Search

Aim: Myostatin is a myokine involved in muscle mass regulation. The associations between circulating myostatin levels and clinical characteristics in patients with acute liver failure (ALF) and late‐onset hepatic failure (LOHF) are unclear. Methods: In this retrospective study, 51 patients with ALF or LOHF were included. Serum myostatin was measured using an enzyme‐linked immunosorbent assay. Results: Myostatin levels were significantly lower in patients with ALF and LOHF than in controls (ALF/LOHF: 2522 pg/mL, controls: 3853 pg/mL, p = 0.003). The prevalence of low myostatin in deceased patients was significantly higher than that in spontaneous survivors and patients who underwent liver transplantation. Patients with low myostatin levels had a high incidence of complications. There was a positive correlation between the psoas muscle index and serum myostatin levels. Patients with low myostatin levels had shorter 1‐year transplant‐free survival and shorter 1‐year overall survival than patients with high myostatin levels. Low serum myostatin levels were associated with poor prognosis independent of the Japanese scoring system for ALF ≥3, King's College criteria, or model for end‐stage liver disease score >30.5. The combination of serum myostatin levels and prognostic models for ALF significantly stratified patients according to 1‐year prognosis. Conclusions: Low serum myostatin levels were associated with a low psoas muscle index, complication rate, and poor prognosis in patients with ALF and LOHF. Assessment of circulating myostatin levels may improve the prediction of outcomes in patients with ALF and LOHF. [ABSTRACT FROM AUTHOR]

Acute liver failure (ALF) induces increased energy expenditure and disrupts the metabolism of essential nutrients. Hepatic encephalopathy is a complication of ALF with a poor prognosis and mainly involves the metabolic disturbance of amino acids in its pathogenesis. In this review, we discuss the nutritional management for ALF in consideration of the pathophysiology of ALF with respect to the impairment of hepatocyte function. It is known that enteral nutrition is recommended for patients with ALF, while parenteral nutrition is recommended for patients who cannot tolerate enteral nutrition. As ALF leads to a hypermetabolic state, the energy intake is recommended to cover 1.3 times the resting energy expenditure. Because of the high risk of hypoglycemia associated with disturbances in glucose metabolism, substantial glucose intake is recommended. Along with the deterioration of glucose metabolism, protein metabolism is also disrupted. As patients with ALF have increased systemic protein catabolism together with decreased protein synthesis, appropriate amounts of amino acids or protein under monitoring serum ammonia levels are recommended. In conclusion, nutritional management based on the understanding of nutritional pathophysiology is a pivotal therapeutic approach for patients with ALF. The approach should be individualized in the acute phase, the recovery phase, and the pretransplant phase. [ABSTRACT FROM AUTHOR]

Aim: The prognosis of patients with acute liver failure has improved dramatically in the past three decades due to advances in medical critical care and use of liver transplantation (LT) in Western countries, where the etiology of acute liver failure is different from that in Japan. We analyzed patients with fulminant hepatitis (FH) and late‐onset hepatic failure (LOHF) admitted to our unit over a 32‐year period to clarify the nature of Japanese patients with FH and LOHF. Methods: A total of 137 Japanese patients with FH and LOHF between 1986 and 2017 were analyzed for etiologies, disease types, treatment protocols, and outcome. Results: Of 137 patients, 124 were FH (53 acute type and 71 subacute type) and 13 LOHF. The major etiology was due to viral infections in 48% of patients. A total of 23.4% of patients recovered without LT, 7.3% received LT, and 69.3% died without LT. The number of patients showed rise and fall without an evident decrease during the period. Patients with autoimmune hepatitis increased after the establishment of autoimmune hepatitis criteria in 1999 (p < 0.001), and that with indeterminate cause decreased (p < 0.01). The mean age was older in the last decade than in the first decade (p = 0.036). Spontaneous and overall survival rates were not different during the period. Conclusions: The prognosis of our patients with FH and LOHF has not improved, probably because of aging and the increasing proportion of etiologies with poor prognosis and difficult‐to‐treat patients without response to medications regardless of advancement of clinical management, including artificial liver support devices and LT. [ABSTRACT FROM AUTHOR]

Aim: We investigated whether an early‐phase prothrombin time‐international normalized ratio (PT‐INR) is an interventional prognostic indicator for patients with acute liver injury, including acute liver failure. Methods: This was a multicenter retrospective observational study. We included 595 patients with alanine aminotransferase levels ≥300 U/L due to acute liver injury who were admitted to Kagoshima University Hospital or other collaborative investigation organizations between January 1, 2010, and December 31, 2015. Patients with alanine aminotransferase levels ≥300 U/L and no previous liver disease were defined as having an acute liver injury. Acute liver failure was defined by PT‐INR ≥1.5 with or without hepatic encephalopathy in acute liver injury patients. Data were obtained retrospectively from case reports and analyzed. Results: The PT‐INR on day 1 was the most accurate independent prognosis predictor in patients with acute liver injury and acute liver failure. On day 1, the transplant‐free survival rates were significantly lower in patients with PT‐INR ≥1.3. The transplant‐free survival rates were also significantly higher in patients with acute liver injury and acute liver failure, in whom the PT‐INR had recovered from ≥1.3 on day 1 to <1.3 by day 8. Conclusion: Early‐phase changes in the PT‐INR can predict the prognosis of patients with acute liver injury and acute liver failure. Furthermore, PT‐INR ≥1.3 could be an interventional marker, whereas PT‐INR <1.3 after 1 week could reflect prognostic improvement. [ABSTRACT FROM AUTHOR]

