Long-term follow-up of patients with acute liver failure of indeterminate aetiology

Objective. To determine the clinical characteristics of patients with acute liver failure of indeterminate cause and their long-term outcome in comparison with patients with acute liver failure of obvious aetiology (acetaminophen and mushroom poisoning, Budd-Chiari syndrome, acute viral hepatitis) and other controls (idiosyncratic drug reactions, autoimmune hepatitis and Wilson's disease). Material and methods. All patients with acute liver failure and listed for liver transplantation in Sweden between 1984 and 2006 were included in a retrospective analysis. Results. A total of 71 patients with acute liver failure were identified, 33 with indeterminate cause (IDC group), 23 with obvious aetiology (OE group) and 15 other controls (OC group). Before admission to the transplant centre, IDC patients were hospitalized in the referring hospital for 9 days (4–15) versus 1.5 days (1–3) in the OE group (p<0.001) and 7 days (2–14) in the OC group (NS). Serum bilirubin was higher (p<0.001), whereas peak creatinine was lower (p=0.001) in the IDC group compared with the OE group but was not significantly different from the OC group. There were no significant differences in 1-, 3-, 5- and 10-year patient and graft survival rates between the IDC group and the OE or the OC group. Conclusions. Patients with acute liver failure of indeterminate cause seem to differ from those with obvious aetiology in clinical and biochemical presentation but are similar to other controls. The overall long-term outcome seems to be similar in patients with an unknown aetiology as in those with a specific aetiology.     

Acute liver failure as the initial manifestation of acute leukaemia

Abstract: Background/Aims: Haematological malignancies seldom cause clinically significant liver disease. Acute liver failure as the initial manifestation of acute leukaemia is very rare and carries a very poor prognosis. Methods/Results: Three cases of acute liver failure secondary to acute leukaemia are described. Each case presented initially as acute liver failure of uncertain cause. Specific treatment for the leukaemia was instituted; however, all three patients died as a consequence of the liver failure. We describe the clinical course and relevant investigations of these patients and discuss possible mechanisms of acute liver failure in this setting. Conclusion: Acute leukaemia presenting as acute liver failure has a very poor prognosis. Although a rare cause of acute liver failure, it should be considered in any patient presenting with acute liver failure with prodromal symptoms and a raised peripheral white cell count, lactate dehydrogenase and uric acid.     

Hybrid bioartificial liver support in cynomolgus monkeys with D-galactosamine-induced acute liver failure

AIM: To evaluate a hybrid bioartificial liver support system (HBALSS) in cynomolgus monkeys with acute liver failure.METHODS: To establish a model of acute liver failure, 0.3 g/kg of D-galactosamine was injected intravenously into cynomolgus monkeys. Chinese human liver cells were introduced into a perfusion bioreactor to carry out hybrid bioartificial liver support treatment. Forty-eight hours after the injection, one group of cynomolgus monkeys received HBALSS care, and a second experimental group received no treatment. Clinical manifestations of all animals, survival time, liver and kidney functions and serum biochemistry changes were recorded. Simultaneous detection of the number, viability and function of hepatocytes in the hybrid bioartificial liver were also performed.RESULTS: Forty-eight hours after the injection of D-galactosamine, serum biochemistry levels were significantly increased, whereas albumin levels and the Fischer index were significantly reduced compared to baseline (all Ps < 0.05). Of the ten monkeys in the HBALSS treatment group, five survived, with an average duration of survival of 128 ± 3 h. All cynomolgus monkeys in the control group died, with a duration of survival of 112 ± 2 h. Survival time was significantly longer with HBALSS treatment (P < 0.05). Moreover, the number, viability and function of hepatocytes were maintained at a high level with HBALSS.CONCLUSION: The novel hybrid bioartificial liver plays a significant role in liver support by significantly reducing serum biochemistry levels and extending animal survival time.     

Acute liver failure due to white phosphorus ingestion

Background: White phosphorus is chemical compound available in military ammunition as well as in explosive powder of recreational use. This latter form is commonly found in Latin America and Asia as a main ingredient of gunpowder used to make street firecrackers. Small firecrackers may be ingested accidentally or used as a toxic agent in suicidal attempts which may cause of acute liver failure and death; however the clinical features, incidence and outcome are poorly described in the literature.Methods: We describe three cases of white phosphorus intoxication with acute liver failure secondary to the consumption of firecrackers. In two cases, ingestion occurred secondary to suicidal attempts and in one, ingestion occurred by accident. In one case, liver injury improved with supportive care, in the other, the patient required liver transplantation and the third case had a fatal outcome.Conclusions: Clinicians providing care of patients with acute hepatitis of unclear etiology should be aware that the ingestion of firecrackers containing white phosphorus might cause acute liver failure that may require liver transplantation.     

