Admission Factor V Predicts Transplant-Free Survival in Acute Liver Failure.

BACKGROUND AND AIMS: Traditional laboratory markers are insensitive in distinguishing between patients with acute liver failure (ALF) who will require urgent liver transplantation (LT) from those who will recover spontaneously, particularly within 24 h of presentation. Coagulation factor-V (FV) may improve the accuracy of outcome prediction in ALF due to its predominant synthesis in the liver and short half-life in plasma. METHODS: Patients enrolled in the ALF Study Group Registry from a single site had FV determined within 24 h of presentation (Derivation-Cohort). Area under the receiver operating characteristic curves (AUROC) dichotomized by ALF etiology [acetaminophen (APAP) or non-APAP] were constructed to evaluate the diagnostic performance of FV for transplant-free-survival (TFS). Multivariate logistic regression modeling was performed using FV and other clinical variables to predict TFS. Accuracy of FV and multivariable model were performed in a Validation-Cohort from a different site. RESULTS: 90-patients (56% with APAP) were included in the Derivation-Cohort. Median FV was significantly higher in TFS versus those who died/LT (31% vs. 15%, respectively; p = 0.001). When dichotomized by etiology, AUROC for FV was 0.77 for APAP (cutoff, sensitivity, specificity 10.5%, 79%, 69%, respectively) and 0.77 for non-APAP (22%, 85%, 67%, respectively). When the optimal cutoffs for FV in the Derivation-Cohort were applied to the Validation-Cohort (N = 51; 59% with APAP), AUROC for FV was 0.75 for APAP (sensitivity/specificity 81/44) and 0.95 for non-APAP (sensitivity/specificity 90/73). In multivariate analyses, AUROC for FV model was 0.86 in the Derivation-Cohort and 0.90 in the Validation-Cohort. CONCLUSION: Admission FV may improve selection of patients who are likely to improve without LT.

Early therapeutic plasma exchange may improve treatment outcomes in severe acute toxic Hepatitis.

BACKGROUND AND OBJECTIVES: Acute toxic hepatitis can result in a different clinical course from a completely curable disease to subacute hepatitis, chronic hepatitis, and fulminant hepatitis failure, which is quite mortal. For this purpose, therapeutic plasma exchange (TPE) can be used for improving treatment outcomes by reducing the harmful substances caused with and/or without liver function in acute toxic hepatitis. We aimed to evaluate treatment outcomes in severe acute toxic hepatitis patients who applied early TPE procedure. MATERIALS AND METHODS: A total of 335 patients who received TPE between 2010-2021 were retrospectively screened and 59 (male/female, 30/29; min/max-age, 22-84) patients with acute toxic hepatitis who underwent TPE in the first 24 h were included in the study. TPE was performed in patients who had high total bilirubin level (>10 mg/dL). Laboratory parameters of the patients before and after the TPE procedure, number of patients developed complications of acute toxic hepatitis and mortality rates were evaluated for effectiveness of TPE. RESULTS: Acute toxic hepatitis was associated with hepatotoxic drugs in 44 (74.5 %), herbal medication 6 (10.2 %), mushroom poisoning 6 (10.2 %) and with substance abuse 3 (5.1 %) in patients. When the patients were compared based on INR, liver function tests, ammonia, lactate and Model For End-Stage Liver Disease (MELD) score at baseline, 48 h after TPE (independently of TPE number) and before final state a statistically significant decrease was observed in all parameters (p < 0.05). Fifty three (90 %) of patients improved without complications, the remaining 6 (10 %) patients were diagnosed with fulminant hepatitis. All these remaining patients died before liver transplantation (LTx) could be performed. CONCLUSION: TPE is a safe, tolerable therapy option and early TPE may improve treatment outcomes in severe acute toxic hepatitis.

Human liver regeneration following massive hepatic necrosis: Two distinct patterns.

BACKGROUND AND AIM: Massive hepatic necrosis is a rare but often fatal complication of various liver injuries. Nevertheless, some patients can survive by spontaneous hepatic regeneration. It is known that surviving hepatocytes and/or progenitor cells can participate in this process but the mechanism of hepatic recovery is vague. METHODS: We examined 13 explanted human livers removed for acute liver failure. Combined immunohistochemistry, digital image analysis, and three-dimensional reconstruction of serial sections were applied. RESULTS: Two patterns of regeneration could be distinguished. In livers with centrilobular necrosis, the surviving injured periportal hepatocytes started to proliferate and arrange into acinar structures and expressed α-fetoprotein. If the injury wiped out almost all hepatocytes, large areas of parenchymal loss were invaded by an intense ductular reaction. The cells at the distal pole of the ductules differentiated into hepatocytes and formed foci organized by the branches of the portal vein. The expanding foci often containing complete portal triads were arranged around surviving central veins. Their fusion eventually could be an attempt to re-establish the hepatic lobules. CONCLUSIONS: Regeneration of human livers following massive hepatic necrosis can occur in two ways-either through proliferation of α-fetoprotein-positive acinary-arranged hepatocytes or through ductular progenitor cells, with the latter being less efficient. Further investigation of these regenerative pathways may help identify biomarkers for likelihood of complete regeneration and hence have therapeutic implications.

