Overview.
Frantic liver failure (FHF) is a syndrome characterized by the sudden onset of massive hepatocellular necrosis or significant abnormalities in liver function, and the onset of hepatic encephalopathy (HE) within 8 weeks after the onset of the first symptoms. It is characterized by acute onset, critical condition, various symptoms, extensive hepatocellular necrosis, lack of effective treatment and high mortality rate.
Causes
The etiology of fulminant liver failure is diverse, and can be divided into infectious, toxin, metabolic, infiltrative, autoimmune, ischemic, radiation injury and unknown causes.
1. Infectious
Viral infection, especially viral hepatitis is the most common cause of fulminant liver failure in China, and other viruses are also occasionally found.
(1) Hepatitis viruses There are 7 kinds of hepatitis viruses, which are hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), hepatitis E virus (HEV), hepatitis Hepatitis G virus (HGV, also known as GBV-C), and TTV in the order of discovery.
(2) Other viral infections Immunocompromised, immunosuppressed, neonatal and AIDS patients infected with other viruses can also lead to fulminant liver failure. For example, herpes simplex virus infection, especially disseminated infection in newborns and immunocompromised people can lead to lethal fulminant liver failure.AIDS patients and immunosuppressed patients infected with varicella-zoster virus can lead to varicella hepatitis and fulminant liver failure. Other infections such as cytomegalovirus and paramyxovirus can also lead to fulminant hepatic failure.
2. Toxicity
(1) Drug-specific reaction Many drugs can cause fulminant hepatic failure, of which the common drugs are anesthetics halothane, isoflurane, methoxyflurane, chloroform, etc., anti-tuberculosis drugs, such as isoniazid, rifampicin, antidepressants such as phenelzine and phenyltoluene sodium, cocaine, chlorpromazine, etc., anticoagulant such as bicoumarol, sulfonamides, such as azoxazole pyridinium salicylate, androstenoids, Bicalutamide, alcoholism, androgens, androgens, androgens, androgens, androgenic drugs. Bicalutamide, alcoholism treatment drug tetraethylthiuram disulfide, recreational drug “dance drug” ecstasy, antihypertensive drug ethylhydrazine phenylpyridazine, antiepileptic drug valproic acid, as well as antithyroid drugs, non-steroidal anti-inflammatory drugs, dystrophin B, methyldopa, cyclophosphamide, 5-fluorouracil, 6-mercaptopurine, sedatives, etc.
(2) Toxic reactions Acetaminophen (acetaminophen) is one of the most common drugs and the most important cause of the occurrence of fulminant hepatic failure in Europe and the U.S. In malnutrition or starvation conditions, hepatic glutathione decreases and the sensitivity to the drug increases, and even therapeutic doses of acetaminophen can cause fulminant hepatic failure. There are also finasteride and salicylates. Certain chemical poisons and natural poisons can cause fulminant hepatic failure, the former such as carbon tetrachloride, galactosamine, alcohol, tetracycline, phosphorus, etc., the latter including certain herbs and poisonous mushrooms, aflatoxin, bacterial toxins, etc..
3. Metabolic
The most common metabolic disease causing fulminant hepatic failure is Wilson’s disease, also known as hepatomegaly, which may be accompanied by hemolytic anemia or hemolytic crisis, cornea may have Kayser-Fleischer ring, serum transaminase and alkaline phosphatase levels are relatively low, sometimes blurred visual field and stone-free cholecystitis.
4. Infiltrative
Including fatty infiltration and tumor infiltration, both can lead to the development of fulminant liver failure. Hepatic infiltration of fat includes acute fatty liver of pregnancy, Reye’s syndrome, etc. A large number of fat droplets occupy most of the volume of hepatocytes, so that hepatocytes can not play their normal functions, and the application of valproic acid or intravenous application of high-dose tetracycline can also cause similar lesions. Liver tumor infiltration leading to fulminant hepatic failure is an uncommon manifestation, which can be caused by primary or metastatic tumors of the liver, including melanoma, malignant lymphoma, small cell lung cancer, urothelial carcinoma, etc. Sometimes, the tumor can extensively metastasize to the hepatic sinusoids without metastatic nodules detectable in the liver, which is clinically manifested as fulminant hepatic failure.
5. Autoimmune
Autoimmune liver disease refers to a series of immune diseases involving the liver. Including autoimmune hepatitis, autoimmune sclerosing cholangitis and autoimmune hepatitis after liver transplantation, the pathogenesis of autoimmune hepatitis after liver transplantation is still unclear. Still’s disease, a rheumatoid disease with adult onset, sometimes involves the liver and leads to fulminant hepatic failure.