Aim: Hepatic encephalopathy (HE) development is crucial in liver transplantation for patients with acute liver injury (ALI) and failure (ALF); to predict HE development, the Japan Hepatic Encephalopathy Prediction (JHEP) model, calculated using age, etiology, prothrombin time (PT), and total bilirubin, was established in 2004, and a referral system to the liver center was implemented using the JHEP model from April 2004. Methods: The JHEP model's ability to predict HE development in 460 consecutive patients with ALI between April 2004 and January 2021 using data from the referral system was evaluated, and the JHEP model was revised. Results: During the observation period, 7.8% patients developed HE. There was no difference in the proportion of HE development among the etiologies. In the Hosmer–Lemeshow test for HE development prediction, the JHEP model, revised JHEP (rJHEP) model, which was calculated without etiology data, and the modified JHEP model, which used the PT international ratio instead of PT in the rJHEP model, were good fitting models. Upon 30% random sampling from the total patients 60 times, the receiver operating curve analysis of both JHEP and rJHEP models for HE development was performed in all the datasets. The area under the curve of the JHEP model was subtracted from that of the rJHEP model (95% confidential interval, 0.000516–0.01793). Conclusions: The referral system using the JHEP model reduced the difference in the risk for HE development among each etiology; the rJHEP model had a better prediction ability for HE development than the JHEP model. [ABSTRACT FROM AUTHOR]

Background: Acute liver failure (ALF) is a rare but potential lethal condition characterized by the sudden development of jaundice, coagulopathy and hepatic encephalopathy in patients without underlying liver disease. In selected patients, emergency liver transplantation is required. Selection of these patients is based on clinical criteria such as the Kings College Criteria (KCC) or the Clichy criteria. Aims: The aim of this work is to provide an overview of potential biomarkers that could improve the prognostic value of KCC. Results: Several promising biomarkers involved in related pathophysiological processes have been identified. Some could be as stand‐alone biomarkers; however, the best prognostic values have been observed in the combination of biomarkers with current models. Among these, the ALFSG Index that combines clinical parameters and circulating blood levels of CK18 claims a higher prognostic value than KCC. Conclusions: In this review, all potential biomarkers for ALF have been summarized to give an overview of the work performed over the last years, and a glimpse of what to expect in this field in the coming years. [ABSTRACT FROM AUTHOR]

Aim: Neuroblastoma amplified sequence (NBAS)‐associated disease has a wide phenotypic spectrum, including infantile liver failure syndrome type 2 (ILFS2, OMIM #616483), short stature with optic nerve atrophy and Pelger–Huët anomaly (SOPH) syndrome (OMIM #614800), and a combined phenotype overlapping ILFS2 and SOPH syndrome. The mutation spectra of NBAS and its genotype–phenotype correlation among Chinese were not clear. Methods: Clinical and genetic data were retrospectively collected from the medical charts of patients with biallelic NBAS mutations, as well as from Chinese patients in previously published reports. Results: Fourteen new patients were identified, including 10 novel mutations: c.648‐1G>A, c.2563_c.2577+5del/p.His855_Gln859del, c.3115C>T/p.Gln1039Ter, c.3284G>A/p.Trp1095Ter, c.2570C>T/p.Ala857Val, c.6859G>T/p.Asp2287Tyr, c.1028G>A/p.Ser343Asn, c.1177_1182delinsAGATAGA/p.Val393ArgfsTer2, c.3432_3435dupCAGT/p.Ala1146GlnfsTer14, and c.680_690dupACTGTTTCAGC/p.Phe231ThrfsTer35. All 14 patients presented as fever‐triggered liver injury, including nine patients that satisfied the criteria of acute liver failure (ALF) in whom c.3596G>A/p.Cys1199Tyr occurred five times. Nine patients had extrahepatic manifestations including short stature, skeletal abnormalities, intellectual disability, ophthalmic abnormalities, low levels of serum immunoglobulins, facial dysmorphism, and cardiac abnormalities. Ten other Chinese patients were collected through a review of published works. Genotype–phenotype analysis in 24 Chinese patients revealed that the percentage of ALF patients with variants in the Sec39 domain was significantly higher than that in the C‐terminal (100% vs. 12.5%, P = 0.000), and the percentage of multi‐organ/system involvement in patients with variants in the Sec39 domain was significantly lower than that in the C‐terminal (40% vs. 100%, P = 0.0128). Conclusions: We reported 14 new patients, 10 novel mutations, and a unique recurrent mutation. Correlation analysis indicated that the domain of missense and non‐frameshift insertion/deletion mutations in NBAS protein is related to phenotype among Chinese patients. [ABSTRACT FROM AUTHOR]

Aim: Acute liver injury (ALI) has a favorable prognosis, whereas acute liver failure (ALF) leads to organ failure and thus has an unfavorable prognosis. The effect of each etiology on the clinical course of ALI remains unclear. This study aimed to determine how each etiology and glucocorticoid on the unfavorable etiology affects the clinical course of ALI. Methods: This prospective observational study enrolled 522 patients with ALI/ALF from 2004 and 2017. To evaluate the influence of etiology on prognosis, decision tree analysis was carried out using age, disease type, etiology, and the presence of hepatic encephalopathy. Results: Of 522 patients, 398 patients satisfied the ALI criteria at registration in this study. The ALI etiologies were as follows: viral hepatitis through oral infection (n = 54), acute hepatitis B virus (HBV) infection (n = 24), acute exacerbation of HBV infection (n = 30), de novo hepatitis due to HBV (n = 5), autoimmune hepatitis (n = 59), drug‐induced liver injury (DILI; n = 85), other viruses (n = 12), and undetermined (n = 129). ALI in 46 patients progressed to ALF after registration. Of 11 patients (age >52 years) with ALF due to acute exacerbation of HBV infection or DILI, seven patients (63.6%) died. Whether glucocorticoid affected the clinical course of ALI due to acute exacerbation of HBV infection or DILI was evaluated using propensity score matching (age, sex, alanine aminotransferase, total bilirubin, and prothrombin time‐international normalized ratio). Glucocorticoid did not improve the prognosis of ALI patients due to the two etiologies. Conclusions: Progression of ALI due to DILI or acute exacerbation of HBV infection to ALF showed a poor prognosis. [ABSTRACT FROM AUTHOR]