Pretransplantation clinical status and outcome of emergency transplantation for acute liver failure

Emergency transplantation for acute liver failure has a significantly inferior outcome than transplantations performed for elective indications. The severity of the pretransplantation clinical illness in this group will contribute to the reduced patient survival. We have reviewed the outcome of our first 100 consecutive adult patients who received transplants for acute liver failure and have evaluated and determined which recipient clinical parameters present on admission and at transplantation act as risk factors in early posttransplantation outcome. In patients who received transplants for nonacetaminophen-induced liver failure (n = 79), no static variable determinable on admission (including age, sex, year of transplantation, hospital admission to transplantation period, and fulminant or late-onset presentation) other than cause was predictive of 2-month patient survival. Fulminant Wilson's disease and idiosyncratic drug reactions with 2-month survival rates of 100% and 12.5%, respectively, had significantly different outcomes from other causes. By the time of transplantation, of four dynamic variables significant in a univariate analysis (serum creatinine, encephalopathy grade, Apache 111 and organ system failure scores, and P values <.05), only the creatinine level was an independent variable in a stepwise logistic regression for 2-month survival (r = .33). In patients who received transplants for acetaminophen hepatotoxicity (n = 21), overdose to hepatectomy period was the only significant static variable, with no parameter predictive of outcome present on admission. Of two dynamic variables that were significant at transplantation (serum bilirubin and Apache 111 score, P < .05) only the latter parameter was an independent variable in the regression model (r = .51). Selection of candidates experiencing acute liver failure for transplantation depends on assessment of both the prognosis of the primary hepatic illiness on admission and, for a successful outcome, the clinical status at the time of proposed grafting.     

Aetiology and outcome of acute liver failure

Background:

Acute liver failure (ALF) is a clinical syndrome characterized by the sudden onset of coagulopathy and encephalopathy. The outcome is unpredictable and is associated with high morbidity and mortality. We reviewed our experience to identify the aetiology and study the outcome of acute liver failure.

Methods:

A total of 1237 patients who presented with acute liver failure between January 1992 and May 2008 were included in this retrospective study. Liver transplantation was undertaken based on the King''s College Hospital criteria. Data were obtained from the units prospectively collected database. The following parameters were analysed: patient demographics, aetiology, operative intervention, overall outcome, 30-day mortality and regrafts.

Results:

There were 558 men and 679 women with a mean age of 37 years (range: 8–78 years). The most common aetiology was drug-induced liver failure (68.1%), of which 90% was as a result of a paracetamol overdose. Other causes include seronegative hepatitis (15%), hepatitis B (2.6%), hepatitis A (1.1%), acute Budd–Chiari syndrome (1.5%), acute Wilson''s disease (0.6%), subacute necrosis(3.2%) and miscellaneous (7.8%). Three hundred and twenty-seven patients (26.4%) were listed for liver transplantation, of which 263 patients successfully had the procedure (80.4%). The current overall survival after transplantation was 70% with a median follow-up of 57 months. After transplantation for ALF, the 1-year, 5-year and 10-year survival were 76.7%, 66% and 47.6%, respectively. The 30-day mortality was 13.7%. Out of the 974 patients who were not transplanted, 693 patients are currently alive. Among the 281 patients who died without transplantation, 260 died within 30 days of admission (26.7%). Regrafting was performed in 31 patients (11.8%), the most common indication being hepatic artery thrombosis (11 patients).

Conclusion:

Paracetamol overdose was the most common cause of acute liver failure. Liver transplantation, when performed for acute liver failure, has good long-term survival.     

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.     

Autopsy case of acute liver failure due to scrub typhus

Scrub typhus (Tsutsugamushi disease) is an acute febrile disease caused by infection with Orientia tsutsugamushi transmitted by mites. Although patients with scrub typhus commonly display mild liver injury, few die of acute liver failure. We describe herein an autopsy case of acute liver failure due to scrub typhus, which was complicated by disseminated intravascular coagulation and showed rapid progression of liver injury just before death. Histopathological findings revealed submassive hepatocellular necrosis, inflammatory cell infiltration in Glisson’s capsules, and sporadic fibrin thrombi in the hepatic sinusoids. Cause of death was primarily associated with acute liver failure related to disseminated intravascular coagulation.     