6. Ischemic
Vascular factors leading to fulminant hepatic failure are rare. Hepatic ischemia can be caused by systemic hemodynamic changes or by localized hemodynamic disturbances.
7. Radiation injury
Radiation injury causing fulminant hepatic failure is not common. Acute radiation sickness or localized high-dose radiotherapy to the liver can sometimes cause fulminant hepatic failure.
8. Other
When hepatitis B virus carriers are treated with interferon and immunosuppressive drugs, liver function may deteriorate, sometimes leading to fulminant liver failure. In addition, in addition to the above causes, there are about 1/3 of patients with fulminant hepatic failure whose etiology is unknown, and it is generally believed that the etiology of this part of patients is related to hepatitis viruses, which can be collectively referred to as non-A-hepatitis.
Symptoms
1. Manifestations of primary disease
Depending on the etiology, there can be related clinical manifestations. For example, in chronic liver disease or cirrhosis on the basis of the occurrence of fulminant liver failure can have liver disease face, liver palms and skin vascular spider nevus, etc., caused by poisoning can have the corresponding toxic manifestations, caused by Wilson’s disease can have corneal K-F ring, caused by tumor infiltration can have the manifestations of the primary tumor.
2.The manifestations of liver failure
Jaundice deepens rapidly in a short period of time, accompanied by obvious elevation of serum aminotransferase and obvious prolongation of prothrombin time and significant decrease of activity; low fever can be found in the early stage of the disease, such as the persistence of low fever, suggesting endotoxemia or persistent hepatocellular necrosis; the general condition is very poor, such as poor appetite, extreme fatigue, irritability, etc.; there are obstinate eructation, nausea, vomiting and obvious abdominal distension; there are obvious bleeding tendency, and there can be subcutaneous hemorrhages, and there is obvious tendency to bleeding. Bleeding tendency, subcutaneous bruises, bruises, often more obvious at the injection site, gingival bleeding, nosebleeds, and in severe cases, upper gastrointestinal bleeding; rapid appearance of peritoneal fluid, usually more than 2 weeks of the disease have peritoneal fluid and hypoalbuminemia; physical examination of the liver shrinks progressively; hepatic odor; hepatic encephalopathy, such as personality changes, reversal of the circadian rhythms, repetitive speech, excessive excitement, behavioral idiosyncrasies, fecal discharge, and other symptoms. Other neuropsychiatric abnormalities such as increased muscle tone, positive pyramidal signs, patellar and/or ankle clonus, disorientation and dyscalculia; tachycardia and hypotension may also be present.
Examination
1. Biochemical examination
(1) Liver function tests Serum bilirubin level is often significantly elevated, some patients may show a rapid rise, alanine aminotransferase (ALT) and azelaic transaminase (AST) are significantly elevated, and ALT/AST <1, suggesting severe hepatocellular damage. If the duration of the disease is more than 2 weeks, the serum albumin level will also decrease, and if it continues to decrease, it suggests that the hepatocytes have sustained serious damage.
(2) Blood ammonia test is still one of the important indicators of hepatic encephalopathy and should be checked regularly.
(3) Renal function test can reflect the degree of renal damage. Since urea is synthesized in the liver, urea nitrogen may not be elevated when the liver is severely damaged, and blood creatinine level can better reflect the renal function.
(4) Electrolyte measurement can help detect electrolyte disorders in time.
(5) Blood gas analysis can detect acid-base imbalance and hypoxemia at an early stage, which is convenient for timely treatment.
(6) Alpha-fetoprotein measurement Detected in the late stage of the disease, if elevated, it suggests that there is regeneration of liver cells.
(7) Measurement of serum cholesterol and cholesteryl ester Cholesterol in patients with fulminant hepatic failure is significantly reduced, even to undetectable in severe cases, and cholesteryl ester is often less than 40% of total cholesterol.
(8) Blood glucose measurement can detect hypoglycemia in time.
(9) Blood Gc protein measurement Gc protein is a kind of alpha globulin synthesized by liver, and one of its main functions is to remove actin released by necrotic hepatocytes. Gc protein is significantly reduced in fulminant liver failure, and if it is lower than 100 mg/L, it suggests that the healing process is poor.
(10) Others Regular amylase test can help to detect pancreatitis in time, and blood amino acid analysis can detect the decrease of branched-chain amino acid/aromatic amino acid ratio in time, which should be corrected in time to prevent hepatic encephalopathy.