Aim: A nationwide survey of acute liver failure (ALF) and late‐onset hepatic failure (LOHF) has revealed that the outcomes of recent patients whose diseases were caused by infection with hepatitis A virus (HAV) have worsened, compared with those of previously reported patients. The factors associated with this deterioration were evaluated. Methods: A total of 83 patients with HAV infection seen between 1998 and 2015 were enrolled. All the patients had a prothrombin time–international normalized ratio of 1.5 or more and hepatic encephalopathy of grade 2 or more severe. The demographic and clinical features of 45 patients seen prior to 2003 (cohort 1) and 38 patients seen during 2004 and thereafter (cohort 2) were compared. Results: Three and four patients in cohort 1 and cohort 2, respectively, received liver transplantations; the survival rates among the remaining patients were 56% for cohort 2 and 79% for cohort 1 (P < 0.05). The mean age (±standard deviation) of the patients was higher in cohort 2 than in cohort 1 (58 ± 11 vs. 48 ± 13 years; P < 0.01). The percentages of patients with underlying metabolic diseases were 22% in cohort 1 and 61% in cohort 2 (P < 0.01). Diabetic mellitus was more common among deceased patients than among rescued patients (29% vs. 8%; P < 0.05) among patients who did not receive liver transplantations, and a multivariate analysis revealed that patient age and disease type were significantly and independently associated with the outcome. Conclusion: The outcomes of recent patients with ALF or LOHF caused by HAV infection have recently worsened mainly because of an increase in underlying metabolic diseases as a consequence of aging. [ABSTRACT FROM AUTHOR]

The high mortality rate due to severe Herpes simplex viral (HSV) hepatitis is associated with the difficulty of its diagnosis. We describe the extremely rapid disease course of a patient who died of severe HSV hepatitis. A 73‐year‐old woman was admitted for a bronchial asthma attack. Her symptoms improved with steroid treatment, but she developed a sore throat and painful swallowing. On day 12 after admission, she suddenly went into shock. Blood test results showed a significant increase in the liver enzyme levels, with remarkable disseminated intravascular coagulation. She died the same day. The autopsy revealed extensive coagulative necrosis of the liver. Viral inclusion of type A Cowdry bodies was found in the residual hepatocytes in the hepatic lobule. Immunostaining revealed HSV type 1 positivity. We diagnosed the cause of death as severe HSV hepatitis. On examination of a stored serum sample, the patient tested positive for the HSV immunoglobulin (Ig)‐M antibody, and the HSV RNA level was very high (1 × 109 copies/mL). Remarkably, the HSV IgG test result was negative, and we diagnosed her as having had an initial HSV infection. Hepatitis due to HSV is very rare in healthy adults; however, there are many reports of immune‐deficient cases. The presence of HSV IgG is decreasing in the elderly population because of the change in living environments/lifestyles. The increasing use of immunosuppressive drugs, such as steroids, for treating diseases in elderly patients could be linked to the increased prevalence of initial HSV infections, resulting in liver injury. [ABSTRACT FROM AUTHOR]

Aim: An artificial liver support (ALS) system sustaining patients with acute liver failure (ALF) in good condition until recovery of the native liver or performance of liver transplantation (LT), is essential for the improvement of the poor prognosis of ALF despite the lack of survival benefit. We aimed to investigate the efficacy of various ALS systems for fulminant hepatitis (FH) carried out in our liver unit so far, focusing on the restoration of consciousness from hepatic encephalopathy. Methods: One hundred and ten consecutive adult Japanese patients with FH admitted to Chiba University Hospital (Chiba, Japan) between 1988 and 2016 who received ALS were analyzed. Results: Recovery rate of consciousness improved with the increased dialysate flow rate and filtrate rate: 37.5% by plasma exchange (PE), 51.9% by PE + continuous hemodiafiltration (CHDF), 57.7% by slow PE (sPE) + high‐flow CHDF (HFCHDF) (QD = 300 mL/min), 88.6% by HFCHDF (QD = 500 mL/min) (+ sPE), and 92.9% by on‐line HDF (OLHDF) (+ sPE). All patients except one, who could not be fully treated because of circulatory failure, recovered consciousness by OLHDF, including those whose liver function were completely abolished. Superiority of HFCHDF (QD = 500 mL/min) and OLHDF was also shown in patients who died without LT or received LT. Conclusions: More effective ALS should be recognized considering the extremely high recovery rate of consciousness. In particular, OLHDF with predilution reduces the cost of substitution fluid by supplying an unlimited amount of dialysate as substitution fluid prepared using an on‐line system, and simplifies the procedure for the management. [ABSTRACT FROM AUTHOR]

Aims: The definition of original acute severe autoimmune hepatitis (AS‐AIH) is unclear. However, its rapid recognition and early treatment is potentially life‐saving. Therefore, we present herein an open, real‐world observational study for the assessment of the efficacy and safety of early high‐dose i.v. corticosteroids in original AS‐AIH patients. Methods: Prospectively collected data from 184 AIH patients were analyzed retrospectively. Original AS‐AIH defined as an acute symptomatic presentation of newly diagnosed AIH (transaminases >10× upper limit of normal, bilirubin >4 mg/dL, and international normalized ratio [INR] ≥1.5) without histological lesions of chronic disease. Results: Thirty‐four of 184 (18.5%) patients had original AS‐AIH. These patients were promptly treated with i.v. corticosteroids (either 1 g methylprednisolone for 3 consecutive days followed by i.v. 1 mg/kg/day prednisolone or i.v. 1.5 mg/kg/day prednisolone from the beginning). Only 1/34 (2.9%) died due to sepsis; none required liver transplantation during follow‐up (65 [1–175] months). No significant differences were detected in baseline characteristics between original AS‐AIH patients and those with insidious presentation (not‐AS‐AIH; n = 117) apart from antinuclear antibodies negativity (P = 0.038), and higher immunoglobulin G, transaminases, INR, and bilirubin in original AS‐AIH patients (P = 0.001 for all). Complete response and corticosteroids withdrawal (for patients treated >12 months) were significantly more frequent in original AS‐AIH (n = 28) than in not‐AS‐AIH (n = 79; P = 0.026 and P = 0.016, respectively). Presence of original AS‐AIH was the only independent predictor for achieving complete response. Conclusions: Prompt initiation of high‐dose i.v. corticosteroids in original AS‐AIH seems safe and efficient as it prevents disease deterioration and the need for liver transplantation. The long‐term overall survival of these patients was high (97% for 5.3 years), and the long‐term treatment response and corticosteroids withdrawal rates were higher compared to not‐AS‐AIH patients. [ABSTRACT FROM AUTHOR]