Early treatment with N-acetylcysteine in children with acute liver failure secondary to hepatitis A

Introduction. Hepatitis A virus can evolve to acute liver failure with a fatal outcome if it is not reversed.Objective. We describe the clinical course of 12 children who presented with hepatitis A acute liver failure and received treatment with oral N-acetylcysteine (NAC).Materials and methods. Of the seventy-two patients with viral hepatitis A, 12 patients who had acute hepatic failure were included. The variables evaluated were age, sex, duration of clinical features prior to hospitalization, signs and symptoms, laboratory parameters [alanine aminotransferase (ALT), aspartate aminotransferase (AST), prothrombin time (PT), partial thromboplastin time (PTT), internal normalization ratio and ammonia], treatment (oral NAC 100 mg/kg/day, lactulose, neomycin and general measures) and clinical course during hospitalization.Results. Six males and six females were included. School-aged and adolescent children predominated. All presented with jaundice, nausea, vomiting and hepatomegaly. Two had stage 2 neurological signs as per the West-Haven scale. All had altered laboratory parameters. All received NAC, six patients for a week and the remaining six for 9-36 days. Treatment was not ceased until patients showed clinical and laboratory improvement. All data were analyzed using both student’s t test and Wilcoxon signed rank with alpha = 0.05, the ALT with P = 0.0003 and 0.005, AST with P = 0.0001 and 0.0005, PT with P = 0.0237 and 0.0005, PTT with P = 0.0515 and 0.0039, ammonia with P = 0.0197 and 0.0015 and direct bilirubin with P = 0.0190 and 0.068. There was good tolerance to medications and a satisfactory clinical course.Discussion. The use of oral NAC appears to be an effective therapeutic alternative for hepatitis A-induced liver failure if it is offered appropriately. It can modify the clinical course to a favorable one and prevent the fatal outcome of hepatic encephalopathy.     

HMGB1 is a promising therapeutic target for acute liver failure

Introduction: Although acute liver failure (ALF) is a rare disease, it continues to have high mortality and morbidity rates due to its many causes. High mobility group box 1 (HMGB1), originally reported as a ubiquitous non-histone chromosomal protein, is a multi-functional protein with varying functions depending on its location, such as in the nucleus, cytoplasm and extracellular space. The role of extracellular HMGB1 as an inflammatory mediator has been well studied, and the elevation of serum HMGB1 has been reported in several diseases that are closely associated with ALF.

Areas covered: In this review, we focus on the relationship between causes of acute liver failure, such as viral infection, drug-induced liver injury, ischemia/reperfusion injury, and acute-on-chronic liver failure, and the role of HMGB1. Furthermore, we also consolidate and summarize the current reports of HMGB1-targeting therapies in hepatic injury models.

Expert commentary: HMGB1 could be a novel therapeutic candidate for ALF, and the clinical testing of HMGB1-targeting therapies for ALF patients is expected.     

Renal failure in acute liver failure.

Renal failure develops in approximately 55% of all patients referred to specialized centres with acute liver failure. The renal failure may be secondary to the liver failure itself (and is termed the hepatorenal syndrome) or the renal failure may be a secondary insult that directly affects both liver and kidney alike (for example paracetamol overdose). The pathogenesis of the hepatorenal syndrome involves the development of a hyperdynamic circulation, with a lowering of renal perfusion pressure, the activation of the sympathetic nervous system, which renders the kidneys more susceptible to modest decreases in perfusion pressure, and increased synthesis of a variety of vasoactive mediators. These mediators can cause renal vasoconstriction, but more importantly they can also decrease the glomerular capillary ultrafiltration coefficient (Kf), thus causing a decline of glomerular filtration rate over and above that caused by renal vasoconstriction alone. The treatment of the renal failure in acute liver failure involves the optimization of renal haemodynamics and haemofiltration. Renal failure will always recover when there is recovery of liver function, and in the absence of a spontaneous hepatic recovery, liver transplantation will reverse the hepatorenal syndrome.     