2. Hematologic examination
(1) Blood routine can judge the degree of bleeding and the effect of hemostatic treatment according to the speed of hemoglobin decline, white blood cell count and classification are often significantly elevated in fulminant liver failure, and platelet examination is also helpful in judging the condition.
(2) Prothrombin time and activity are the most valuable indicators reflecting the degree of liver damage. In severe hepatocellular damage, blood coagulation factors drop rapidly, causing prolongation of prothrombin time and decrease of activity.
(3) Detection of coagulation factors If coagulation factor V is <20%, it suggests poor healing. In addition, the rise of coagulation factors and fibrinogen degradation products may reflect the regeneration of the liver.
(4) Other Tests If necessary, tests for DIC can be performed.
3. Microbiological and immunological examination
(1) Tests related to viral hepatitis include anti-HAV-IgM, HBsAg, anti-HBs, HBeAs, 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, etc. and anti-Cytomegalovirus and E-BV. Anti-cytomegalovirus and E-B virus antibodies.
(2) Bacteriological examination: blood culture, urine culture, stool culture, sputum culture and ascites culture should be done according to the need. The culture of peritoneal fluid should emphasize bedside inoculation with blood culture bottles, and fungal smear microscopy and culture should be done when necessary.
(3) Endotoxin detection Possible horseshoe crab test.
(4) Immunity test: autoimmune antibody test, including anti-nuclear antibody, anti-smooth muscle antibody, anti-mitochondrial antibody, etc., serum total complement and complement C3 test, and circulating immune complex test.
4. Other auxiliary examinations
(1) B-mode ultrasonography: To observe the size of liver and exclude bile duct obstruction and gallbladder disease.
(2) Electroencephalogram (EEG) The waveform is consistent with the clinical condition, the wave amplitude increases and the frequency slows down with the aggravation of the condition, and it is divided into six grades from A to F. Grade A is the normal EEG, and the patient is awake; grade B to D EEG, the wave amplitude increases and the frequency slows down, and the patient’s mental state is confuse (grade B), wooden stiffness (grade C), and stupor (grade D), and grade D is the three-phase wave of hepatic encephalopathy, and it is the high-voltage, slower-frequency, diffuse three-phase wave; grade E, the wave amplitude decreases and the frequency remains constant, and the patient is in deep stupor. Grade E wave amplitude decreases and frequency remains unchanged, the patient is in deep coma, and grade F EEG activity stops completely.
(3) Intensive care monitoring can detect arrhythmia, potassium changes, respiratory and blood pressure abnormalities in time.
(4) CT Liver size changes can be observed and before and after comparisons can be made, and cerebral edema can be observed.
(5) Magnetic resonance examination (MRI) Magnetic resonance spectroscopy (MRS) Measurement of lactate content in the brain, if the lactate in the brain is elevated, it suggests poor healing.
(6) Nuclide scanning of liver Computer-captured γ-photography was performed after injection of human albumin with 99Tc-labeled galactosyl diethylenetriamine pentaacetic acid, to observe the binding of 99mTc-GSA to the receptor in the liver, which helps to determine the reserve of liver function and to judge the prognosis of healing.
(7) Epidural intracranial pressure monitoring It is generally advocated to be installed in grade III-IV hepatic encephalopathy for monitoring intracranial pressure, which should be less than 2.7 kPa (20 mmHg) after treatment.
Diagnosis
The diagnosis of fulminant hepatic failure should be made on the basis of clinical manifestations of jaundice, liver shrinkage and encephalopathy, and biochemical investigations of hyperbilirubinemia, elevated aminotransferase activity, and extreme decreases in coagulation factors such as prothrombinogen and coagulation factor V. Abdominal ultrasonography is used to visualize changes in liver size and structure, signs of chronic liver disease or space-occupying lesions, as well as blood vessels and bile ducts. Pathogenetic diagnosis should be based on detailed clinical analysis and serologic and toxicologic tests, and ultimately histologic examination.
Differential diagnosis
1. Psychosis
Hepatic encephalopathy with psychiatric symptoms as the only prominent manifestation is easily misdiagnosed as psychosis. Therefore, patients with mental confusion of unknown cause should be alerted to the possibility of hepatic encephalopathy.
2. Metabolic encephalopathy
Such as diabetic ketoacidosis, hypoglycemia, uremia, hypernatremia, hyponatremia and so on. According to the corresponding history of underlying diseases, combined with relevant laboratory tests, blood gas analysis can help to identify.