Aim: Acute liver failure (ALF) is a syndrome of severe liver injury that may need urgent liver transplantation and is associated with significant risk of death. Early outcome prediction and further possibilities to increase accuracy of prognosis scores are important. Methods: We examined 30 patients with ALF, according to the novel criteria of the Intractable Hepato‐Biliary Diseases Study Group, who underwent transjugular liver biopsy (TJLB) and investigated the relevance of histology for correct diagnosis and etiology. We assessed the suitability of necrosis (%), hepatic venous pressure gradients (HVPG), and hepatocentral venous gradients of serum biomarkers for outcome prediction. For this purpose, we calculated the difference of biomarker levels between hepatic vein (HV) and superior vena cava (SVC) blood samples. Results: Histology of TJLB specimens contributed to finding the etiology in 83%. Necrosis (%) and HVPGs were not significantly different between outcome groups. In gradient measurements, caspase 3/7 activity and total cytokeratin 18 (CK‐18) (M65) had significant and relevant levels different from zero. Although they were not accurate for outcome prediction, differences between outcome groups were detected in caspase activation: levels of caspase 3/7 activity in the HV and caspase‐cleaved CK‐18 (M30) in the SVC were significantly higher in spontaneously recovered patients. Conclusions: Our results underline the role of caspase activation in spontaneous recovery from ALF. Furthermore, the calculation of hepatocentral venous biomarker gradients could represent a new diagnostic tool whose clinical potential needs to be further investigated. [ABSTRACT FROM AUTHOR]

Aim There are no beneficial therapies except for emergency liver transplantation for acute liver failure (ALF). However, in Japan, which has a serious problem in the shortage of donor livers, therapies other than transplantation must be further investigated for patients with ALF. Pro-inflammatory cytokines promoting tissue destruction are predominant at an early phase of ALF. Corticosteroid (CS) influences monocyte/macrophage differentiation, by suppressing pro-inflammatory genes, indicating CS treatment might be beneficial during the early phase of ALF. Our aim was to elucidate the efficacy of CS pulse therapy in decreasing pro-inflammatory cytokine levels in the early stage of ALF. Methods Ten consecutive adult Japanese patients with fulminant hepatitis in the early stage, three treated with artificial liver support (ALS) and CS pulse therapy (ALS + CS group) and seven treated with ALS (ALS group), were enrolled. Clinical and biochemical data on admission were matched between the groups and retrospectively analyzed for serum concentrations of interleukin-6, tumor necrosis factor-α, and interleukin-1β over a 2-week period. Results Mean cytokine levels on admission were not different between the two groups. Tumor necrosis factor-α was significantly reduced on day 7 in patients with CS. Serum levels of pro-inflammatory cytokines tended to be reduced in patients with CS compared to those without during the observation period, although the differences were not significant. Conclusions It might be possible that introduction of CS pulse therapy in the early stage of ALF could reduce levels of pro-inflammatory cytokines, which might inhibit the cascade of progression of ALF. [ABSTRACT FROM AUTHOR]

Aim Our aim was to analyze serial changes in the predictive variables and a scoring system retrospectively adapted to evaluate outcomes in pediatric patients with acute liver failure (ALF). Methods We retrospectively collected data on 65 patients with ALF. The 65 patients were divided into two groups according to the need for liver transplantation (LT) as follows: LT group ( n = 54) and non-LT group ( n = 11). The early determination scoring system of the indications for LT proposed by the Intractable Hepato-Biliary Diseases Study Group of Japan (JIHBDSG) was used in our study. The area under the receiver operating characteristic curve (AUROC) was calculated for the JIHBDSG score between the LT group and non-LT group at the time of diagnosis (day 0) and day 3, and day 5 after the diagnosis. Results A JIHBDSG score of >3 at day 5 was found to identify the patients requiring LT with 83.7% sensitivity, 81.8% specificity, and 83.3% diagnostic accuracy. Based on a comparison of AUROC values, the JIHBDSG score on day 5 (AUROC 0.91) was higher than that on day 0 (AUROC 0.75) and day 3 (AUROC 0.84). Conclusion We showed that a serial analysis of the JIHBDSG score might be useful for predicting outcomes of ALF in pediatric patients who fulfilled the criteria of LT indication in our center. However, further studies are needed to validate our results. [ABSTRACT FROM AUTHOR]

Aim Apoptosis is associated with various types of hepatic disorders. We have developed a novel cell-transfer drug delivery system (DDS) using a multifunctional envelope-type nano device that targets liver sinusoidal endothelial cells (LSECs). The purpose of this study was to determine the efficacy of the novel DDS containing siRNA at suppressing apoptosis in LSECs. Methods Bax siRNA was transfected into a sinusoidal endothelial cell line (M1) to suppress apoptosis induced by an anti-Fas antibody and staurosporine. C57BL/6J mice were divided into three groups: (i) a control group, only intravenous saline; (ii) a nonselective group, injections of siRNA sealed in the nonselective DDS; and (iii) an LSEC-transfer efficient group, injections of siRNA sealed in an LSEC-transfer efficient DDS. Hepatic cell apoptosis was induced by an anti-Fas antibody. Results Bax siRNA had an anti-apoptotic effect on M1 cells. Serum alanine aminotransferase was reduced in the LSEC-transfer efficient group, as were cleaved caspase-3 and the number of terminal deoxynucleotidyl transferase dUTP nick end labeling positive hepatocytes. Silver impregnation staining indicated that the sinusoidal space was maintained in the LSEC-transfer efficient group but not in the other groups. Electron microscopy showed that the LSECs were slightly impaired, although the sinusoidal structure was maintained in the LSEC-transfer efficient group. Conclusion Hepatocyte apoptosis was reduced by the efficient suppression of LSEC apoptosis with a novel DDS. Protecting the sinusoidal structure by suppressing LSEC damage will be an effective treatment for acute liver failure. [ABSTRACT FROM AUTHOR]

