Liver Stiffness Determined by Transient Elastography Is a Simple and Highly Accurate Predictor for Presence of Liver Cirrhosis in Clinical Routine.

INTRODUCTION: Early detection of patients with advanced chronic liver disease is critical for the prevention of complications and inclusion in surveillance programs for hepatocellular carcinoma. In daily clinical care, it remains challenging to differentiate early cirrhosis from lower fibrosis grades without performing a liver biopsy. The aim of the present study was to assess the performance of different non-invasive detection tools to differentiate cirrhosis from lower fibrosis grades. METHODS: Data of 116 patients (51 male, 65 female) with chronic liver disease of various origins undergoing liver biopsy was analyzed. Routine laboratory values, liver stiffness measurement (LSM) by transient elastography, and histological liver assessment were collected. RESULTS: Robust and significant correlations with the histological fibrosis stage were identified for LSM (r = 0.65), the FAST score (0.64), the FIB-4 (0.48), serum aspartate aminotransferase (AST) concentration (0.41), NFS (0.33), international normalized ratio (INR; 0.30), methacetin breath test results (-0.40), and serum albumin concentration (-0.29) by spearman rank correlation. Receiver operating characteristic curves were built for these parameters to separate patients with cirrhosis from those with any other fibrosis stage. The highest AUC was achieved by LSM (0.9130), followed by the FAST score (0.8842), the FIB-4 (0.8644), the NFS (0.8227), INR (0.8142), serum albumin (0.7710), and serum AST (0.7620). The most promising clinical applicability would be an LSM value of 12.2 kPa, achieving 95.7% sensitivity and 75.3% specificity. CONCLUSION: LSM and FAST score seem to be robust non-invasive measurements for liver fibrosis. LSM and FAST scores may have the potential to reliably detect patients with liver cirrhosis in clinical routine settings.

Mechanisms and aetiology-dependent treatment of acute liver failure.

This review compiles the mechanisms of acute liver failure (ALF) as well as the current and potential therapeutic approaches, including aetiology-specific treatment, and the issues encountered with such approaches. On a cellular level, ALF is characterized by massive hepatocyte death due to different types of cellular demise. Compensatory hyperplasia and functional recovery are possible when the regenerative capacity is sufficient to sustain hepatic function. ALF has a high mortality of about 30% and can lead to death in a very short time despite maximum therapeutic intervention. Besides aetiology-specific therapy and intensive care, the therapeutic option of emergency liver transplantation has significantly improved the prognosis of patients with ALF. However, due to limiting factors such as organ shortage, many patients die on the waiting list. In addition to graft assessment, machine perfusion may have the potential to recondition marginal organs and thus expand the organ donor pool.

Performance of the Liver Maximum Function Capacity Test, Fibrinogen, and Transient Elastography in Patients with Acute Liver Injury.

BACKGROUND: Acute liver failure (ALF) occurs as a rare, sudden, extensive loss of liver function in a previously healthy liver. In advanced cases, ALF may require liver transplantation (LT). Available prognostic parameters have limited accuracy to decide, which patient to consider for LT. The liver maximum function capacity test (LiMAx) can accurately determine liver function and was assessed as predictor of survival, along with coagulation parameters and liver stiffness in nonacetaminophen-induced ALF. METHODS: Various liver function tests, including LiMAx measurements, coagulation factors, and transient elastography (TE), were analyzed retrospectively for associations with clinical outcome in 34 patients with ALF or acute hepatitis (AH). Data were compared between patients with spontaneous recovery (SR) and non-SR (3-month mortality/LT; NSR). RESULTS: The analysis included 34 patients (22 ALF, 12 AH; 19 males, 15 females; age 36.7 ± 14.6 years) with drug-induced liver injury (DILI) (n = 12), autoimmune hepatitis (AIH; n = 13), AIH-DILI overlap (n = 1), viral (n = 9), or cryptogenic liver failure (n = 1). Thirty-one patients recovered spontaneously, 2 patients died, and 1 patient underwent LT. The LiMAx was 197.6 (±68.4) for SR versus 92.33 (±65.0) for NSR (p = 0.0157). Fibrinogen was significantly lower in patients with NSR than in SR patients (209.0 vs. 106.3; p = 0.02). Mean liver stiffness measured by TE was 39.3 for NSR and 17.3 for SR (p = 0.26). KCC was fulfilled in only 4 patients (3 SR, 1 NSR). LiMAx results correlated positively with serum fibrinogen and antithrombin III concentrations and correlated negatively with liver stiffness. No other analyzed factor could differentiate between SR and NSR. CONCLUSION: Decision-making in ALF remains challenging. LiMAx and fibrinogen might predict the prognosis in patients with nonacetaminophen-induced ALF and in combination could be feasible tools to decide if LT is necessary.