Activin A and follistatin in acute liver failure

BACKGROUND: Liver regeneration may be impaired in acute liver failure due to either inhibition of the proliferative response or ongoing liver cell death. Activin A, a member of the TGFbeta superfamily, inhibits hepatocyte DNA synthesis and induces apoptosis. METHODS: Levels of activin A and its binding protein follistatin in the serum of 23 patients with acute liver failure were determined by enzyme-linked immunosorbent assay. RESULTS: Serum activin A was significantly increased in acute liver failure patients (median 2.15 ng/ml, range 0.28-6.87 ng/ml) compared to normal controls (median 0.25 ng/ml, range 0.19-0.53 ng/ml; = 10; 0.001). However, this was not linked to the final disease outcome. Higher levels of activin A were found in the serum of patients with acute liver failure due to paracetamol overdose (median 2.87 ng/ml, range 0.72-6.87 ng/ml; = 17) than in patients with acute liver failure due to non-A to E hepatitis (median 1.10 ng/ml, range 0.28-2.70 ng/ml; = 6; 0.05). Serum follistatin was also increased in acute liver failure patients (median 2.84 ng/ml, range 0.57-13.24 ng/ml) compared to normal controls (median 0.68 ng/ml, range 0.32-3.70 ng/ml; 0.01). CONCLUSION: Serum activin A is increased in acute liver failure and could be a factor in the inhibition of liver regeneration.     

Acute liver failure associated with Garcinia cambogia use

Millions of Americans regularly use herbal supplements, but many are unaware of the potential hidden dangers. Numerous supplements have been associated with hepatotoxicity and, indeed dietary/herbal supplements represent an increasingly common source of acute liver injury. We report a case of acute liver failure requiring liver transplantation associated with the use of Garcinia cambogia, a supplement widely promoted for weight loss. When patients present with acute hepatitis or liver failure from an unknown etiology, a careful history of supplement use should be performed.     

Pro-inflammatory Interleukin-18 and Caspase-1 serum levels in liver failure are unaffected by MARS treatment

BackgroundThe pro-inflammatory cytokine IL-18 and its activator Caspase-1 are involved in acute liver failure and acute-on-chronic-liver-failure. In acute liver failure and acute-on-chronic-liver-failure, the MARS system has been used to support liver function. Enhancement of IL-18, as seen in other extracorporeal-support systems like hemodialysis might thus have mitigated beneficial effects of the MARS system in acute hepatic failure.Patients and methodsWe measured serum concentrations of IL-18 and Caspase-1 in 10 patients with acute liver failure and 10 patients suffering from acute-on-chronic-liver-failure, who were all treated with MARS. Thirteen patients suffering from chronic hepatic failure and 15 healthy individuals served as controls. Data are given as mean with 95% CI.ResultsBaseline IL-18 serum concentrations were significantly increased in acute liver failure and acute-on-chronic-liver-failure patients as compared to chronic hepatic failure (P = 0.0039 and P = 0.0011, respectively) and controls (P = 0.0028 and P = 0.0014, respectively). Caspase-1 serum concentrations were as well significantly elevated in the acute liver failure and acute-on-chronic-liver-failure groups as compared to chronic hepatic failure patients (P = 0.0039 and P = 0.0232, respectively) and controls P < 0.0001 and P < 0.0007, respectively). IL-18 and Caspase-1 did not change significantly during MARS treatment in acute liver failure and acute-on-chronic-liver-failure patients.ConclusionsMARS had no effect on IL-18 and Caspase-1 serum concentrations in acute liver failure and acute-on-chronic-liver-failure, providing no evidence of harmful effects by the increase of these potentially hepatocidal cytokines.     

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.     

Advances in the management of acute liver failure

Acute liver failure(ALF)is an uncommon but dramatic clinical syndrome characterized by hepatic encephalopathy and a bleeding tendency due to abrupt loss of liver function caused by massive or submassive liver necrosis in a patient with a previously healthy liver.The causes of ALF encompass a wide variety of toxic,viral,metabolic,vascular and autoimmune insults to the liver,and identifying the correct cause can be difficult or even impossible.Many patients with ALF develop a cascade of serious complications involving almost every organ system,and death is mostly due to multi-organ failure,hemorrhage,infection,and intracranial hypertension.Fortunately,the outcome of ALF has been improved in the last 3 decades through the specific treatment for the disease of certain etiology,and the advanced intensive care management.For most severely affected patients who fail to recover after treatment,rapid evaluation for transfer to a transplantation center and consideration for liver transplantation is mandatory so that transplantation can be applied before contraindications develop.This review focuses on the recent advances in the understanding of various contributing etiologies,the administration of etiology-specific treatment to alleviate the liver injury,and the management of complications(e.g.,encephalopathy,coagulopathy,cardiovascular instability,respiratory failure,renal failure,sepsis and metabolic disturbance)in patients with ALF.Assessment of the need for liver transplantation is also presented.     