Aim The prognosis of acute-on-chronic liver failure (ACLF) is extremely poor in comparison to acute liver failure (ALF). We aimed to establish methods for the early diagnosis of ACLF and its severity to identify the patients with a poor prognosis. Methods The laboratory data at admission of 30 ACLF and 46 ALF patients were compared. Three established prognosis prediction models (Model for End-Stage Liver Disease [MELD]; MELD modified by serum sodium concentration, [MELD-Na]; and the Japan hepatic encephalopathy prediction model [J-HEPM]) were assessed using area under the receiver-operator curve (AUROC) values. Results No significant difference was found in the laboratory data of the two patient groups. J-HEPM was able to predict the outcome of the ACLF subjects (AUROC = 0.93). Conclusion Although ACLF could not be differentially diagnosed from ALF at admission from the laboratory data alone, the J-HEPM effectively predicted the prognosis of liver failure in patients with ACLF. These findings indicate that ACLF patients with high J-HEPM scores require earlier and more intensive care than ALF patients. [ABSTRACT FROM AUTHOR]

Aim The outcome of acute liver failure (ALF) is influenced by its etiology, making etiological consideration of ALF important. However, specific etiology could not be identified in 30-40% of adult patients in a Japanese nationwide survey. We examined our patients with severe (SH) and fulminant hepatitis (FH) of indeterminate etiology for the better understanding of ALF. Methods We investigated 106 adult patients with SH or FH including 24 of indeterminate etiology between 2000 and 2013, retrospectively. Results Of 24 patients, 12 were men. Seventeen were SH and seven FH (three FH acute type and four FH subacute type). Eighty-three percent of patients were positive for antinuclear antibody. Seventeen recovered without liver transplantation (LT), two received LT and five died without LT. Histology of 15 patients showed a pattern of acute hepatitis (massive necrosis in four, submassive necrosis in one, severe acute hepatitis in two and acute hepatitis in eight). The involvement of immune-mediated liver injury was histologically suggested in some patients. Conclusion There was no large cluster of etiology in our patients with indeterminate cause. The causes of ALF of indeterminate etiology were the mixture of various minor or rare ones, if precise diagnosis of acute AIH was done. Outcome of our patients with indeterminate cause was not poor if they were treated as early as possible after the diagnosis of severe disease. Careful examination of unknown viral infection, drugs, toxins, undefined metabolic disorders and histology may help detect some of these etiologies. [ABSTRACT FROM AUTHOR]

Aim Older age has been widely believed to be associated with a poor prognosis of acute liver failure. We aimed to evaluate the impact of older age on outcomes of Japanese patients with severe and fulminant hepatitis in an era of a highly aging society. Methods We investigated 105 consecutive adult patients with fulminant hepatitis ( FH) or severe hepatitis ( SH) admitted to our liver unit between 2000 and 2013, consisting of 14 elderly patients (≥65 years) and 91 younger ones (<65 years). Results In elderly patients, the proportion of women was greater ( P < 0.001), the levels of aspartate aminotransferase and lactate dehydrogenase on admission were lower ( P = 0.011 and P = 0.010, respectively), and the survival rate without liver transplantation was lower ( P = 0.024) than younger ones. Two of seven SH and all seven FH elderly patients died, whereas all 45 SH and 16 of 46 FH younger patients recovered. Seventy-one percent of elderly patients had underlying diseases with medications, and 57% had additional complications after the start of treatment for acute liver failure. Patients aged 70 years or more showed even poorer prognoses than younger ones and those aged 65-69 years ( P = 0.0052 and P = 0.036, respectively). Conclusion Older age was associated with a poor prognosis of patients with SH and FH. One of the reasons other than complications and loss of organ reserve by aging would be that elderly patients consulted us at a more advanced stage of illness than younger ones. [ABSTRACT FROM AUTHOR]

Aim We measured liver stiffness ( LS) in patients with acute liver failure ( ALF) using acoustic radiation force impulse ( ARFI) elastography and investigated the usefulness of measuring LS for predicting the prognosis of ALF patients. Methods From April 2010 to December 2013, we evaluated 63 patients with acute liver disease. The subjects included 41 patients with acute hepatitis ( AH), 16 patients with severe AH ( SAH), who had no hepatic encephalopathy despite plasma prothrombin time of 40% or less, and six patients with fulminant hepatitis ( FH) diagnosed according to the criteria of the Japanese Study Group. The relationships among shear wave velocity ( SWV), clinical diagnosis, liver function tests and prognosis were evaluated. Receiver-operator curve ( ROC) analysis was performed to investigate whether ARFI elastography exhibits potential usefulness for the prediction of FH. Results The mean SWV on admission were 1.98 ± 0.55, 2.61 ± 0.58 and 3.66 ± 0.86 m/s in the AH, SAH and FH groups, respectively. The SWV was significantly higher in the FH group than in the other groups ( P < 0.001), and in the SAH group than in the AH group ( P = 0.002). The area under the ROC for predicting FH was 0.924 (sensitivity, 83.3%; specificity, 93.0%). The SWV was significantly increased in non-survivors, while remaining decreased in survivors ( P = 0.002). Conclusion The SWV measured by ARFI elastography reflects severity of liver damage, and serial changes in SWV predict the prognosis of ALF patients. The SWV is an early and precise biomarker of FH. [ABSTRACT FROM AUTHOR]