Patients with NAFLD exhibit more advanced fibrosis in liver biopsy than patients with other chronic liver diseases.

INTRODUCTION: Despite extremely high and seemingly rising prevalence of non-alcoholic fatty liver disease (NAFLD), awareness for this health condition is still low. In the present study we analyzed, if this is reflected in clinical routine for advanced diagnostic measures. METHODS: Retrospective data of 93 patients with histologically determined fibrosis stage and confirmed etiology was analyzed. Patients were grouped according to chronic liver disease alone (n=40), concomitant chronic liver disease and NAFLD (n=29), or NAFLD alone (n=24). Fibrosis stage and presence of cirrhosis were main outcome measures. RESULTS: Patients with NAFLD were significantly older and had significantly higher body mass index and CAP-values than patients with chronic liver disease. Significantly higher fibrosis stages were observed in patients with NAFLD than in those with chronic liver disease alone (p=0.003). Presence of cirrhosis was significantly higher in patients with NAFLD than in patients with chronic liver disease (p=0.01). This was not associated with a significantly different age distribution over fibrosis stages between chronic liver disease and NAFLD. Undergoing liver biopsy 10 years earlier could have possibly prevented progression to cirrhosis in up to 7 patients with NAFLD. This could have potentially saved 35,000 € yearly health care resources. CONCLUSION: These findings suggest that the time course for development of liver fibrosis and cirrhosis is not fundamentally different between patients with NAFLD or with other chronic liver diseases. Higher rates of cirrhosis observed in patients with NAFLD could potentially be ameliorated by earlier diagnostic work-up and improved monitoring.

Interruption of bile acid uptake by hepatocytes after acetaminophen overdose ameliorates hepatotoxicity.

BACKGROUND & AIMS: Acetaminophen (APAP) overdose remains a frequent cause of acute liver failure, which is generally accompanied by increased levels of serum bile acids (BAs). However, the pathophysiological role of BAs remains elusive. Herein, we investigated the role of BAs in APAP-induced hepatotoxicity. METHODS: We performed intravital imaging to investigate BA transport in mice, quantified endogenous BA concentrations in the serum of mice and patients with APAP overdose, analyzed liver tissue and bile by mass spectrometry and MALDI-mass spectrometry imaging, assessed the integrity of the blood-bile barrier and the role of oxidative stress by immunostaining of tight junction proteins and intravital imaging of fluorescent markers, identified the intracellular cytotoxic concentrations of BAs, and performed interventions to block BA uptake from blood into hepatocytes. RESULTS: Prior to the onset of cell death, APAP overdose causes massive oxidative stress in the pericentral lobular zone, which coincided with a breach of the blood-bile barrier. Consequently, BAs leak from the bile canaliculi into the sinusoidal blood, which is then followed by their uptake into hepatocytes via the basolateral membrane, their secretion into canaliculi and repeated cycling. This, what we termed 'futile cycling' of BAs, led to increased intracellular BA concentrations that were high enough to cause hepatocyte death. Importantly, however, the interruption of BA re-uptake by pharmacological NTCP blockage using Myrcludex B and Oatp knockout strongly reduced APAP-induced hepatotoxicity. CONCLUSIONS: APAP overdose induces a breach of the blood-bile barrier which leads to futile BA cycling that causes hepatocyte death. Prevention of BA cycling may represent a therapeutic option after APAP intoxication. LAY SUMMARY: Only one drug, N-acetylcysteine, is approved for the treatment of acetaminophen overdose and it is only effective when given within ∼8 hours after ingestion. We identified a mechanism by which acetaminophen overdose causes an increase in bile acid concentrations (to above toxic thresholds) in hepatocytes. Blocking this mechanism prevented acetaminophen-induced hepatotoxicity in mice and evidence from patients suggests that this therapy may be effective for longer periods after ingestion compared to N-acetylcysteine.

Creld2 function during unfolded protein response is essential for liver metabolism homeostasis.

