Cause Of Liver Injury Research Articles

Importance of Hepatitis C Virus RNA Testing in Patients with Suspected Drug-Induced Liver Injury.

The aims were to review the diagnosis, testing and presentation of acute hepatitis C (HCV) in patients initially diagnosed to have drug-induced liver injury (DILI) enrolled in the US DILI Network. All patients with suspected DILI underwent testing for competing causes of liver injury and returned for 6-month follow-up. Causality was adjudicated by consensus expert opinion. Between 2004 and 2016, 1518 patients were enrolled and adjudicated and underwent 6months of follow-up. Initial locally acquired anti-HCV results were available in 1457 (96%), but HCV RNA in only 795 (52%). Stored sera were available for repeat testing, so that results were available on all 1518 patients (1457 for anti-HCV and 1482 for HCV RNA). A total of 104 subjects (6.9%) had evidence of HCV infection-10 positive for HCV RNA alone, 16 for anti-HCV alone and 78 for both. All 104 HCV-positive cases were reviewed, and 23 cases were adjudicated as acute HCV. All presented with acute hepatocellular injury with median ALT 1448 U/L, alkaline phosphatase 232U/L and total bilirubin 10.8mg/dL. Twenty-two (96%) patients were jaundiced. While all 23 cases initially had been suspected of having DILI, 19 were adjudicated as acute HCV and not DILI at the 6-month follow-up; while 4 were still considered DILI. Twenty-three of 1518 (1.5%) cases of suspected DILI were due to acute HCV infection. We recommend that initial and follow-up HCV RNA testing should be performed to exclude HCV in patients with acute hepatocellular injury and suspected DILI.

Meta-analysis of the association between MBOAT7 rs641738, TM6SF2 rs58542926 and nonalcoholic fatty liver disease susceptibility

Nonalcoholic fatty liver disease (NAFLD) is a kind of liver disease caused by factors other than excessive alcohol use. It is the leading cause of liver injury in developed countries. The membrane-bound O-acyltransferase 7 (MBOAT7) and transmembrane 6 superfamily member 2 (TM6SF2) are associated with lipid metabolism. Studies found a mutation on MBOAT7, rs641738 and another on TM6SF2, rs58542926 were associated with liver diseases, including NAFLD. However, the results were inconclusive and inconsistent. In the present meta-analysis, the databases Pubmed, Embase, Chinese National Knowledge Infrastructure, and Chinse Biomedical Literature Database were searched for related studies. The deadline of publications was July 10th, 2018. The data from included studies were extracted by 2 independent investigators. STATA 12.0 software was used in the present meta-analysis. A total of 9 papers with 20 studies, including 5415 cases and 17896 controls were identified for the meta-analysis. The results indicated lower risks of NAFLD for CC genotype of TM6SF2 rs58542926 in homozygous, heterozygous, dominant and recessive models (CC vs. TT: OR = 0.33; CC vs. CT: OR = 0.58; CC vs. CT + TT: OR = 0.64; CC + CT vs. TT: OR = 0.32). These decreased risks of NAFLD also existed in Asians in all genetic models except allelic model, and in Caucasians in the heterozygous model (CC vs. CT, OR = 0.52) and the dominant model (CC + CT vs. TT, OR = 0.50). No association existed between MBOAT7 rs641738 and NAFLD risks in all genetic models (CC vs. TT: OR = 0.91; CC vs. CT: OR = 0.96; CC vs. CT + TT: OR = 0.95; CC + CT vs. TT: OR = 0.91; C vs. T: OR = 0.99). CC genotype of TM6SF2 rs58542926 was associated with a significantly lower risk of NAFLD, while MBOAT7 rs641738 was not related to NAFLD risks.

Expert consensus on the clinical management of pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome.

Hepatic sinusoidal obstruction syndrome (HSOS) is a hepatic vascular disease presenting with abdominal distension, pain in the hepatic region, ascites, jaundice, and hepatomegaly. In China, this disease is often associated with the oral intake of plants that contain pyrrolidine alkaloids. The existing guidelines are limited to HSOS associated with hematopoietic stem cell transplantation in Western countries. The Hepatobiliary Diseases Committee of the Chinese Society of Gastroenterology convened an expert consensus conference on the diagnosis and treatment of PA-HSOS to evaluate current research in China and abroad. The "Nanjing criteria" developed by the committee to diagnose PA-HSOS include a confirmed history of PA-containing plant use and (i) abdominal distention and/or pain in the hepatic region, hepatomegaly, and ascites; (ii) elevation of serum total bilirubin or abnormal laboratory liver tests; (iii) evidence on enhanced computed tomography or magnetic resonance imaging; or (iv) pathological evidence that rules out other known causes of liver injury. Supportive symptomatic treatment, anticoagulant therapy, and placement of a transjugular intrahepatic portosystemic shunt for patients who do not respond to medical treatment are effective for the treatment of PA-HSOS. The benefits of glucocorticoids and prostaglandin E1 in PA-HSOS are not clear.