Apolipoprotein A5 alleviates LPS/D-GalN-induced fulminant liver failure in mice by inhibiting TLR4-mediated NF-κB pathway.

BACKGROUND: Fulminant liver failure (FHF) is a serious clinical problem and liver transplantation is the major intervention. But the overall survival rate of FHF is low owing to the donated organ shortage. Apolipoprotein A-V (ApoA5) is a regulator of triglyceride metabolism and has been reported to act as a predictor for remnant liver growth after preoperative portal vein embolization and liver surgery. This study aimed to investigate the therapeutic effect of ApoA5 on lipopolysaccharide/D-galactosamine (LPS/D-GalN)-induced fulminant liver failure in mice. METHODS: FHF mouse model was established using LPS/D-GalN and ApoA5 plasmid was injected by tail vein prior to LPS/D-GalN treatment. The expressions of ApoA5, toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and nuclear factor kappa B p65 (NF-κBp65) were assessed by real-time PCR and western blotting. Serum alanine aminotransferase (ALT) and tumor necrosis factor-α (TNF-α) levels were measured using automatic biochemical analyzer. Histological assessment and immunohistochemical (IHC) staining were conducted. Survival rate after LPS/D-GalN administration was also determined with Kaplan-Meier curve. Meanwhile, the expression of ApoA5 in injured huh7 cells was tested. Cell apoptosis analysis was performed after huh7 cells were transfected with ApoA5 plasmid and stimulated with LPS. RESULTS: The expressions of ApoA5 decreased both in injured huh7 cells and FHF mice. ApoA5 overexpression reduced cell death rate using flow cytometry. ApoA5 not only decreased the serum ALT and TNF-α levels but also attenuated hepatic damage in hematoxylin-eosin (HE)-stained liver section. The protein expressions of TLR4, MyD88 and NF-κBp65 were inhibited when ApoA5 overexpressed. But the inhibitory effect would weaken with the increasing concentration of LPS in spite of ApoA5 overexpression. Besides, ApoA5 improved liver injury in a dose-dependent manner and the survival rate in FHF mice increased with increasing concentration of ApoA5. CONCLUSION: ApoA5 had a protective effect against LPS/D-GalN-induced fulminant liver failure in mice within a certain range by inhibiting TLR4-mediated NF-κB pathway.

Mesenchymal stem cells prolong survival and prevent lethal complications in a porcine model of fulminant liver failure.

BACKGROUND: Fulminant liver failure (FLF) is a life-threatening disease. METHODS: Lethal FLF was induced by ischemia-reperfusion (I-R) injury in mini-pigs, and MSCs were infused via splenic vein after reperfusion. RESULTS: Accumulated survival within 28 days was significantly improved by MSCs (P = 0.0348). Notably, MSCs maintained blood-gas homeostasis in the first 24 hours and prevented FLF-induced elevation of prothrombin time, international normalized ratio, and creatinine and ammonia levels in the first 3 days. With MSCs, serum levels of liver enzymes gradually decreased after 3 days, and platelet count was back to normal at 1 week of FLF. MSCs promoted liver regeneration within 2 weeks and differentiated into functional hepatocytes at 2-4 weeks after transplantation, evidenced by increase in Ki67-positive cells, detectable human hepatocyte growth factor, human vascular endothelial growth factor, human hepatocyte-specific antigen, and human albumin-expressing cells in the liver at different time points. Reactive oxidative species (ROS) were accumulated after FLF and eliminated at 4 weeks after MSC transplantation. CONCLUSIONS: Together, MSCs prolong the survival and prevent lethal sequelae of I-R injury-induced FLF by maintenance of liver-function homeostasis and rescue of ROS in the acute stage and by homing and differentiation into hepatocytes in the subacute stage.

Series of 10 dengue fever cases with unusual presentations and complications in Sri Lanka: a single centre experience in 2016.