The unfolded protein response (UPR) is associated with hepatic metabolic function, yet it is not well understood how endoplasmic reticulum (ER) disturbance might influence metabolic homeostasis. Here, we describe the physiological function of Cysteine-rich with EGF-like domains 2 (Creld2), previously characterized as a downstream target of the ER-stress signal transducer Atf6. To this end, we generated Creld2-deficient mice and induced UPR by injection of tunicamycin. Creld2 augments protein folding and creates an interlink between the UPR axes through its interaction with proteins involved in the cellular stress response. Thereby, Creld2 promotes tolerance to ER stress and recovery from acute stress. Creld2-deficiency leads to a dysregulated UPR and causes the development of hepatic steatosis during ER stress conditions. Moreover, Creld2-dependent enhancement of the UPR assists in the regulation of energy expenditure. Furthermore, we observed a sex dimorphism in human and mouse livers with only male patients showing an accumulation of CRELD2 protein during the progression from non-alcoholic fatty liver disease to non-alcoholic steatohepatitis and only male Creld2-deficient mice developing hepatic steatosis upon aging. These results reveal a Creld2 function at the intersection between UPR and metabolic homeostasis and suggest a mechanism in which chronic ER stress underlies fatty liver disease in males.

Transaminase Concentrations Cannot Separate Non-Alcoholic Fatty Liver and Non-Alcoholic Steatohepatitis in Morbidly Obese Patients Irrespective of Histological Algorithm.

BACKGROUND: In current general practice, elevated serum concentrations of liver enzymes are still regarded as an indicator of non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). In this study, we analyzed if an adjustment of the upper limit of normal (ULN) for serum liver enzymes can improve their diagnostic accuracy. METHODS: Data from 363 morbidly obese patients (42.5 ± 10.3 years old; mean BMI: 52 ± 8.5 kg/m2), who underwent bariatric surgery, was retrospectively analyzed. NAFL and NASH were defined histologically according to non-alcoholic fatty liver activity score (NAS) and according to steatosis activity fibrosis (SAF) score for 2 separate analyses, respectively. RESULTS: In 121 women (45%) and 45 men (46%), elevated values for at least one serum parameter (ALT, AST, γGT) were present. The serum concentrations of ALT (p < 0.0001), AST (p < 0.0001) and γGT (p = 0.0023) differed significantly between NAFL and NASH, irrespective of the applied histological classification method. Concentrations of all 3 serum parameters correlated significantly positively with the NAS and the SAF score, with correlation coefficients between 0.33 (ALT/NAS) and 0.40 (γGT/SAF). The area under the curves to separate NAFL and NASH by liver enzymes achieved a maximum of 0.70 (ALT applied to NAS-based classification). For 95% specificity, the ULN for ALT would be 47.5 U/L; for 95% sensitivity, the ULN for ALT would be 17.5 U/L, resulting in 62% uncategorized patients. CONCLUSION: ALT, AST, and γGT are unsuitable for non-invasive screening or diagnosis of NAFL or NASH. Utilizing liver enzymes as an indicator for NAFLD or NASH should generally be questioned.

Hepatokines and adipokines in NASH-related hepatocellular carcinoma.

The incidence of hepatocellular carcinoma (HCC) is increasing in industrialised societies; this is likely secondary to the increasing burden of non-alcoholic fatty liver disease (NAFLD), its progressive form non-alcoholic steatohepatitis (NASH), and the metabolic syndrome. Cumulative studies suggest that NAFLD-related HCC may also develop in non-cirrhotic livers. However, prognosis and survival do not differ between NAFLD- or virus-associated HCC. Thus, research has increasingly focused on NAFLD-related risk factors to better understand the biology of hepatocarcinogenesis and to develop new diagnostic, preventive, and therapeutic strategies. One important aspect thereof is the role of hepatokines and adipokines in NAFLD/NASH-related HCC. In this review, we compile current data supporting the use of hepatokines and adipokines as potential markers of disease progression in NAFLD or as early markers of NAFLD-related HCC. While much work must be done to elucidate the mechanisms and interactions underlying alterations to hepatokines and adipokines, current data support the possible utility of these factors - in particular, angiopoietin-like proteins, fibroblast growth factors, and apelin - for detection or even as therapeutic targets in NAFLD-related HCC.

Lipoprotein and Metabolic Profiles Indicate Similar Cardiovascular Risk of Liver Steatosis and NASH.

