxacin) at 100mg/kg can promote liver regeneration in animals with fulminant liver failure, but there are no clinical application reports.

　　The treatment of complications

　　The treatment of hepatic encephalopathy: avoid forceful diuresis, control infection, control upper gastrointestinal bleeding, prohibit the use of sedatives, lower blood ammonia, strictly limit protein in the diet, traditional hypotensive drugs are not effective, sodium glutamate can worsen cerebral edema and fluid and sodium retention, and cannot pass through the blood-brain barrier. Arginine cannot exert its due effect due to the lack of arginase in liver cells during liver failure and the disorder of ornithine cycle. Lactulose is one of the basic drugs for the treatment of hepatic encephalopathy, which can be decomposed into lactic acid in the colon, acidify the intestinal environment, reduce the absorption of ammonia, promote intestinal peristalsis, and accelerate the excretion of toxic substances in the intestines. The usual dose is 80～160ml/d of 50% lactulose solution, taken 3～4 times, to maintain 3～4 loose stools per day and a stool pH<6. Branched-chain amino acids may have a certain effect on correcting amino acid imbalance and alleviating hepatic encephalopathy. In addition, it can also be tried by intravenous infusion of levodopa 200～400mg/d.

　　The treatment of cerebral edema includes: raising the head to 30°, increasing ventilation to maintain the partial pressure of carbon dioxide at 3.3～4kPa (25～30mmHg), avoiding causes that increase intracranial pressure such as coughing, vomiting, and the use of vasodilator drugs, controlling fever, hypertension, and agitation, avoiding excessive fluid infusion, correcting hypercapnia and severe hypoxemia, and also allowing the patient to hyperventilate, keeping the partial pressure of carbon dioxide in arterial blood at 3.3～4kPa (25～30mmHg). Low-temperature therapy. Mannitol is the main method for treating cerebral edema. When the intracranial pressure rises to 2.7～3.3kPa (20～25mmHg), if the plasma osmolality is <320mOsm/L, mannitol 0.5～1g/kg should be rapidly administered intravenously within 5 minutes, and repeated application should be used to prevent the rebound of intracranial pressure. If the plasma osmolality ≥320mOsm/L, it is not suitable to use mannitol. In patients without urine, mannitol is only suitable for hemodialysis or continuous arteriovenous blood filtration. If repeated application of mannitol and other comprehensive treatments is ineffective, consideration should be given to using pentobarbital 100～150mg, administered intravenously every 15 minutes for a total of 4 times, followed by a continuous intravenous infusion of 1～3mg/(kg·h). If the patient's cerebral edema continues to worsen, emergency liver transplantation should be performed.

　　After the diagnosis of secondary infection is established, if there is no bacterial drug sensitivity basis temporarily, it is generally preferred to use broad-spectrum antibiotics for treatment, such as ceftriaxone (ceftriaxone) 1～2g, once daily intravenous infusion, or gentamicin combined with piperacillin, or aztreonam combined with vancomycin. The dose should be adjusted in a timely manner according to the degree of renal injury. After the results of bacterial culture and drug sensitivity come out, the adjustment should be made according to the drug sensitivity results. For fungal infections, it is recommended to use fluconazole (fluconazole) and itraconazole (itraconazole) for treatment. The dosage of fluconazole is 400mg for the first dose in adults, followed by 200～400mg/d, for a course of 7～14 days.

　　3. The treatment of primary peritonitis includes:

　　(1) General support and liver protection treatment.

　　(2) Application of antibiotic treatment: When the white blood cell count in ascites is greater than 1×10^9/L or neutrophils are greater than 0.5×10^9/L; or clinical symptoms are consistent, with a white blood cell count in ascites greater than 0.5×10^9/L or neutrophils greater than 0.25×10^9/L; or clinical symptoms are typical regardless of the ascites cell count; antibiotic treatment should be applied in all these cases. The bacteria causing peritonitis are mainly intestinal flora, and it is generally recommended to use third-generation cephalosporins, such as cefotaxime 2g, once every 8 hours, or ceftriaxone (ceftriaxone) 2g, once daily. For patients allergic to beta-lactams, a drug effective against G+ cocci (such as vancomycin or clindamycin) should be used in combination with a drug effective against G- bacilli (such as aztreonam, aminoglycosides, or quinolones).

　　(3) Diuresis: Spironolactone (Antisterone) and furosemide can be used, which play an important role in increasing the protein concentration of ascites, improving the调理activity and complement components of ascites, and enhancing the resistance of ascites.