BACKGROUND: Dengue has global importance as a dreaded arboviral infection. It has 4 serotypes of epidemiological imporatnce. The classification denotes two clinical spectrums- dengue fever (DF) and dengue haemorragic fever (DHF). Most cases are stereotype and amenable to fluid resuscitation. However, unusual manifestations cause fatalities and often overlooked. This study describes 10 such dengue cases to fill the knowledge gaps. CASE PRESENTATION: All 10 patients presented to the Teaching Hospital, Peradeniya, Sri Lanka during mid-year epidemic of dengue in 2016. The mean age is 27 years (range 12-51 years) comprising 6 females and 4 males. The group had 7 DHF, 3 DF and 2 primary dengue infections who predominantly had severe bleeding into gut. Other potentially life threatening problems were acute severe hepatitis, severe septic shock, myocarditis, erratic rapid plasma leak, intracranial bleeding, diarrhoea and decompenstaed dengue shock due to 3rd space fluid leak. Blood transfusions and other empirical therapeutic methods were used apart from meticulous fluid management to suit issues of each patient. Bedside ultrasound scanning helped early detection of critical phase. All recovered fully. CONCLUSIONS: Dengue is an extremely challenging infection to treat in the globe today. Above unusual presentation and complications could be fatal, if not detected early where therapeutic window period is very short. Clinicians need awareness of these problems which are not uncommon, but underreported and often overlooked. The clinical management of each patient was described for the purpose sharing the experiences.

Chronic hepatitis B carriers with acute on chronic liver failure show increased HBV surface gene mutations, including immune escape variants.

BACKGROUND: The pathogenesis of acute-on-chronic liver failure (ACLF) in chronic hepatitis B (CHB) is not well understood. The aim of this study was to investigate whether there is an association between HBV polymerase (P)/overlapping surface (S) gene and basal core promoter (BCP)/precore (PC) variants and development of ACLF in CHB. METHODS: Two CHB patient cohorts were compared: (i) ACLF (N = 12) (11/12 M, median age 52 yrs., 5/9 genotype C, 6/12 HBeAg+), (ii) 27 treatment native CHB carriers (15/27 M, median age 44 yrs., 9 genotype B, 10 genotype C, 1 genotype A, 5 genotype D, 2 genotype E). Clonal sequencing of PCR-amplified HBV P/S and BCP/PC gene fragments was done and HBV diversity, frequency of immune escape (IE) and drug resistance (DR) mutations and mutations in BCP/PC gene (G1896A and A1762T/G1764A), were compared between each group. RESULTS: Our data showed the incidence of IE and clusters of mutations in the HBV S region was significantly greater in ACLF patients vs. treatment naïve CHB patients (p < 0.05). Additionally, a significantly higher frequency of G1896A and A1762T/G1764A mutations were found in HBeAg negative than in ACLF patients (p < 0.0001). CONCLUSION: In our study, ACLF was not associated with a specific genomic mutation. However, higher frequency of IE mutations along with various mutations clustering in the HBV S region could contribute to or be an outcome of ACLF in CHB infection. (words 226).

Testing of microencapsulated porcine hepatocytes in a new model of fulminant liver failure in baboons.

BACKGROUND: There is no standard therapy for acute liver failure. Hepatocyte transplantation has been proposed for temporary liver function support, while the injured liver regenerates or while waiting for transplantation. We have previously shown such efficacy for microencapsulated porcine hepatocytes in mice with fulminant liver failure. We aimed to establish a large animal model for fulminant liver failure to assess the efficacy of microencapsulated porcine hepatocytes in temporary liver function support. METHODS: The model was developed in baboons; for testing microencapsulated hepatocytes, the best condition was 75% hepatectomy and 60 min warm ischemia time. Fulminant liver failure was characterized by steep increases in liver biochemical parameters, severe steatosis, and massive hepatocyte necrosis during the first 10 days. Hepatocytes from miniature swine were microencapsulated in alginate-poly-l-lysine microspheres, and transplanted intraperitoneally immediately after hepatectomy and warm ischemia (80-120 mL packed hepatocytes in 200-350 mL microspheres, about 30%-50% of the baboon's native liver volume). RESULTS: In the control group, three of five animals were sacrificed after 6-10 days because of fulminant liver failure, and two of five animals recovered normal liver function and survived until elective euthanasia (28 days). In the treatment group of four animals, one animal developed liver failure but survived to 21 days, and three animals recovered completely with normal liver function. CONCLUSIONS: The results indicate that microencapsulated porcine hepatocytes provide temporary liver function support in baboons with fulminant liver failure. These data support development of this cell therapy product toward clinical trials in patients with acute liver failure.

[Indications to liver transplantation]. / Indikace k transplantaci jater - kdy odeslat nemocného.