BACKGROUND AND AIM: Nonalcoholic fatty liver disease (NAFLD) affects about 25% of the global population, with no reliable noninvasive tests to diagnose nonalcoholic steatohepatitis (NASH) and to differentiate between NASH and nonalcoholic fatty liver (NAFL) (steatosis alone). It is unclear if NAFL and NASH differ in cardiovascular risk for patients. Here, we compared obese NAFLD patients with a healthy cohort to test whether cholesterol compounds could represent potential noninvasive markers and to estimate associated risks. METHOD: Serum samples of 46 patients with histologically confirmed NAFLD (17 NAFL, 29 NASH) who underwent bariatric surgery were compared to 32 (9 males, 21 females) healthy controls (HCs). We analyzed epidemiological data, liver enzymes, cholesterol and lipid profile, and amino acids. The latter were analyzed by nuclear magnetic resonance spectroscopy. RESULTS: Total serum and high-density lipoprotein (HDL) cholesterol were significantly lower in the NAFLD group than in HCs, with a stronger reduction in NASH. Similar observations were made for sub-specification of HDL-p, HDL-s, SHDL-p, and LHDL-p cholesterols. Low-density lipoprotein (LDL)-s and LLDL-p cholesterol were significantly reduced in NAFLD groups. Interestingly, SLDL-p cholesterol was significantly higher in the NAFL group with a stronger elevation in NASH than in HCs. The amino acids alanine, leucin, and isoleucine were significantly higher in the NAFL and NASH groups than in HCs. CONCLUSION: We show in this study that cholesterol profiles, apolipoproteins, and amino acids could function as a potential noninvasive test to screen for NAFLD or even NASH in larger populations. However, few differences in cholesterol profiles were identified between the NAFL and NASH groups, indicating similar cardiovascular risk profiles.

GALAD Score Detects Early Hepatocellular Carcinoma in an International Cohort of Patients With Nonalcoholic Steatohepatitis.

BACKGROUND & AIMS: The prevalence of nonalcoholic steatohepatitis (NASH) associated hepatocellular carcinoma (HCC) is increasing. However, strategies for detection of early-stage HCC in patients with NASH have limitations. We assessed the ability of the GALAD score, which determines risk of HCC based on patient sex; age; and serum levels of α-fetoprotein (AFP), AFP isoform L3 (AFP-L3), and des-gamma-carboxy prothrombin (DCP), to detect HCC in patients with NASH. METHODS: We performed a case-control study of 125 patients with HCC (20% within Milan Criteria) and 231 patients without HCC (NASH controls) from 8 centers in Germany. We compared the performance of serum AFP, AFP-L3, or DCP vs GALAD score to identify patients with HCC using receiver operating characteristic curves and corresponding area under the curve (AUC) analyses. We also analyzed data from 389 patients with NASH under surveillance for HCC in Japan, followed for a median of 167 months. During the 5-year screening period, 26 patients developed HCC. To compensate for irregular intervals of data points, we performed locally weighted scatterplot smoothing, linear regression, and a non-linear curve fit to assess development of GALAD before HCC development. RESULTS: The GALAD score identified patients with any stage HCC with an AUC of 0.96 - significantly greater than values for serum levels of AFP (AUC, 0.88), AFP-L3 (AUC, 0.86) or DCP (AUC, 0.87). AUC values for the GALAD score were consistent in patients with cirrhosis (AUC, 0.93) and without cirrhosis (AUC, 0.98). For detection of HCC within Milan Criteria, the GALAD score achieved an AUC of 0.91, with a sensitivity of 68% and specificity of 95% at a cutoff of -0.63. In a pilot Japanese cohort study, the mean GALAD score was higher in patients with NASH who developed HCC than in those who did not develop HCC as early as 1.5 years before HCC diagnosis. GALAD scores were above -0.63 approximately 200 days before the diagnosis of HCC. CONCLUSIONS: In a case-control study performed in Germany and a pilot cohort study in Japan, we found the GALAD score may detect HCC with high levels of accuracy in patients with NASH, with and without cirrhosis. The GALAD score can detect patients with early-stage HCC, and might facilitate surveillance of patients with NASH, who are often obese, which limits the sensitivity of detection of liver cancer by ultrasound.

How to Define Acute Liver Failure Patients with Pre-Existing Liver Disease without Signs of Cirrhosis.