Aim Increased serum α-fetoprotein ( AFP) has been associated with a good prognosis following acute liver failure ( ALF), but the levels of the fucosylated fraction of AFP ( Lens culinaris agglutinin-reactive fraction of AFP [ AFP-L3]) following acute liver injury remain unknown. The aim of the present study was to investigate the clinical significance of AFP and AFP-L3 in patients with acute liver injury. Methods We investigated the serum levels of AFP and highly sensitive AFP-L3% in 27 patients with acute-onset autoimmune hepatitis ( AIH), 28 patients with acute hepatitis ( AH) and 22 patients with ALF at the onset using a highly sensitive immunoassay (micro-total analysis system). Results The serum AFP levels were increased in patients with AIH, AH and ALF, but the levels did not significantly differ among them. However, the mean AFP-L3% level was significantly higher in patients with AIH than in patients with AH ( P = 0.0039). Moreover, significantly more patients with AIH demonstrated AFP-L3 positivity (≥10%) when compared with patients with AH ( P = 0.014). Although the percentage of AFP-L3 positivity increased with AFP levels, at low serum AFP levels (<10 ng/mL), significantly more patients with AIH demonstrated AFP-L3 positivity than did patients with AH ( P = 0.024) or ALF ( P = 0.038). Conclusion We demonstrated for the first time that highly sensitive AFP-L3% levels were increased at the onset of AIH. The mechanism underlying the increase in AFP-L3 remains to be elucidated, but this finding may reflect an alteration of the glycosylation such as hyperfucosylation, which can influence the modifications of self-antigens in hepatocytes. [ABSTRACT FROM AUTHOR]

Aim Acute liver failure ( ALF) is a worldwide problem despite its rare incidence because of its extremely high mortality. There are no beneficial therapies except for emergency liver transplantation for ALF. However, in Japan where the problem of a shortage of donor livers still remains, therapies other than transplantation must be further investigated for patients with ALF. Our aim was to elucidate the efficacy of high-dose corticosteroid ( CS) in decreasing liver enzyme levels in the early stage of ALF. Methods Thirty-one consecutive Japanese patients with viral ALF in the early stage were prospectively examined for their clinical and biochemical features and treatment responses during 2 weeks after the start of treatment. Nineteen were treated with high-dose methylprednisolone, and 12 having clinical and biochemical backgrounds with no significant difference were treated without CS. Results The aspartate aminotransferase : alanine aminotransferase ratio became lower in patients treated with CS than in controls ( P < 0.05). Fifteen of 19 patients in the CS group and eight of 12 in the control group recovered ( P = 0.36). Hepatitis B viral infection and advanced liver damage at the start of treatment were associated with poor prognosis ( P < 0.05). Complications during the therapy were not greater in the CS group than control ( P = 0.64). Conclusion The introduction of high-dose CS in the early stage of ALF was effective in suppressing the destruction of hepatocytes. CS-treated patients showed slightly higher survival rates and slightly more improved liver regeneration than controls, although the differences were not statistically significant. [ABSTRACT FROM AUTHOR]

Aim To summarize the annual nationwide survey on fulminant hepatitis ( FH) and late-onset hepatic failure ( LOHF) between 2004 and 2009 in Japan. Methods The annual survey was performed in a two-step questionnaire process to detail the clinical profile and prognosis of patients in special hospitals. Results Four hundred and sixty ( n = 227 acute type; n = 233 subacute type) patients had FH and 28 patients had LOHF. The mean age of patients with FH and LOHF were 51.1 ± 17.0 and 58.0 ± 14.4 years, respectively. The causes of FH were hepatitis A virus in 3.0%, hepatitis B virus ( HBV) in 40.2%, other viruses in 2.0%, autoimmune hepatitis in 8.3%, drug allergy-induced in 14.6% and indeterminate etiology in 29.6% of patients. HBV reactivation due to immunosuppressive therapy was observed in 6.8% of FH patients. The short-term survival rates of patients without liver transplantation ( LT) were 48.7% and 24.2% for the acute and subacute type, respectively, and 13.0% for LOHF. The prognosis was poor in patients with HBV reactivation. The implementation rate for LT in FH patients was equivalent to that in the previous survey. The short-term survival rates of total patients, including LT patients, were 54.2% and 40.8% for the acute and subacute type, respectively, and 28.6% for LOHF. Conclusion The demographic features and etiology of FH patients has gradually changed. HBV reactivation due to immunosuppressive therapy is problematic. Despite advances in therapeutic approaches, the prognosis of patients without LT has not improved. [ABSTRACT FROM AUTHOR]

In 2011, the Intractable Liver Diseases Study Group of Japan, established novel diagnostic criteria for 'acute liver failure ', and published the classification criteria for the etiologies of acute liver failure and late-onset hepatic failure (LOHF) in 2013. According to this classification, HBV carriers showing acute hepatitis exacerbation were divided into 3 subgroups; asymptomatic or inactive HBV carriers without drug exposure, asymptomatic or inactive HBV carriers developing HBV reactivation during and after immunosuppressive therapies and/or antineoplastic chemotherapies and those with previously resolved HBV infection showing iatrogenic HBV reactivation. In an annual nationwide survey in 2013, however, a patient with previously resolved HBV infection was enrolled, in whom LOHF developed as a result of HBV reactivation despite in the absence of immunosuppressive therapies and/or antineoplastic chemotherapies. Thus, the study group revised the classification criteria in 2015; HBV carriers developing acute hepatitis exacerbation were classified into asymptomatic or inactive HBV carriers and patients with previously resolved HBV infection, and both groups were further sub-classified into those receiving immunosuppressive therapies and/or antineoplastic chemotherapies and those without such drugs exposure. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) is an important cause of acute liver failure (ALF) worldwide. Two clinical entities are responsible for HBV-related ALF: acute hepatitis B and acute exacerbation of chronic HBV infection. Differentiation between these clinical entities is sometimes difficult, especially when past status of hepatitis B surface antigen (HBsAg) is unknown. A quantitative analysis of serum immunoglobulin M (IgM) antibody to the hepatitis core antigen (anti-HBc) may be helpful in the differential diagnosis. The recent definition of ALF in chronic HBV infection is somewhat problematic, because clinical, laboratory and radiological findings cannot reliably predict the presence of underlying liver cirrhosis in patients with acute exacerbation of chronic HBV infection. Explant liver shows underlying liver cirrhosis in >50% of these cases, even when there is no clinical evidence of liver cirrhosis. Therefore, it is advisable to exclude these patients in clinical trials because of the high incidence of underlying liver cirrhosis. The clinical course, however, is not different and neurologic complications are responsible for about half of the deaths, so a priority for liver transplantation should be maintained in these patients. The prognosis of HBV-related ALF is quite grim without liver transplantation with transplant-free survival rates ranging from 26% to 53%. To date, there is not enough evidence that antiviral therapy or artificial liver support devices can enhance the patient's survival, therefore, liver transplantation is still the only effective treatment option that can alter the grave prognosis of HBV-related ALF. [ABSTRACT FROM AUTHOR]