3. Craniocerebral lesions
Various cerebrovascular accidents (cerebral hemorrhage, cerebral infarction, subdural hemorrhage), intracranial tumors, brain abscess, encephalitis, meningitis, etc. may present with coma and lethargy. According to the neurological symptoms and signs, combined with cranial CT or MR examination, and cerebrospinal fluid examination, most of them can be clearly diagnosed.
4. Toxic encephalopathy
Encephalopathy caused by alcoholism, drug intoxication, heavy metal poisoning, according to the history of alcoholism, drug use and special occupational exposure, combined with laboratory examination, can help differential diagnosis. Particular attention is paid to the differentiation of alcohol-related diseases, such as acute alcoholism and withdrawal syndrome after abstinence from alcohol is similar to the manifestation of HE. The key to differentiation is the history of alcohol consumption, elevated blood alcohol concentration, and bradycardia, fever, and tremor are more pronounced when abstaining from alcohol.
Timed testing of blood amylase in patients with fulminant liver failure may be helpful in making the diagnosis, but amylase is elevated in only 1/3 of patients.
Treatment
1. Basic supportive therapy
Patients with fulminant hepatic failure should ensure that there is enough energy intake, to ensure that the daily caloric intake reaches more than 2000kcal, in order to reduce the proteolysis in the body, 10% glucose 1500～2000ml should be dripped every day, and the moderate application of fat milk can improve the negative nitrogen balance of the patients, but the input should be slow, and can be used to 10% fat milk 500ml dripped in a period of time not shorter than 4h, as appropriate Fresh plasma, human albumin or whole blood should be transfused once a day or 2~3 days.
2. Treatment of complications
(1) Treatment of hepatic encephalopathy Avoid strong diuresis, control infection, control upper gastrointestinal bleeding, prohibit sedative drugs, reduce blood ammonia, strictly limit dietary protein, traditional blood ammonia-lowering drugs have poor efficacy, monosodium glutamate will aggravate cerebral edema and sodium retention, and can not pass the blood-cerebrospinal fluid barrier, arginine can not play a proper role due to the lack of arginase in the hepatocytes in hepatic failure, and ornithine cycling disorder. The effect of Lactulose is one of the basic drugs in the treatment of hepatic encephalopathy, and it is appropriate to maintain paste-like stools 3 to 4 times a day and stool pH <6. Branched-chain amino acids may be useful in correcting amino acid imbalance and alleviating hepatic encephalopathy. Levodopa can also be used intravenously.
(2) Management of cerebral edema includes: head elevation of 30°, application of mannitol is the main treatment for cerebral edema, when intracranial pressure rises to 2.7-3.3kPa (20-25mmHg), if plasma osmolality is <320mOsm/L, mannitol should be pushed static quickly and repeated to prevent the intracranial pressure from rebound, if plasma osmolality is ≥320mOsm/L, then it is not suitable to use Mannitol, in anuric patients, is indicated only for hemodialysis or continuous arterio-venous hemofiltration. In patients who fail to respond to combination therapy such as repeated applications of mannitol, pentobarbital should be considered, with 4 doses of IV push every 15 minutes. If the patient’s cerebral edema continues to deteriorate, emergency liver transplantation should be performed.
(3) The treatment of primary peritonitis includes: ① general support and hepatoprotective treatment. ② Application of antibiotic therapy: the bacteria causing peritonitis are mainly intestinal flora, generally recommended the use of third-generation cephalosporins, such as cefotaxime, or ceftriaxone (ceftriaxone), patients with allergy to β-lactams should be selected to use a drug that is effective against G globules (eg, vancomycin or chlorlincomycin) plus a drug that is effective against G bacilli (eg, amitranan, aminoglycosides or quinolones). (iii) Diuresis: spironolactone (amphotericin) and furosemide can be used, which play an important role in increasing the protein concentration of ascites, improving the conditioning activity of ascites and its complementary components, and increasing the resistance of ascites.
(4) Hepatorenal syndrome The patient’s kidneys themselves do not have organic lesions, and the key to its treatment is to improve liver function. Limit the intake of fluid, sodium, potassium and protein; apply vasoactive drugs, continuous intravenous dopamine to increase renal blood flow, or captopril (mercaptopropionic acid) can be applied, and other drugs such as 8-ornithine pressor and calcium channel blocking drugs such as verapamil (isobarbital), indomethacin (cardiac painkillers), nimodipine, etc., can be tried; dialysis can be applied early in the appropriate cases, which is effective in relieving the condition. If conservative treatment is ineffective, LeVeen peritoneal effusion-venous reflux cannulation can be performed when the conditions are available, with one-way piston silicone catheter to lead the ascites from the peritoneal cavity to the external jugular vein, which is a simple and less dangerous operation with long-lasting effect, and liver transplantation is also available.