BACKGROUND: The definition of acute liver failure (ALF) usually implies no previous liver injury. Though, some patients admitted to liver transplantation centers with the diagnosis of ALF are obese or have diabetes. Elevated liver enzymes were not recorded previously, and no signs of cirrhosis or prior decompensation of the liver function were ever present. Still, these patients differ from the "typical" ALF-patient. GOALS: In this study, we aimed to confirm acute-on-chronic-liver failure (AOCLF) in patients diagnosed with ALF and to identify possible differences between ALF and AOCLF. STUDY: Patients were retrospectively recruited from all patients admitted to the University Hospital Essen with diagnosis of ALF between 2008 and 2015. Data of 163 patients were evaluated, resulting in a reclassification of 32 patients as AOCLF (remaining ALF: 131). Demographic and clinical data as well as serum parameters, including cell death markers, were correlated with clinical outcome. RESULTS: Patients with AOCLF were significantly older, had a higher body mass index (BMI), and were more often male. The cause for liver failure in these patients differed significantly from patients who had an actual ALF. Significant differences were also found for serum liver enzymes. Outcome of patients did not differ between AOCLF and ALF. Though, lower BMI and MELD and higher AST and GLDH were predictors for a beneficial outcome. CONCLUSION: AOCLF is still commonly misdiagnosed as ALF. While clinical outcome does not significantly differ between ALF and AOCLF, risk factors for adverse outcome may significantly differ between these entities.

Nonalcoholic-Fatty-Liver-Disease and Nonalcoholic Steatohepatitis: Successful Development of Pharmacological Treatment Will Depend on Translational Research.

BACKGROUND: Nonalcoholic-fatty-liver-disease/nonalcoholic steatohepatitis (NAFLD/NASH) is expected to become the leading liver disease worldwide. Typical liver-related complications are fibrosis, cirrhosis, and the development of hepatocellular cancer (HCC) with the need for liver transplantation. Up to now there is no approved pharmacotherapy. Indeed, this might be due to the complexity of this disease. While the cheapest therapeutic approach is still a lifestyle change leading to weight loss, the proportion of people achieving sufficient weight reduction without additional support is low. Newly developed drugs are expensive and lack a breakthrough in therapeutic success. One reason might be that drugs developed often derive from murine models. Unfortunately, there is little overlap between genes in human and mice that are responsible for the development of NAFLD/NASH. This review aims at summarizing latest developments as well as stress again that more translational research is necessary. SUMMARY: Therapy of NAFLD/NASH is easy and very complex at the same time, as the current main target is weight reduction. Since this is in fact not easily achieved and maintained by many affected individuals, pharmacotherapy to halt the progression of NAFLD/NASH is urgently warranted. More translational studies are needed to understand the metabolic mechanisms and interactions between the liver, gut, oxidative stress and the processes leading to NAFLD progression and HCC development, even in the absence of cirrhosis.

Rotational thromboelastometry can detect factor XIII deficiency and bleeding diathesis in patients with cirrhosis.

BACKGROUND & AIMS: Patients with progressive liver disease exhibit complex coagulation disorders. Factor XIII plays a crucial role in the last steps of haemostasis, and its deficiency is associated with an increased incidence of bleeding diathesis. However, current conventional coagulation tests cannot detect factor XIII deficiency. In this study, we examined factor XIII activity and the ability of rotational thromboelastometry to detect factor XIII deficiency and bleeding diathesis in patients with cirrhosis. METHODS: We retrospectively studied 74 patients with cirrhosis, comparing the results of conventional coagulation tests (international normalized ratio, activated partial thromboplastin time, platelet count, fibrinogen level), rotational thromboelastometry, factor XIII activity and clinical scores. RESULTS: Patients with cirrhosis exhibited reduced factor XIII activity. Factor XIII activity was positively correlated with conventional coagulation parameters and rotational thromboelastometry values, such as maximum clot formation (MCF)extem (r=.48, P<.0001) and MCFfibtem (r=.60, P<.0001). However, maximum lysis (ML)extem and MLaptem were not correlated with factor XIII activity. Three-month mortality rates (P=.0469) and bleeding complications (P<.0001) were significantly associated with lower factor XIII activity. Patients with haemorrhage exhibited significantly altered rotational thromboelastometry values. CONCLUSIONS: Reduced levels of MCFextem and MCFfibtem but not high levels of MLextem and MLaptem are associated with factor XIII deficiency in patients with liver disease. Therefore, substituting factor XIII should be considered for such patients to strengthen clot formation in patients experiencing haemorrhage or those who have undergone interventions.