Injury pattern recognition to discriminate competing causes of liver injury.

Competing causes of liver injury may be difficult to discriminate. Characterization of the typical phenotype of each injury defined by latency, time to improvement and biochemical pattern, could be helpful to identify the most likely of competing causes. Liver injury characteristics of both bortezomib-associated drug-induced liver injury (DILI) and hepatitis B virus (HBV) reactivation associated with bortezomib are derived from PubMed listed publications. Bortezomib-associated DILI has very short latency of days and AP is found elevated, while liver injury due to HBV reactivation occurs after several months of bortezomib therapy. Therefore, a patient's liver injury pattern occurring 3months into bortezomib therapy should be attributed to HBV reactivation. Identification of liver injury characteristics for competing causes of liver injury can be helpful to identify the most likely cause and improve clinical outcome.

Mifepristone: An Uncommon Cause of Drug-Induced Liver Injury

Mifepristone is frequently used in large doses for management of Cushing’s syndrome. This is a case of a 35-year-old woman with Cushing’s syndrome, who presented with abdominal pain and jaundice. A month prior to admission, she had been started on a daily dose of 1,200 mg mifepristone. After evaluating for various other causes of liver injury, biopsy revealed cholestatic pattern of liver disease, likely associated with drug-induced hepatotoxicity. Mifepristone was discontinued and her symptoms resolved. We believe this is one of the first few reported cases of drug-induced liver injury (DILI) associated with mifepristone use.

P300/CBP inhibitor A-485 alleviates acute liver injury by regulating macrophage activation and polarization.

High morbidity and mortality are associated with acute liver injury (ALI) for which no effective targeted drugs or pharmacotherapies are available. Discovery of potential therapeutic targets as well as inhibitors that can alleviate ALI is imperative. As excessive inflammatory cytokines released by macrophages are a critical cause of liver injury, we aimed to find novel compounds that could inhibit macrophage expression of inflammatory cytokines and alleviate liver injury.Methods: A high throughput assay was established to screen a small molecule inhibitor library of epigenetic targets. A highly selective catalytic p300/CBP inhibitor A-485 was identified as a potent hit in vitro and administrated to the lipopolysaccharide (LPS)/D-galactosamine (GalN)-induced mice in vivo. For in vitro analysis, RAW264.7 cells and primary BMDM cells exposed to LPS were co-incubated with A-485. A model of acute liver injury induced by LPS and GalN was used for evaluation of in vivo treatment efficacy.Results: A-485 inhibited LPS-induced inflammatory cytokine expression in a concentration-dependent manner in vitro. Significantly, A-485 administration alleviated histopathological abnormalities, lowered plasma aminotransferases, and improved the survival rate in the LPS/GalN-stimulated mice. Integrative ChIP-Seq and transcriptome analysis in the ALI animal model and macrophages revealed that A-485 preferentially blocked transcriptional activation of a broad set of pathologic genes enriched in inflammation-related signaling networks. Significant inhibition of H3K27ac/H3K18ac at promoter regions of these pivotal inflammatory genes was observed, in line with their suppressed transcription after A-485 treatment. Reduced expression of these pathological pro-inflammatory genes resulted in a decrease in inflammatory pathway activation, M1 polarization as well as reduced leukocyte infiltration in ALI mouse model, which accounted for the protective effects of A-485 on liver injury.Conclusion: Using a novel strategy targeting macrophage inflammatory activation and cytokine expression, we established a high-throughput screening assay to discover potential candidates for ALI treatment. We demonstrated that A-485, which targeted pathological inflammatory signaling networks at the level of chromatin, was pharmacologically effective in vivo and in vitro. Our study thus provided a novel target as well as a potential drug candidate for the treatment of liver injury and possibly for other acute inflammatory diseases.

Hepatobiliary Manifestations in Systemic Disease.

Liver disease in children occurs via a multitude of primary illnesses such as autoimmune hepatopathy, biliary atresia, and nonalcoholic fatty liver disease. However, jaundice, hepatitis, and alterations in liver tests can often be a manifestation of systemic diseases. The liver is involved in many critical functions such as circulation, immunity, toxin clearance, and metabolism; when the heart, lungs, gastrointestinal tract, immune system, or endocrine systems are compromised, the liver will be affected. This article reviews common causes of liver injury as well as highlights key associations that should not be missed when diagnosing and managing children with liver disease. Becoming familiar with patterns of liver injury and arranging clues in the context of a thorough history and physical examination can help providers navigate the broad differential diagnosis of secondary liver disease. [Pediatr Ann. 2018;47(11):e458-e464.].

