Artificial liver support in acute liver failure.

The concept that a bioartificial device could compensate for the loss of hepatic function and thus improve the outcome of acute liver failure (ALF) was first suggested more than three decades ago. Currently, and reflecting renewed interest in this possibility, three such devices are undergoing clinical evaluation. Each has been shown to perform metabolic functions normally performed by the liver, thus affecting the serum biochemistry of patients with ALF. However, despite potential merit, these devices have not yet been shown to improve the outcome of patients with ALF. Also, some major safety issues remain to be resolved, in particular the risk of transmission of unknown zoonoses to man.     

Portal hypertension in acute liver failure.

Twenty five patients with acute liver failure were measured for hepatic venous pressure gradient as an index of portal pressure during the course of a transjugular liver biopsy. Hepatic venous pressure gradient ranged from 4 to 24.5 mm Hg with a mean of 12.8 (5.3) mm Hg (normal values less than 5 mm Hg). All patients but one had increased portal pressure gradient. Portal hypertension correlated with the degree of architectural distortion of the liver, as suggested by a direct correlation between hepatic venous pressure gradient and the area of reticulin collapse, evaluated by means of a morphometric analysis on Sirius red stained liver slides (r = 0.43, p less than 0.05). Hepatic venous pressure gradient was significantly higher in patients with ascites (15.1 (5) mm Hg, n = 15) or renal failure (14.4 (5.3) mm Hg, n = 16) than in those without (9.3 (3.4) mm Hg and 10.1 (4) mm Hg, respectively; p less than 0.05). Portal hypertension was associated with systemic vasodilation and a hyperkinetic circulatory state, with decreased arterial pressure, and peripheral resistance and increased cardiac output.     

Liver transplantation for acute liver failure.

Under conservative management, the mortality rate of acute liver failure is very high. Liver transplantation is an established life-saving therapy, offering survival rates between 60 and 90%. The decision for liver transplantation should be based on prognostic criteria, including patient's age, aetiology of liver disease, degree and onset of encephalopathy, serum bilirubin, prothrombin time or international normalized ratio (INR), serum creatinine, factor V level and arterial pH. Auxiliary liver transplantation is becoming an attractive treatment modality, allowing temporary bridging of liver function until recovery of the native liver. For children with acute liver failure, living related transplantation represents an additional option. In adult patients, living donation is not yet established since the maximum extent of liver resection safely tolerated and the amount of liver tissue necessary for sufficient graft function is still a matter of debate.     

Thrombopoietin in acute liver failure

Thrombopoietin (TPO) is the primary regulator of platelet production. TPO is produced in the liver and levels are low in patients with cirrhosis. Because thrombocytopenia is common in patients with acute liver failure (ALF), we measured TPO concentrations (normal TPO range, 31 to 136 pg/mL) in 51 patients with ALF to determine if low levels were associated with thrombocytopenia. TPO levels from hospital day 2 were elevated in 43% of patients, normal in 47%, and decreased in 10% of patients. Levels were higher in acetaminophen-induced than in non-acetaminophen-induced ALF, 160 (12 to 549) pg/mL versus 73 (18 to 563) pg/mL, respectively, P =.031. TPO levels did not correlate with platelet count and were not related with survival or infection. We analyzed daily TPO levels for the first week of hospitalization in 12 patients with acetaminophen-induced ALF and observed a gradual increase from a median admission level of 50 (5 to 339) pg/mL to a median peak level of 406 (125 to 1,081) pg/mL occurring on day 5 (3 to 6). Platelets were reduced in 11 of the 12 patients with a nadir platelet count of 52 (19 to 156) x 10(9) cells/L occurring on day 5.5 (1 to 6). The peak TPO level did not correlate with the nadir platelet count (P =.43). In conclusion, the normal inverse relationship between platelet count and TPO levels was not observed in ALF. Despite severe hepatic dysfunction, serum TPO levels were initially normal and increased during hospitalization in acetaminophen-induced ALF, but did not prevent the development of thrombocytopenia.     

Flutamide-associated acute liver failure

The nonsteroidal antiandrogenic drug flutamide [4'-nitro-3'-(trifluoromethyl)isobutyranilide] is a safe and generally well-tolerated drug used for the treatment of prostate cancer. We describe the case of a 74-year-old male who developed life-threatening acute liver failure during flutamide therapy. Other causes of acute liver failure were appropriately ruled out and there was no evidence of active prostate cancer or liver metastases. The use of the Naranjo probability scale indicated a highly probable relationship between the development of acute liver failure and flutamide therapy. Severe liver dysfunction has been rarely documented in patients treated with flutamide, even though cases of fulminant liver failure have been described. A few cases have been reported also among patients with hirsutism being treated with flutamide. The mechanisms responsible for the occurrence of hepatotoxicity during treatment with flutamide are unknown. Mitochondrial dysfunction seems to be implicated. The potential of flutamide to act as a potent hepatotoxin should be borne in mind when treatment with this drug is being planned.     