Low transferrin and high ferritin concentrations are associated with worse outcome in acute liver failure.

BACKGROUND & AIMS: Serum ferritin and transferrin have been identified as prognostic markers in patients with chronic diseases. In this study, we investigated if these parameters can predict outcome in patients with acute liver failure. METHODS: A total of 102 consecutive patients with acute liver failure were retrospectively analysed. The patients were grouped by outcome: spontaneous recovery vs liver transplantation and/or death or survival vs death. Routine laboratory parameters, transferrin and ferritin concentrations in serum, and anthropomorphic data collected on admission were analysed. RESULTS: Non-spontaneously recovering patients had higher ferritin (12 252±25 791 vs 4434.4±9027.2 µg/L; P<.05) and lower transferrin levels (140.4±66.7 vs 206.9±65.8 mg/dL; P<.05) than spontaneously recovering patients. Similarly non-survivors exhibited higher serum ferritin and lower transferrin than non-transplanted survivors. Patients with severe hepatic inflammation (A3) had higher ferritin levels compared to patients with mild-moderate inflammation (A1-2) (5280±5094 vs 2361±2737 µg/L; P=.025). ROC analysis of single parameters was performed in non-transplanted patients, resulting in an area under the curve, sensitivity and specificity of 0.812%, 83.3%, and 77.1% for age, 0.871%, 84.1% and 75% for transferrin and 0.802%, 91.7% and 62.9% for ferritin. A model incorporating age, MELD and transferrin had the best predictive value with an area under the curve of 0.947, a sensitivity of 100% and corresponding specificity of 77.8%. CONCLUSIONS: High ferritin and low transferrin levels are associated with worse outcome in patients with acute liver failure. A model incorporating age, MELD score and transferrin outperformed MELD score for 90-day overall survival of non-transplanted patients.

Cell death mechanisms in human chronic liver diseases: a far cry from clinical applicability.

The liver is constantly exposed to a host of injurious stimuli. This results in hepatocellular death mainly by apoptosis and necrosis, but also due to autophagy, necroptosis, pyroptosis and in some cases by an intricately balanced combination thereof. Overwhelming and continuous cell death in the liver leads to inflammation, fibrosis, cirrhosis, and eventually hepatocellular carcinoma. Although data from various disease models may suggest a specific (predominant) cell death mode for different aetiologies, the clinical reality is not as clear cut. Reliable and non-invasive cell death markers are not available in general practice and assessment of cell death mode to absolute certainty from liver biopsies does not seem feasible, yet. Various aetiologies probably induce different predominant cell death modes within the liver, although the death modes involved may change during disease progression. Moreover, current methods applicable in patients are limited to surrogate markers for apoptosis (M30), and possibly for pyroptosis (IL-1 family) and necro(pto)sis (HMGB1). Although markers for some death modes are not available at all (autophagy), others may not be specific for a cell death mode or might not always definitely indicate dying cells. Physicians need to take care in asserting the presence of cell death. Still the serum-derived markers are valuable tools to assess severity of chronic liver diseases. This review gives a short overview of known hepatocellular cell death modes in various aetiologies of chronic liver disease. Also the limitations of current knowledge in human settings and utilization of surrogate markers for disease assessment are summarized.

Acute Liver Failure - It's Just a Matter of Cell Death.

BACKGROUND: Acute liver failure (ALF) is characterized by a sudden loss of hepatic function due to hepatocyte cell death and dysfunction in previously healthy individuals. The clinical presentation of ALF is associated with coagulopathy (international normalized ratio ≥1.5) and hepatic encephalopathy, although the latter may be less pronounced. Without appropriate and timely intensive care or liver transplantation (LTx), ALF will result in multi-organ failure and death. Various causes may induce ALF, with acetaminophen (APAP) intoxication and acute hepatitis B infection as most common causes in industrialized countries. While conventional terminology discerns acute, acute-on-chronic and acute-on cirrhosis liver failure, some chronic liver diseases (i.e. autoimmune hepatitis (AIH), Wilson's disease) can remain undiagnosed until an initial presentation as ALF. KEY MESSAGES: Upon definite diagnosis of ALF, the underlying cause must be identified, since etiology affects prognosis and clinical management. Individual prognosis should be evaluated with one of various available scoring systems. Most widely used are Model for End-Stage Liver Disease, the King's College Criteria and the Clichy criteria. Other markers, that is, cell death markers, lactate or thyroid status, may improve diagnostic accuracy of classic scores, though routine use of these is not yet established. Etiology-specific treatment under intensive care should be performed, if possible (APAP and amanita intoxication, acute viral hepatitides and AIH). LTx is the only curative option for other causes, unknown reasons of ALF or when etiology-specific therapy fails. In ambiguous cases, that is, suspected drug induced ALF or AIH, co-infection with hepatitis E virus should be tested, as this might be more common than it is currently supposed to be. CONCLUSIONS: Despite major improvements in clinical management of ALF patients, a significant proportion of ALF cases remains without clear identification of the underlying cause or unrecognized multiple causes. In depth analyzes of ambiguous ALF cases is warranted to further improve clinical management.