(5) Upper gastrointestinal hemorrhage: Prevention is very important because of the risky outcome. Patients with fulminant hepatic failure should be given acid-control drugs such as H2-receptor antagonist ranitidine orally or proton pump inhibitor omeprazole orally; early transfusion of fresh plasma and supplementation of coagulation factors; and application of β-blocker propranolol orally, which can reduce portal pressure and prevent bleeding caused by portal hypertensive gastropathy. Once the upper gastrointestinal bleeding occurs should take effective measures in time.
(6) Treatment of DIC in fulminant hepatic failure There is still disagreement on whether to use heparin, and some people believe that early and large-scale use of heparin does not reduce the incidence of bleeding, but rather exacerbates or causes the possibility of bleeding. It is also believed that heparin should be administered to patients with no obvious clinical signs of bleeding but laboratory tests suggestive of DIC, and the usual amount is heparin 0.5~1mg/kg, added to 5%~10% glucose 250~500ml, once every 4~6 hours, so that the coagulation time (in vitro method) can be maintained at 20~30 minutes. In addition supplemental coagulation factors can be given fresh whole blood or plasma, preferably when taken fresh blood.
(7) Treatment of ARDS First of all, ventilation should be improved, and intermittent positive pressure ventilation (IPPV) can achieve more satisfactory results; in addition, pulmonary edema should be actively controlled, early application of high-dose adrenocorticotropic hormone, prevention and treatment of DIC and supplementation of exogenous alveolar surface-active substances. The treatment of hepatopulmonary syndrome relies on liver transplantation, and the condition can be significantly improved after liver transplantation. The application of pulmonary vasoconstrictor drugs has not shown obvious efficacy, and some people have reported that arterial oxygenation function has been significantly improved after treatment with garlic, which needs to be further confirmed.
(8) Cardiac lesions in fulminant liver failure The most common is hemorrhagic changes, mainly due to coagulation mechanism disorders, which can be prevented by supplemental coagulation factors and hemostatic therapy, and cardiac arrhythmias should be treated by cardiac electric monitoring, correcting acid-base imbalance and electrolyte disorders, and applying anti-arrhythmic drugs. There is no satisfactory treatment for hyperdynamic circulation, and blood volume can be supplemented appropriately, and vasoactive drugs such as dopamine can be applied to ensure effective cerebral blood perfusion if necessary. Acute portal hypertension can be treated with propranolol, which can reduce cardiac output and hepatic arterial blood flow, thus lowering portal pressure, and 1-blocker prazosin, which can also reduce portal pressure by lowering hepatic vascular resistance.
3. Liver function support therapy
(1) Artificial liver support therapy Artificial liver support therapy can prolong the survival of these patients until the arrival of the donor liver. In addition, since fulminant liver failure is a potentially reversible disease, artificial liver support therapy can help patients get through the dangerous period and enter the recovery period, and it is even believed that the survival rate of artificial liver support therapy reaches 55.2%, which is similar to the efficacy of liver transplantation.
(2) Liver transplantation ①In-situ liver transplantation In-situ liver transplantation is currently the most effective treatment for fulminant liver failure. Auxiliary in situ liver transplantation Auxiliary in situ liver transplantation is to remove a part of the patient’s liver and transplant a part of the patient’s relative’s liver to that part, so as to make the liver recover its function rapidly. After the patient passes the danger period, the liver regeneration can stop the immunosuppressant drugs, and the transplanted liver can be rejected and gradually atrophy or be taken out, and the patient relies on his/her own liver to maintain his/her life.
Prognosis
The survival rate of fulminant liver failure varies depending on the patient’s condition and the cause of the disease. In young patients with acetaminophen poisoning or hepatitis A, the survival rate can be up to 50%; in patients over 40 years old and with hepatitis caused by certain medications, the survival rate can be less than 10%; the morbidity and mortality rate after in situ liver transplantation has been reduced to 20%-30%, and the 1-year survival rate is 55%-80%.
Prevention
Prevention of fulminant hepatic failure should first start from the cause, actively prevent hepatitis B, universal hepatitis B vaccination, especially for high-risk groups can effectively prevent hepatitis B and D. Since chronic hepatitis C overlapping infection with hepatitis A is easy to cause fulminant hepatic failure, hepatitis A vaccination for patients with chronic hepatitis C and non-immune high-risk groups can prevent HAV-induced fulminant hepatic failure. fulminant liver failure caused by HAV.