　　4. Hepatorenal syndrome:The patient's kidneys do not have organic lesions, and the key to treatment lies in improving liver function. Other treatments include correcting hypovolemia, which can be administered intravenously with 500-1000ml of fluid within 1 hour. If urine output increases to more than 30ml/h, continue to rehydrate, but be cautious not to overhydrate and cause pulmonary edema; prevent triggering factors such as strong diuresis, large volume paracentesis, electrolyte imbalance, hemorrhage, infection, the use of nephrotoxic drugs, and the use of non-steroidal anti-inflammatory drugs such as indomethacin that inhibit prostaglandin synthesis; limit the intake of fluids, sodium, potassium, and protein; use vasoactive drugs, which can be continuously administered intravenously with dopamine at a dose of 2-4?g/(kg?h) to increase renal blood flow, or use captopril (thiopropyl alanine) 12.5-25mg, twice daily, other drugs such as 8-ornithine vasopressin (Ornipressin) and calcium channel blockers such as verapamil (isoptin), indomethacin (心痛定), nimodipine, etc. can also be tried; for appropriate cases, early dialysis treatment can be applied, which has a certain therapeutic effect on alleviating the condition; for patients who do not respond to conservative treatment, LeVeen peritoneal fluid-venous return catheterization can be performed when conditions are met, using a unidirectional piston silicone catheter to drain peritoneal fluid from the peritoneal cavity to the external jugular vein. The surgery is simple with low risk and has a relatively persistent therapeutic effect, and liver transplantation can also be performed.

　　5. Upper gastrointestinal bleeding:The prognosis is severe, therefore, prevention is very important. For patients with fulminant liver failure, acid-inhibiting drugs such as ranitidine, a H2-receptor antagonist, 150mg, twice daily by oral administration, or proton pump inhibitor omeprazole 20mg, twice daily by oral administration, should be given; fresh plasma transfusion should be performed early to supplement coagulation factors; propranolol, a beta-receptor blocker, 10mg, three times daily by oral administration, can reduce portal vein pressure and prevent bleeding caused by portal hypertension gastritis.

　　Once upper gastrointestinal bleeding occurs, effective measures should be taken in a timely manner:

　　(1) Actively supplement blood volume and coagulation factors.

　　(2) Hemostatic measures: famotidine 40mg, twice daily by intravenous push or omeprazole 40mg, twice daily by intravenous push, to maintain the pH in the stomach >6; thrombin 2000U mixed with a small amount of water for oral administration, once every 30 to 60 minutes, reduce the dose after hemostasis; thrombinase (Lishizhi) 1 to 5kU, intravenous injection; local spraying of thrombin or Monsell solution under endoscopy; norepinephrine 4 to 8mg added to 100 to 150ml of cold physiological saline for oral administration, repeat after 10 to 15 minutes, and aspirate gastric juice to observe the hemostatic effect, give up if there is no effect for 3 to 4 times; vasopressor drug posterior pituitary hormone 5 to 10U added to 100ml of 10% glucose for slow intravenous infusion, with certain efficacy: ③ Prevention and treatment of complications: it is necessary to promptly clear the intestinal blood clots, acidify the intestinal environment, appropriately apply antibiotics for treatment, and prevent the occurrence of hepatic encephalopathy and primary peritonitis.

　　6. Treatment of DIC in fulminant liver failure:There is still controversy about the use of heparin. Some people believe that the early and large-scale use of heparin cannot reduce the incidence of bleeding, but may even worsen or cause bleeding. Some people also believe that for patients with no obvious bleeding signs in clinical practice but with DIC indicated by laboratory tests, heparinization should be performed, with a common dose of heparin 0.5 to 1mg/kg, added to 250 to 500ml of 5% to 10% glucose for intravenous infusion, once every 4 to 6 hours, to maintain the coagulation time (test tube method) at 20 to 30 minutes. In addition, fresh whole blood or plasma can be administered to supplement coagulation factors, preferably fresh blood taken at the time of collection.

　　7, Treatment of ARDS:Firstly, ventilation should be improved. The commonly used positive end-expiratory pressure (PEEP) is not suitable for patients with fulminant hepatic failure and ARDS because PEEP can reduce hepatic arterial blood flow, cause a decrease in cardiac output and other hemodynamic changes, and can also trigger cerebral edema. Intermittent positive pressure ventilation (IPPV) can achieve a relatively satisfactory therapeutic effect; in addition, active control of pulmonary edema should be carried out, and large doses of adrenal cortical hormones should be used early, and DIC should be prevented and treated, as well as the supplementation of exogenous pulmonary surfactant. In terms of the treatment of liver-lung syndrome, liver transplantation is relied upon, and the condition can be significantly improved after liver transplantation. The use of pulmonary vasoconstrictors has not shown significant efficacy, and some reports have indicated that the treatment with garlic can significantly improve arterial oxygenation function, which needs further confirmation.