Obesity and Its Correlation With Severe Alcoholic Hepatitis

Introduction: The prevalence of obesity in the United State has been rising in the last two decades. While the association of obesity with alcohol-associated liver disease and cirrhosis is recognized, little is known about possible correlations between severe alcohol hepatitis(AH) and obesity. In contrast to obesity, underweight MBI and its correlation with alcoholic hepatitis is not studied yet. Our aim in this study is to examine whether obesity defined by different body mass index (BMI) groups is associated with the severity of AH and to assess potential correlations between mortality and BMI in those who develop severe AH. Our second aim was to explore correlations between underweight and severe AH. Methods: We performed a single center, retrospective chart review study of patients, between the ages 18 and 80 with AH from January 2008 to January 2018. AH was defined as recent alcohol consumption with elevations in the AST and ALT levels (ratio >1.5), bilirubin level >3 mg/dL and no other causes of liver injury or chronic liver disease. Obesity was classified based on BMI into class I: BMI 30-34.99, class II:35-39.99 and class III: 40 and above. Underweight was defined by BMI < 20. Results: Three hundred and sixty one patients met the criteria of AH, the mean age was 47.6 +/- 10.4 years. Male gender was predominant (65%), while Caucasians represented 92% of the cohort. The mean Maddrey discriminant function(MDF) and MELD scores were 44.4 +/- 42.0 and 22.5 +/- 8.0, respectively. Severe AH, based on MDF ≥32, was found in 198 patients representing 55% of the cohort. Among obese patients, BMI 35-39.9 was associated with severe AH with an odd ratio 2.2 and P-value 0.04. We found an association between BMI and mortality in severe AH. BMI 35-39.9 was associated with higher mortality rate when compared to other BMI groups with an odd ratio of 3.6 and P=Value of 0.004. When compared with moderate AH, (Maddrey Conclusion: Patients with BMI 35-39.9 are more likely to present with severe AH compared to other BMI groups. BMI 35-39.9 correlates with death in severe AH. These data indicate that obesity is a risk factor for severe disease and poor outcome in AH.906 Figure 1 No Caption available.

A Conspectus: Hepatotoxicity Caused by Drug’s

Liver is the principle organ for metabolism of various drugs, endotoxins. Hepatotoxicity is one of the reversible conditions. Drugs are an vital cause of liver injury. Drug-induced injury to the liver can mimic any form of acute or chronic liver disease. The action of cytochrome P450 can induce acute injury to liver, through which drug will break down into electrophiles or free radicals. These spontaneous metabolites can covalently bind to protein and unsaturated fatty acids or induce lipid peroxidation, respectively. The clinical presentation of liver damage may be either cytolytic or cholestatic. Systemic hypersensitivity reaction against the applied agent may be one of the major causes of liver damage. Drug- or toxin-induced liver damage includes vascular damage, induction of liver tumours and development of liver cirrhosis. The most important pre-emptive measure is judicious drug used by the prescribing physician. Early recognition of hepatotoxicity and termination of the offending agent is essential for treatment. The diagnosis may be confirmed by additional diagnostic measures (e. g. liver biopsy) or the clinical course after exposure to the causing agent has been stopped. Therefore, the main aim is to prevent chronic liver damage through early and correct diagnosis. Due to the extensive variety of possibly liver toxic drugs and chemical agents this aspect is a major challenge to physicians. Taking into account the significance of drug-induced hepatotoxicity as a key cause of liver damage, this review pitch light on various drugs which induce hepatotoxicity, with their mechanism of liver damage and clinical scenario.

Intracellular lipids are an independent cause of liver injury and chronic kidney disease in non alcoholic fatty liver disease-like context