Liver regeneration is considered to be retarded or suppressed in patients with acute liver failure. However, the mechanisms for this suppression remain to be elucidated. In order to evaluate deficiencies in liver regeneration in patients with acute liver failure, we focused on the cross-communication of growth-associated factors in experimental models. In primary cultured rat hepatocytes, the levels of cellular p53 and transforming growth factor-alpha (TGF-alpha), as well as DNA synthesis increased by the addition of hepatocyte growth factor (HGF). When p53 activity was suppressed, TGF-alpha expression and DNA synthesis were reduced. DNA synthesis was also reduced when TGF-alpha activity was suppressed. In rats after partial hepatectomy, hepatic HGF and p53 protein levels increased, followed by an increase of hepatic TGF-alpha levels and hepatocyte proliferation. Circulating levels of HGF and TGF-alpha correlated with changes in the hepatic levels. The suppression of TGF-alpha activity reduced the proliferation of hepatocytes in these rats. In patients suffering from acute hepatitis, serum HGF levels increased followed by an increase of serum TGF-alpha levels. In contrast, in patients with acute liver failure, the increase of serum TGF-alpha levels was suppressed depending on the severity of hepatic failure, even though serum HGF levels markedly increased. The patients' hepatic levels were consistent with serum levels. Cross-communication of growth associated factors may be important in the progression of liver regeneration, and impaired regenerative capacity in patients with acute liver failure may be attributable, at least in part, to a disruption of communication of growth-associated factors. [ABSTRACT FROM AUTHOR]

Acute liver failure (ALF) is a widespread problem with typically unfavorable prognosis. With the implementation of a liver support device in the clinical setting for treatment of patients with ALF, anticipated improvements include prolonging time available for spontaneous recovery and bridging to liver transplantation. Liver support could also serve to prevent systemic manifestations of ALF such as renal failure, pulmonary edema, systemic inflammatory response syndrome and cerebral edema evolving to brain death. Both non-cell based and cell based (bio-artificial) systems have been used in clinical trials. Systems with closed or open loop organization present different advantages and disadvantages; systems also differ in the membrane pore size for filtrate/dialysate exchange. Further optimization of liver assist devices is still required; when a system has proved to be successful in treating the debilitating results of ALF, the benefits will be enormous to liver failure patients. [ABSTRACT FROM AUTHOR]

The annual incidence of fulminant hepatitis (FH) in Japan has decreased from 3700 patients in 1972 to 1000 patients in 1989, 1050 patients in 1995 and 426 in 2004. The most frequent cause of FH in Japan is hepatitis B virus (HBV)-related hepatitis, which accounts for around 40%, with hepatitis A accounting for around 10%; drug reaction accounts for around 10%; other hepatitis, including an unknown cause, accounts for around 40%. The acute type FH, which has a disease duration as 10 days or shorter before the development of encephalopathy (onset-coma days [OCD]), mainly consists of hepatitis A and B and has relatively better prognosis, with an approximately 40% survival rate without transplantation. The subacute type FH, which has 11 to 56 days OCD, mainly consists of unknown hepatitis including acute-onset autoimmune hepatitis and has poorer prognosis of about 20% survival. Approximately 25% of FH patients underwent liver transplantation and about 80% of them survived. High volume plasma exchange (PE) and hemodialysis filtration (HDF) have been the most common and principal therapies and they are administered to about 90% and 70% of patients, respectively. The progress of artificial liver support such as combination treatment of PE with HDF is considered to play a role in the slight improvement of the survival proportion of patients with acute type FH in recent years. [ABSTRACT FROM AUTHOR]

Acute liver failure caused by viruses, drugs, or liver resection, is marked by a massive degree of hepatocyte apoptosis and impaired hepatocyte proliferation, the mechanisms of which, however, still remain to be understood. The choice between life and death is associated with events in regulation of the immune system. The liver is continuously exposed to a large antigenic load that includes pathogens, toxins and dietary antigens. Bacterial toxins, including endotoxin and staphylococcal enterotoxin, have been implicated in the pathogenesis of multi-organ failure associated with liver damage through production of cytokines and chemokines. Inflammation involves the sequential activation of signaling pathways leading to the production of both pro- and anti-inflammatory mediators. Among pro-inflammatory mediators, tumor necrosis factor-α (TNF-α)/TNF receptor (TNFR) systems play central roles in the physiological regulation of apoptosis as well as inflammation and immunity. These pleiotropic biological effects of TNF-α result from its ability to initiate different intracellular signaling pathways, which induce both pro-apoptotic and anti-apoptotic molecules. Hepatocytes appear to be poorly responsive to pro-apoptotic stimuli by TNF-α. Tumor necrosis factor-α, however, induces excessive hepatocyte apoptosis, once cells are sensitized by D-galactosamine or actinomycin D, suggesting that TNF-α itself also induces molecules that protect cells from apoptosis by TNF-α. Besides the apoptosis-inducing signal, the binding of TNF-α to TNFR1 triggers a series of intracellular events that result in the activation of nuclear factor-κB (NF-κB), phosphatidylinositol 3-kinase (PI3K)/Akt, and c-Jun NH2-terminal kinase (JNK). Inhibition of NF-κB may be a two-edged sword against liver injury, which inhibits pro-inflammatory gene expression in leukocytes and causes the sensitization of hepatocytes to TNF-α-induced apoptosis. A variety of mechanisms exist to modulate the activity of intracellular molecules and thereby affect the ultimate outcome of a liver cell's fate. [ABSTRACT FROM AUTHOR]