Liver transplantation should be considered in patients with end-stage liver disease in whom this operation would extend life expectancy beyond what the natural history of underlying disease would predict or in whom transplantation is likely to substantially improve the quality of life. Liver transplantation is indicated in end-stage liver disease, in selected liver tumors and in fulminant liver failure. The most common indication in adult to transplantation is decompensated liver cirrhosis with life expectancy one year or less. Evaluation and referral to transplantation center should be considered when a major complication of liver cirrhosis occurs - ascites, bleeding due to portal hypertension, hepatorenal syndrome or hepatic encephalopathy. MELD score 15 is recommended to list patients with end-stage liver disease. In recent years the indication of decompensated cirrhosis B and C is declining, on contrary, there is an increase in indication for hepatocellular carcinoma and NASH. An extension of indications has been observed recently - patients above 70 years of age, patients with neuroendocrine tumors among others. In 2016 in Czech Republic total 179 livers were transplanted, but only a small fraction of potential candidates was referred to transplant centers.

Fulminant liver failure resulting from massive hepatic infarction associated with hemolysis, elevated liver enzymes, and low platelets syndrome.

Hepatic infarction is an extremely rare and fatal complication associated with hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. It can develop into fulminant liver failure, which increases both maternal and neonatal mortality rates. A 34-year-old woman with no remarkable past medical history developed eclampsia after delivery at 40 weeks of gestation. Imaging indicated massive hepatic infarction and rupture followed by cardiac arrest and fulminant liver failure. Despite liver replacement therapy with plasma exchange and continuous hemodiafiltration, the patient gradually deteriorated with persistent bacterial infection until death at 98 days after delivery. The management of fulminant liver failure complicated with HELLP syndrome should be multidisciplinary. Liver transplantation, the only radical treatment for fulminant liver failure, is worth attempting, if applicable.

Recent advances in management of acute liver failure.

Acute liver failure (ALF) is a life-threatening illness, where a previously normal liver fails within days to weeks. Sudden loss of synthetic and detoxification function of liver results in jaundice, encephalopathy, coagulopathy, and multiorgan failure. The etiology of ALF varies demographically. The mortality of ALF is as high as 40-50%. The initial care of patients with ALF depends on prompt recognition of the condition and early detection of etiology. Management includes intensive care support, treatment of specific etiology if present and early detection of candidates for liver transplantation. Liver transplantation remains the only therapeutic intervention with proven survival benefit in patients with irreversible ALF. Living related liver transplantation, auxiliary liver transplantation, and  ABO-incompatible liver transplantation are coming up in a big way. Liver assist devices and hepatocyte transplant remain experimental and further advances are required. Public health measures to control hepatitis A, B, E, and drug-induced liver injury will reduce the incidence and mortality of ALF.

The First Case of Daratumumab-Induced Fulminant Hepatic Failure.

Drug-induced liver failure is a relatively uncommon condition with a vast spectrum of clinical manifestations, and it is a leading cause of acute hepatic failure in the United States. We describe the first case of fulminant hepatic failure induced by chemotherapeutic drug daratumumab, a common FDA-approved agent. A 77-year-old male, with a history of multiple myeloma, was admitted for left lower extremity cellulitis, two weeks after receiving his first intravenous infusion of daratumumab. He developed fulminant hepatic failure in the hospital a few days later. Despite multiple doses of N-acetylcysteine, his liver function continued to decline, and he expired shortly after.

Fulminant Hepatic Failure as the Initial Presentation of Hodgkin Lymphoma in 4 Patients With Human Immunodeficiency Virus.

In the era of antiretroviral therapy (ART), Hodgkin Lymphoma (HL) is a common non-AIDS-defining cancer with increasing incidence in people with human immunodeficiency virus (PWH). Through review of these cases, we identify clinical patterns such as declining CD4 count despite ART, hyperbilirubinemia and recurrent fever, which preceded diagnosis. Identifying these important signs and symptoms may lead to earlier diagnosis and initiation of therapy. Fulminant hepatic failure limits the ability to give standard of care chemotherapy, likely jeopardizing outcomes in this patient population. Alternative bridging therapies should be considered until hepatic function improves.

An Unusual Presentation of Extremely Early Neonatal Cirrhosis in Shwachman-Diamond Syndrome: A Case Report.

Exocrine pancreatic insufficiency, haematological dysfunction, and skeletal abnormalities are the three clinical characteristics of the rare inherited bone marrow failure syndrome (IBMFS), known as Shwachman-Diamond syndrome (SDS). Cirrhosis at a neonatal age is uncommon and is typically not documented, as in neonatal presentation. Here, we present a case of SDS in which bi-cytopenia with macro-nodular cirrhosis emerged before the age of one month. Utilising genetic testing on the infant and both parents, we were able to confirm the diagnosis. We were expecting a higher-level liver transplant set-up, but the infant passed away in the interim. Genetic studies play a significant part in the diagnosis of difficult cases.