　　8, Cardiac lesions in fulminant hepatic failure:The most common change is hemorrhagic, mainly caused by coagulation dysfunction, which can be prevented by supplementing coagulation factors and hemostatic treatment. Electrocardiogram monitoring should be performed for arrhythmias, correcting acid-base imbalance and electrolyte disorders, and using anti-arrhythmic drugs for treatment. There is currently no satisfactory therapy for hyperdynamic circulation, and blood volume can be appropriately supplemented, and dopamine and other vasoactive drugs can be used as needed to ensure effective cerebral blood perfusion. The treatment for acute portal hypertension can be tried with propranolol, which can reduce cardiac output and reduce hepatic arterial blood flow to lower portal pressure. Prazosin, a 1-antagonist, can also lower portal pressure by reducing hepatic vascular resistance. Due to hyponatremia in liver failure, if blood sodium is >120mmol/L and there are no neurological symptoms, sodium supplementation may not be required intravenously. When blood sodium is <120mmol/L and neurological symptoms appear, 200-300ml of 3%-5% sodium chloride can be supplemented intravenously per day, and recovery can be achieved in 7-10 days; when hypokalemia occurs, if blood potassium is <3.0mmol/L and there is no oliguria, potassium chloride 3-6g/d can be taken orally. If oral potassium supplementation does not improve, intravenous potassium chloride 1-2g/d can be supplemented. Potassium supplementation must be cautious in asymptomatic patients to avoid fatal hyperkalemia, and even without potassium supplementation, using potassium-sparing diuretics can also lead to fatal hyperkalemia. Therefore, blood potassium levels must be frequently monitored, and potassium supplementation and potassium-sparing diuretics should be immediately stopped when hyperkalemia occurs. Intravenous injection of 20ml of 10% calcium gluconate, 100ml of 50% glucose plus 10U of insulin, intravenous infusion of 5% sodium bicarbonate, and the use of high-dose furosemide should be considered. Dialysis treatment may be necessary if needed; for early respiratory alkalosis, the main treatment should be the correction of excessive ventilation, and oxygen should be inhaled to correct hypoxemia if necessary. When combined with metabolic alkalosis, hypokalemia and hypochloremia should be corrected, and 20-40g of L-arginine hydrochloride can be supplemented intravenously per day. For late-stage respiratory alkalosis combined with metabolic alkalosis and acidosis, the main treatment should be the active correction of electrolyte disorders, and it is strictly forbidden to use acidic or alkaline drugs blindly.

　　3. Liver Function Support Treatment

　　1. Artificial Liver Support Therapy:Liver transplantation as an effective treatment for fulminant hepatic failure is limited by the scarcity of donor livers, high costs, relatively high mortality, and the need for lifelong immunosuppressive drug use. Moreover, sometimes the patient's condition does not allow waiting for the arrival of the donor liver. Therefore, artificial liver support therapy can extend the survival period of these patients until the donor liver arrives. In addition, since fulminant hepatic failure is a potentially reversible disease, artificial liver support therapy can help patients through the critical period and enter the recovery period. Some even believe that the survival rate of artificial liver support therapy reaches 55.2%, which can achieve similar efficacy to liver transplantation.

　　Early liver function support treatment includes total body washout, cross-circulation between patients and animal livers, splenic liver transplantation to make the spleen liver-like, and detoxification systems such as blood adsorption perfusion, hemodialysis, and plasma removal (plasmapheresis). Among these methods, only the detoxification system has a certain therapeutic effect on liver failure. It has now developed into bioartificial liver, which is assembled from the tissues or cells of allogeneic or xenogeneic donor livers and biocompatible materials. The core is an extracorporeal circulation device for cultured liver cells, known as a bioreactor. When the patient's blood passes through the bioreactor, it exchanges substances with the cultured liver cells through a semi-permeable membrane with a molecular retention of 70,000 to 100,000 (hollow fiber type) or directly (multilayer plate type, encapsulated bed type) to achieve the effect of artificial liver support. Some people also encapsulate liver cells in semi-permeable microcapsules and implant them in the peritoneal cavity, where they can exert the function of liver cells within 6 to 8 weeks. Since the liver cells do not come into contact with the immune system, immunosuppressive drugs are not required. Studies have shown that maintaining normal liver function requires at least 20% of the liver, while the most widely used hollow fiber type artificial liver can only reach 5% of normal liver function, so artificial liver support therapy cannot completely replace liver transplantation.

　　2. Liver Transplantation Treatment:

　　(1) Orthotopic Liver Transplantation (orthotropic liver transplantation): Orthotopic liver transplantation is currently the most effective method for treating fulminant hepatic failure. It is generally believed that liver transplantation is indicated for patients with chronic liver diseases or metabolic disorders with a life expectancy of less than one year or an unacceptable quality of life, including primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, chronic viral hepatitis, biliary atresia, metabolic diseases, fulminant hepatic failure, alcoholic cirrhosis, and inoperable liver malignancies without vascular invasion and extrahepatic metastasis. Due to the strong regenerative capacity of the liver, it is difficult to determine the indications for liver transplantation in fulminant hepatic failure. It is generally believed that liver transplantation should be performed for patients with fulminant hepatic failure with poor prognosis. The currently more commonly used standard is the Royal College Hospital standard (Table 1), and some people believe that liver transplantation should be performed before the appearance of cerebral edema indicated by CT.