Abstract: Measurement of serum human hepatocyte growth factor (HGF) by enzyme-linked immunosorbent assay (ELISA) is useful for the early diagnosis and prediction of prognosis of patients with acute liver failure (ALF). This ELISA methodology, however, is neither rapid nor convenient for use at the bedside. In this study, we have developed a rapid semi-quantitative immunochromatographic (IC) assay and evaluated its usefulness in assessing patients with acute hepatic injury. Only 100μl of serum is required; the assay can be easily completed in 20min. The values obtained using this novel assay correlated well with the values obtained using the standard ELISA protocol. In addition, the values obtained in the IC assay correlated with clinical course; increased serum HGF levels were associated with an increased frequency of ALF and death. These results indicate that this rapid semi-quantitative IC assay for HGF is useful for the early diagnosis of ALF and prediction of clinical outcome in acute hepatic injury. [Copyright &y& Elsevier]

Abstract: Significant evidence of the pharmacological and physiological effects of branched-chain amino acids (BCAA) has accumulated, attracting the interest of not only clinicians but also basic medical researchers. We summarize here the characteristic features of BCAA catabolism, focusing on the initial two enzymes in the pathway, branched-chain aminotransferase and branched-chain α-keto acid dehydrogenase complex. In addition, we describe a unique characteristic of the valine catabolic pathway. Finally, we present evidence obtained in animal studies that indicates that BCAA treatment may be appropriate for liver cirrhosis, but not acute liver failure. [Copyright &y& Elsevier]

Acute liver failure (ALF) was reproduced in young mice exposed daily for 12 days to the industrial surfactant, Toximul 3409F (Tox), and infected on postnatal day (P) 14 with sublethal doses of mouse-adapted human influenza B (Lee) virus (FluB). Combined Tox + FluB treatment potentiated mortality due to non-necrotic ALF. This study tested the hypothesis that mortality would decline if the known losses in energy production due to compromised fatty-acid β-oxidation were compensated by pharmacological manipulation of hepatic glycogen stores. Glycogen levels, body weights, and mortality were determined without and with injections of insulin-like growth factor-1 (IGF-1). On P25, 13 days after Tox exposure ceased, glycogen levels (mg/100 mg) were: 4.0 (control), 1.7 (Tox), 4.3 (FluB), and 2.9 (Tox + FluB). Corresponding cumulative mortalities were 0, 14, 2, and 38%. Following daily IGF-1 injections from P12 to P17, liver glycogen levels on P25 were: 3.5 (IGF-1), 3.9 (IGF-1 + Tox), 12.3 (IGF-1 + FluB), and 5.6 (IGF-1 + Tox + FluB). Unexpectedly, IGF-1 treatment increased mortality to 67% (IGF-1), 89% (IGF-1 + Tox), 63% (IGF-1 + FluB), and 81% (IGF-1 + Tox + FluB). For all groups there was a significant correlation between mortality and poor weight gain. This is the first report of persistent glycogen reductions after surfactant exposure and withdrawal. Their role in potentiating FluB-induced mortality remains to be established. [Copyright &y& Elsevier]

In two cases of hepatic arterial flow interruption after hepatopancreatic surgery, continuous PGE1 infusion from the superior mesenteric artery (SMA) was applied to oxygenate the liver through the portal vein. Case 1 was a 69-year-old woman with a non-functioning islet cell tumor of the pancreas. She underwent pancreatic resection following hepatic arterial infusion of anticancer drugs. Serum alanine aminotransferase (ALT) was elevated to 5500 IU/l on postoperative day (POD) 2; angiography revealed complete celiac artery obstruction. Continuous PGE1 was administered from SMA at a rate of 0.01 μg/kg/min for 7 days. Serum ALT was normalized within 2 weeks and the peak level of serum total bilirubin (T. Bil) was 4.5 mg/dl. Case 2 was a 66-year-old man suffering from metastatic liver cancer. Complete obstruction of the proper hepatic artery was noted at the time of liver resection after hepatic arterial chemotherapy. Serum ALT was elevated to 2930 IU/l on POD 1, and PGE1 infusion from SMA was done for the succeeding 7 days. Necrotic area was so vast that serum T. Bil rose to 19 mg/dl. However, it decreased with time. Both cases required 3 months for necrotic liver shrinkage. Doppler ultrasonography revealed that PGE1 infusion actually increased portal blood flow. In conclusion, based on the preceding experimental backgrounds and clinical experiences, continuous PGE1 infusion via the SMA can be a useful measure to prevent severe liver damage after hepatic arterial flow interruption through portal blood oxygenation. [Copyright &y& Elsevier]

Acute liver failure (ALF) is defined by the presence of hepatic encephalopathy due to severe liver damage in patients without pre-existing liver disease. Although the mortality of ALF without liver transplantation is over 80%, the survival rates of ALF patients have improved considerably with the advent of liver transplantation, up to 60–80% in the last decade. Living donor liver transplantation (LDLT), which has mainly evolved in Asian countries where organ availability from deceased donors is extremely scarce, has also improved the survival rate of ALF patients. According to recent reports, the overall survival rate of adult ALF patients who underwent LDLT is 60% to 90%. Although there is still controversy regarding the graft type, the optimal graft volume, and ethical issues of defining the indications for LDLT in ALF patients with respect to donor risk, LDLT has become an established treatment option for ALF in areas where the use of deceased donors organs is severely restricted. [ABSTRACT FROM AUTHOR]