儿童急性肝衰竭

儿童急性肝衰竭是一种以肝性脑病、黄疸、凝血障碍和腹水为主要表现的临床综合征,常导致多器官功能障碍,病死率较高,是重症医学面临的救治难题。由于儿童这个群体的特殊性,儿童急性肝衰竭和成人相比在定义、病因以及诊治过程中均有其独特性。近年来随着医学技术的发展,尤其是重症医学的发展使得急性肝衰竭的预后有所改善。儿童肝移植的发展也为儿童急性肝衰竭的治疗提供了更多的机会。     

Drug-induced acute liver failure

Acute liver failure is the most severe expression and represents the first cause of fatalities related to drugs. As a consequence, it is also the first cause of drug withdrawal from the pharmaceutical market. The incidence of drug-induced hepatotoxicity in the general population has been recently estimated to be around 14/100,000 inhabitants in a Western country. Drugs appear to be responsible for 10-52% of all causes of acute liver failure. In Western countries, paracetamol (acetaminophen) represents the first cause of all liver failures. The contribution of non-paracetamol drugs given at normal doses is equivalent to that of combined viral hepatitis A and B. The natural prognosis varies between drugs. The spontaneous mortality rate ranges from 32% to 50% for paracetamol intoxication and more than 75% for other drugs. The preventive occurrence of drug hepatotoxicity and the course to acute liver failure is rather limited. It is recommended to stop the administration of a suspected drug when alanine aminotransferase levels increase to more than 3-5 times the upper limit of normal. In paracetamol intoxication, the rapid administration of N-acetylcysteine is a classical antidote. At the stage of liver failure, treatment is mostly supportive. Since irreversible damage is unpredictable, early transfer to a transplantation centre should be considered.     

Schmidt syndrome presenting as acute liver failure.

The Schmidt Syndrome (Type II Autoimmune-Syndrome) is characterised by an autoimmune adrenalitis in combination with a chronic lymphocellular thyreoiditis resulting in insufficiency of these organs in adulthood. Combination with diabetes is possible. The diagnosis is usually established by clinical examination and analysis of serum hormone levels (adrenocorticotropin hormone [ACTH], cortisol, thyroid stimulating hormone [TSH], triiodothyronine [fT3], thyroxine [fT4]). In the present case, initial diagnosis was rapid progressive liver failure of unknown origin with consecutive multiple organ dysfunction syndrome including dysfunction of heart, lungs, and kidneys. Frequent and less frequent causes of liver failure were ruled out, e.g. viral or autoimmune hepatitis, Budd-Chiari-syndrome, toxic, or drug induced liver failure. In retrospect, the multiple organ dysfunction syndrome was caused by hypoperfusion due to severe hypovolemia and hypoperfusion was induced by adrenocortical insufficiency proven by endocrinological testing. The clinical course of this case stresses the importance of the hormone balance in the critical ill patient. The guideline for treatment of patients with assumed hormonal dysregulation should include a full hormone status prior to substitution. The present case report also illustrates the importance of clinical signs and careful consideration of the medical history in detecting an autoimmune endocrine disease.     

Role of liver transplantation in acute liver failure

Orthotopic liver transplantation is employed as salvage therapy for individuals who are unable to recover from acute liver failure. Prognostic models are helpful but not entirely accurate in predicting those who will eventually require liver transplantation. There are specific criteria for United Network for Organ Sharing category 1a (urgent) listing of these patients. Unfortunately, clinical deterioration develops rapidly and many require removal from the waiting list prior to transplantation. With advances in critical care management and surgical technique, 1-year post-transplant survival rates have improved to 60 to 80%. Alternatives to conventional orthotopic liver transplantation include living donor liver transplantation, ABO-incompatible grafts, and auxiliary liver transplantation. There are many ethical and psychosocial issues inherent to transplanting these sick patients due to the urgent nature of acute liver failure. Fortunately, the long-term survival and quality of life in these transplant recipients is good.     

Autoimmune acute liver failure: an emerging etiology for intractable acute liver failure

Diagnosis of acute onset autoimmune hepatitis (AIH) is the most challenging task because of atypical clinicopathological features. We examined the nature of acute onset AIH consisting of nonsevere, severe, and fulminant AIH based on our published data and other published papers, and propose how to diagnose and treat this intractable hepatitis. We analyzed clinical, biochemical, immunological, radiological, and histological features of acute onset AIH. Thirty percent of fulminant hepatitis was due to AIH and autoimmune acute liver failure (ALF) was not rare. The important characteristic of acute onset AIH is its histological, radiological, and clinical heterogeneity. Sometimes acute onset AIH develops into ALF in a sub-acute clinical course without appropriate diagnosis and treatment, and becomes resistant to immunosuppressive therapy and has poor prognosis. Unenhanced computed tomography (CT) often shows heterogeneous hypoattenuation in autoimmune ALF. The revised original scoring system (1999) performed better in patients with acute onset AIH than the simplified scoring system (2008). Liver regeneration from periportal progenitor cells to mature hepatocytes was impaired in ALF, resulting in resistance to immunosuppressive therapy. Precise histological evaluation (the presence of centrilobular necrosis/collapse) along with the revised original scoring system and CT findings of heterogeneous hypoattenuation after systematic exclusion of other causes 36 plays an important role in the diagnosis. The most important strategy for autoimmune ALF is to diagnose and treat acute onset AIH before its development into ALF. Liver transplantation should be considered before the occurrence of infectious complications in the case of fulminant liver failure.     

Current concepts in acute liver failure

Acute liver failure (ALF) is a severe condition secondary to a myriad of causes associated with poor outcomes. The prompt diagnosis and identification of the aetiology allow the administration of specific treatments plus supportive strategies and to define the overall prognosis, the probability of developing complications and the need for liver transplantation. Pivotal issues are adequate monitoring and the institution of prophylactic strategies to reduce the risk of complications, such as progressive liver failure, cerebral oedema, renal failure, coagulopathies or infections. In this article, we review the main aspects of ALF, including the definition, diagnosis and complications. Also, we describe the standard-of-care strategies and recent advances in the treatment of ALF. Finally, we include our experience of care patients with ALF.