　　Due to the lack of donor livers, and the minimum volume required for liver transplantation is 25% of the total liver, some people have divided donor livers among several patients for transplantation, especially children. It is now believed that liver transplantation can be performed in children as young as two years old. The one-year survival rate after liver transplantation can reach 65% to 80%, but if the patient develops multi-organ failure including renal failure and respiratory failure, even after liver transplantation, the mortality rate still reaches 100%. For fulminant liver failure caused by viral hepatitis, recurrence of hepatitis can occur after transplantation, and recurrence of hepatitis B often leads to acute hepatitis, chronic hepatitis, liver cirrhosis, or liver failure within one year, resulting in death or retransplantation. The outcome of recurrence of hepatitis C is better than that of hepatitis B. Treatment after recurrence of hepatitis is more difficult, interferon therapy can easily cause graft rejection, and long-term, high-dose application of anti-HBs immunoglobulin can effectively prevent re-infection of HBV in the transplanted liver. Another problem after liver transplantation is that the patient needs to take immunosuppressive drugs for life, and generally cyclosporine (cyclosporine) and FK506 (tacrolimus) are used for immunosuppression with good therapeutic effects.

　　(2) Auxiliary orthotopic liver transplantation: Due to the shortage of donor livers for orthotopic liver transplantation, many patients die before they can receive a donor liver. Auxiliary orthotopic liver transplantation involves the removal of part of the patient's liver, and then a part of the patient's relative's liver is transplanted into this site, allowing the liver to quickly recover function. After the patient has passed the critical period, the liver can regenerate and the immunosuppressive drugs can be discontinued. The transplanted liver is gradually atrophied or removed due to rejection, and the patient relies on their own liver to maintain life. The advantages of this method are that the donor liver source is more sufficient, the patient does not need to take immunosuppressive drugs for life, and thus can avoid many adverse reactions. Since the left lobe of the liver accounts for 25% of the total liver volume, this is the minimum volume required for liver transplantation, so most auxiliary orthotopic liver transplants are left lobe transplants. For patients with fulminant liver failure, auxiliary orthotopic liver transplantation can save the lives of most patients, help the patient's own liver to recover and regenerate, and is particularly suitable for patients under 40 years of age. The source of the donor liver has no significant effect on the efficacy, that is, the living donor liver of the relative is not superior to the donor liver in terms of special advantages.

　　IV. Prognosis:The survival rate of fulminant hepatic failure varies due to different patient conditions and etiologies, with a survival rate of up to 50% in young patients caused by acetaminophen poisoning or hepatitis A, and a survival rate of less than 10% in patients over 40 years of age and hepatitis caused by certain drugs, with a mortality rate reduced to 20% ~ 30% after orthotopic liver transplantation, and a 1-year survival rate of 55% ~ 80%. Since liver transplantation can effectively save patients' lives, liver transplantation should be performed in a timely manner for patients with poor prognosis, and the indicators for poor prognosis are also indications for liver transplantation. The standard commonly used is still the standard of the Royal College Hospital in the UK, and many scholars have also conducted research on prognostic indicators.

　　Some people believe that the presence of cerebral edema on the radiograph indicates a poor prognosis, and liver transplantation should be performed before significant cerebral edema appears on the radiograph; After analyzing 204 cases of fulminant hepatic failure, Dhinan et al. proposed that the presence of significant intracranial pressure elevation, prothrombin time > 100s, and age > 50 years, and the interval between the onset of hepatic encephalopathy and jaundice > 7 days all suggest a poor prognosis in patients with fulminant hepatic failure associated with viral hepatitis; Indian scholars believe that the presence of cerebral edema, gastrointestinal bleeding, serum bilirubin ≥ 15mg/dl, age ≤ 6 years or ≥ 40 years, coma grade III or above, infection, prothrombin time prolonged compared to control > 25s, prothrombin concentration < 50%, blood glucose < 45mg/dl, blood sodium < 125mEq/L, blood potassium > 5.5mEq/L all suggest a poor prognosis; The maximum international normalized ratio (INR) reached during the course of the disease is the most sensitive indicator for predicting prognosis, with a mortality rate of 86% when INR ≥ 4, and a mortality rate of 27% when INR < 4; A serum Gc protein (group-specific component) < 100mg/L at admission also suggests a poor prognosis.