Use of Oral N-Acetylcysteine (NAC) in Non-Acetaminophen-Induced Acute Hepatic Failure.

BACKGROUND: Acute liver failure (ALF) is a syndrome rather than a specific disease with several possible causes, and viral hepatitis is a major cause. The objective of the study was to assess the benefit of N-acetylcysteine (NAC) in non-acetaminophen-induced acute liver failure (NAI-ALF). METHODS: A total of six patients with a diagnosis of acute liver failure (ALF) were included in the study. All six patients received oral NAC for 72 hrs. The parameters evaluated were demographic, clinical, biochemical, outcome, and length of ICU and hospital stay. The primary outcome was a reduction in mortality with the use of NAC in NAI-ALF. The secondary outcomes were to evaluate the safety of NAC and assess factors predicting mortality. RESULTS: All patients improved and returned to normal or near-normal liver function with the use of NAC. No side effects were noted, and the use of NAC was associated with a shorter hospital stay. CONCLUSION: In patients with non-acetaminophen-related acute liver failure, N-acetyl-L-cysteine (NAC) significantly improves overall survival and also decreases the length of hospital stay.

Fatal outcome of dengue fever with multi-organ failure and hemorrhage: A case report.

Dengue fever is a prevalent viral disease caused by a single-stranded positive RNA virus belonging to the Flaviviridae family, genus flavivirus. It is characterized by fever, headache, myalgias, leukopenia, rash, and plasma leakage, which may progress to compensated or uncompensated shock and multi-organ failure. Liver involvement is a common feature of Dengue fever and is usually manifested by nausea, vomiting, abdominal discomfort, anorexia, hepatomegaly, and elevated serum transaminase levels. Severe disease is associated with laboratory parameters such as mean Platelet count < 20,000/mm, Aspartate Transaminase Levels >45 IU, and lymphocytes <1500. The Expanded Dengue Syndrome (EDS), a term coined by World Health Organization in 2012, refers to an atypical presentation of Dengue fever that manifests with generalized impacts on normal physiology. This case report presents a 29-year-old male with EDS who presented at a Tertiary Care Hospital in Karachi and died a week later due to liver failure.

Acute Liver Failure Secondary to Pyogenic Hepatic Abscess.

Hepatic abscesses are rare and can be pyogenic or amebic. Pyogenic hepatic abscesses are treated with antibiotics, percutaneous drainage when larger than 5 cm, and rarely requires surgical treatment. Clinical and laboratory manifestations of pyogenic hepatic abscesses include fever, abdominal pain, and elevations in liver enzymes. There is little documentation that a pyogenic hepatic abscess can cause acute liver failure. We present a case of a patient who developed acute liver failure secondary to a 14 cm pyogenic liver abscess. The patient's hepatic function normalized with percutaneous drain placement and antibiotics.

Enterovirus-Induced Severe Rhabdomyolysis and Acute Fulminant Liver Failure in an Immunocompetent Adult Requiring Liver Transplantation: A Case Report.

The authors report a case of a young healthy adult with severe rhabdomyolysis and acute fulminant liver failure with multiple organ dysfunction syndromes (MODS), possibly from an enterovirus infection. To the best of our knowledge, this is the first-ever reported case of enterovirus-induced rhabdomyolysis and acute liver failure (ALF) in an immunocompetent adult. It is vital that the treating physician be aware of the association between viral infections, viral myositis, and severe rhabdomyolysis with acute liver failure, which can facilitate the optimal management of such patients. Prompt recognition may provide an opportunity for early interventions, including intravenous immunoglobulin and liver transplantation, if warranted.

What you need to know about: acute liver failure.

Acute liver failure is a rare but important clinical syndrome, with a high mortality rate. Prompt recognition, appropriate management and early referral to a liver transplant centre can lead to good outcomes in these critically unwell patients. This article gives an overview of the key clinical challenges and optimal management of patients with acute liver failure. Acute liver failure is defined and a comprehensive list of aetiologies and suggested investigations is provided. The clinical challenges of sepsis, renal impairment, coagulopathy, hypoglycaemia, haemodynamic instability and cerebral oedema are discussed. Quadruple H therapy, a combination of therapies aimed to reduce cerebral oedema in acute liver failure, is described. A systemic guide to managing patients with acute liver failure is provided, as are indications for referral to a liver transplant centre.