Economic growth leads to increase of obesity and associated hepatocellular carcinoma in developing countries.

 Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the third leading cause of cancer related death worldwide. In recent years, the prevalence of HCC has increased in both developing and developed countries. Most HCC cases develop in the presence of advanced chronic liver disease related to viral hepatitis. In particular hepatitis B virus and hepatitis C virus infections are considered as major HCC risk factors worldwide. However, current studies provide strong evidence for increasing numbers of HCC in nonalcoholic fatty liver disease (NAFLD). NAFLD represents the hepatic manifestation of metabolic syndrome which is based on obesity and insulin resistance. Epidemiologic data clearly demonstrates that NAFLD and obesity-related disorders are significant risk factors for tumor development in general and HCC in particular. As a consequence of life style changes towards higher calorie intake and less exercise, obesity and metabolic syndrome are spreading all over the world. Due to this increase in obesity and metabolic syndrome NAFLD-related HCC will become a major health care problem in the future. In conclusion, better understanding of the impact of NAFLD and obesity in the development of HCC will improve our treatment strategies of HCC and allow preventive measures.

Vitamin D counteracts fibrogenic TGF-ß signalling in human hepatic stellate cells both receptor-dependently and independently.

OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is closely linked to obesity and constitutes part of the metabolic syndrome, which have been associated with low serum vitamin D (VD). Due to known crosstalk between VD and transforming growth factor (TGF)-ß signalling, VD has been proposed as an antifibrotic treatment. DESIGN: We evaluated the association between VD, the vitamin D receptor (VDR) and liver fibrosis in primary human hepatic stellate cells (phHSC) and 106 morbidly obese patients with NAFLD. RESULTS: Treating phHSC with VD ameliorated TGF-ß-induced fibrogenesis via both VDR-dependent and VDR-independent mechanisms. Reduction of fibrogenic response was abolished in cells homozygous for GG at the A1012G single nucleotide polymorphisms within the VDR gene. Compared with healthy livers, NAFLD livers expressed higher levels of VDR mRNA and VDR fragments. VDR mRNA was lower in patients homozygous for GG at A1012G and expression of pro-fibrogenic genes was higher in patients carrying the G allele. CONCLUSIONS: VD may be an antifibrotic treatment option early in the onset of fibrosis in specific genotypes for VDR. Known polymorphisms of the VDR may influence the response to VD treatment.

Etiology, outcome and prognostic factors of childhood acute liver failure in a German Single Center.

Pediatric acute liver failure (PALF) is a progressive, potentially fatal clinical syndrome occurring in previously healthy children. Our study aimed to determine the current leading causes of PALF in a single center in Germany, identifying possible prognostic markers. Thirty-seven pediatric patients with PALF were included. Medical records were reviewed for demographic, laboratory and clinical data. Laboratory results on admission and at peak value, PELD and MELD score on admission, and intensive care support were assessed. Fifteen patients recovered spontaneously, 14 died without transplantation, and 8 received a liver transplant. Patients who survived were significantly older than patients who died. Specific causes of PALF could be identified as infectious diseases (16%), metabolic diseases (14%), toxic liver injury (11%), immunologic diseases (8%), or vascular diseases (8%). Causes of PALF remained indeterminate in 43%. High ammonia, low albumin, and low ALT levels on admission were associated with worse outcome. Absence of need of ventilation, hemodialysis, and circulatory support predicted spontaneous recovery. In conclusion, infections are the most common known cause of PALF. However, in a large proportion of patients the cause for PALF remains cryptic. Ammonia and albumin levels may be of prognostic value to predict outcomes.