Citrin deficiency presenting as acute liver failure in an eight-month-old infant

Citrin deficiency typically presents as neonatal intrahepatic cholestasis and resolves in late infancy. Here we report a case of citrin deficiency that presented as acute liver failure in late infancy in an apparently healthy child. The full-term male infant weighed 3400 g at birth, and exhibited normal development for eight months, at which time he contracted bronchial pneumonia. The infant developed jaundice and laboratory tests indicated elevated bilirubin and ammonia levels and an abnormal coagulation profile. Plasma amino acid analysis showed elevated levels of tyrosine, methionine, citrulline, and arginine. Citrin deficiency was suspected, and genomic DNA analysis revealed a mutation (IVS16ins3kb) in SLC25A13, which encodes a mitochondrial aspartate-glutamate carrier protein. The infant was immediately put on a lactose-free, medium-chain-triglyceride-enriched formula with ursodeoxycholic acid and lipid-soluble vitamins. However, cholestasis and abnormal laboratory indices persisted, and the infant died at the age of 11.5 mo, two days before a scheduled liver transplantation. This case demonstrates that citrin deficiency can present in late infancy as acute liver failure triggered by infection, and may require liver transplantation.     

Acute liver failure

Acute liver failure (ALF) is defined as hepatic encephalopathy complicating acute liver injury. The most common etiologies are acute viral hepatitis A and B, medication overdose (e.g., acetaminophen), idiosyncratic drug reactions, ingestion of other toxins (e.g., amanita mushroom poisoning), and metabolic disorders (e.g., Reye's syndrome). Despite advances in intensive care management, mortality continues to be high (40-80%) and is partly related to ALF's complications, such as cerebral edema, sepsis, hypoglycemia, gastrointestinal bleeding, and acute renal failure. Several prognostic models have been developed to determine which patients will spontaneously recover. Treatment is directed at early recognition of the complications and general supportive measures. The only proven therapy for those who are unlikely to recover is liver transplantation. Therefore, recognition of ALF is paramount, and urgent referral to a transplant center is critical to assess transplantation status.     

Molecular neurobiology of acute liver failure

Acute liver failure results in encephalopathy and brain edema that is characterized by astrocytic cell swelling. Molecular biological techniques have led to the identification of alterations in expression of several genes coding for key astrocytic proteins in acute liver failure. Such proteins include amino acid transporters, structural proteins, the endothelial cell glucose transporter GLUT-1, the mitochondrial "peripheral-type" benzodiazepine receptor, and the water channel protein aquaporin IV. Magnetic resonance spectroscopic studies reveal increased brain lactate concentrations that are positively correlated with severity of encephalopathy and brain edema in acute liver failure, suggesting a deficit of cellular oxidative capacity and impending brain energy failure. Mild hypothermia prevents brain edema in acute liver failure, and mechanisms responsible for this beneficial effect include reduced blood-brain ammonia transfer as well as normalization of astrocytic amino acid transport and brain energy metabolism. Further elucidation of the molecular mechanisms responsible for brain edema and encephalopathy in acute liver failure will undoubtedly lead to novel treatment strategies for these complications.     

Splanchnic metabolism of fuel substrates in acute liver failure

BACKGROUND/AIMS: This study aimed to characterize the exchange of fuel substrates in the splanchnic circulation in acute liver failure. METHODS: Liver vein catheterization was used in 22 patients with acute liver failure after development of hepatic encephalopathy grade III-IV Healthy controls, patients with cirrhosis and patients with acute on chronic liver disease were also studied. RESULTS: In acute liver failure there was splanchnic removal of glucose (0.21+/-0.44 mmol/min), release of lactate (0.34+/-0.37 mmol/min), pyruvate (0.08+/-0.06 mmol/min) and ketone bodies (0.04+/-0.02 mmol/min), while extraction of amino acids and free fatty acids was insignificant. In the acute liver failure group, a normal hepatic venous oxygen saturation (0.69+/-0.12) and normal pyruvate/lactate ratio suggested absence of hypoxia even though the acetoacetate/beta-hydroxybutyrate ratio was decreased. Only in the acute liver failure group did the measured splanchnic oxygen content difference exceed what could be accounted for even by hypothesizing complete oxidation of all extracted blood-borne fuel substrates; oxidation of endogenous substrates may be quantitatively important in this condition. CONCLUSION: Acute liver failure was associated with a state of accelerated glycolysis in the splanchnic region, leading to release of lactate in the absence of splanchnic hypoxia.