ObjectiveEctopic lipid accumulation in the liver and kidneys is a hallmark of metabolic diseases leading to non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD). Moreover, recent data have highlighted a strong correlation between NAFLD and CKD incidences. In this study, we use two mouse models of hepatic steatosis or CKD, each initiated independently of the other upon the suppression of glucose production specifically in the liver or kidneys, to elucidate the mechanisms underlying the development of CKD in the context of NAFLD-like pathology. MethodsMice with a deletion of G6pc, encoding glucose-6 phosphatase catalytic subunit, specifically in the liver (L.G6pc−/− mice) or the kidneys (K.G6pc−/− mice), were fed with either a standard diet or a high fat/high sucrose (HF/HS) diet during 9 months. These mice represent two original models of a rare metabolic disease named Glycogen Storage Disease Type Ia (GSDIa) that is characterized by both NAFLD-like pathology and CKD. Two other groups of L.G6pc−/− and K.G6pc−/− mice were fed a standard diet for 6 months and then treated with fenofibrate for 3 months. Lipid and glucose metabolisms were characterized, and NAFLD-like and CKD damages were evaluated. ResultsLipid depot exacerbation upon high-calorie diet strongly accelerated hepatic and renal pathologies induced by the G6pc-deficiency. In L.G6pc−/− mice, HF/HS diet increased liver injuries, characterized by higher levels of plasmatic transaminases and increased hepatic tumor incidence. In K.G6pc−/− mice, HF/HS diet increased urinary albumin and lipocalin 2 excretion and aggravated renal fibrosis. In both cases, the worsening of NAFLD-like injuries and CKD was independent of glycogen content. Furthermore, fenofibrate, via the activation of lipid oxidation significantly decreased the hepatic or renal lipid accumulations and prevented liver or kidney damages in L.G6pc−/− and K.G6pc−/− mice, respectively. Finally, we show that L.G6pc−/− mice and K.G6pc−/− mice developed NAFLD-like pathology and CKD independently. ConclusionsThis study highlights the crucial role that lipids play in the independent development of both NAFLD and CKD and demonstrates the importance of lipid-lowering treatments in various metabolic diseases featured by lipid load, from the “rare” GSDIa to the “epidemic” morbid obesity or type 2 diabetes.

Hepatocellular carcinoma as a leading cause of cancer-related deaths in Japanese type 2 diabetes mellitus patients.

We reported a cross-sectional study on causes of liver injury in Japanese type 2 diabetes mellitus (T2D) patients (JG 2013). We assessed overall and cause-specific mortality risk during follow-up of patients enrolled in JG 2013. This was a longitudinal, multicenter cohort study. Of the 5642 Japanese T2D patients who visited T2D clinics of nine hospitals in the original study, 3,999 patients were followed up for an average of 4.5years. Expected deaths in T2D patients were estimated using age-specific mortality rates in the general population (GP) of Japan. Standardized mortality ratios (SMRs) were calculated to compare mortality between T2D patients and GP. All-cancer mortality was significantly higher in T2D patients than in the GP [SMR 1.58, 95% confidence interval (CI) 1.33-1.87]. Among malignancies, hepatocellular carcinoma (HCC) conferred the highest mortality risk in T2D patients (SMR 3.57, 95% CI 2.41-5.10). HCC-associated mortality risk in T2D patients remained significantly high (SMR 2.56, 95% CI 1.64-3.97) after adjusting for high positivity rates of hepatitis B surface antigen (1.7%) and anti-hepatitis C virus (5.3%). In T2D patients with platelet counts < 200 × 103/μl, SMR of HCC increased from 3.57 to 6.58 (95% CI 4.34-9.58). T2D patients with platelet count > 200 × 103/μl showed no increase in mortality risk (SMR 0.68) of HCC. HCC-associated mortality risk was the highest among all cancers in Japanese T2D patients. Regular follow-up may be important for T2D patients with platelet counts < 200 × 103/μl for early detection of HCC.

Beware of HCV and HEV in Patients with Suspected Drug-Induced Liver Injury.

Without a specific biomarker the diagnosis of drug-induced liver injury (DILI) relies on exclusion of other causes of liver injury. This review examines the importance of testing for hepatitis C (HCV) and hepatitis E (HEV) in patients with suspected DILI. Several national DILI registries have reported HCV and HEV infection in patients initially diagnosed with DILI. Particularly in patients with suspected DILI who have acute hepatocellular liver injury, acute HCV and acute HEV infection should be considered even in the absence of traditional risk factors. For HCV infection, testing for HCV RNA and HCV antibody are recommended. For HEV, the high prevalence of HEV IgG antibody means that HEV IgM antibody testing is suggested to exclude this infection. There should be a high clinical suspicion for acute HCV and HEV infection in patients with acute hepatocellular liver injury suspected of being due to DILI.

PRINCIPLES OF DIAGNOSIS AND THERAPY OF DRUG-INDUCED LIVER INJURY IN CHILDREN WITH TUBERCULOSIS

Drug-induced liver injury is a disease that occurs during the administration of medications, which is controlled or has a positive dynamics after the drug administration is discontinued, and the renewed prescription of which causes a relapse of clinical and laboratory signs of liver injury. No unified diagnostic criteria have been developed yet. We used the following diagnosis criteria: any excess of the levels of total bilirubin, direct bilirubin, transaminases; temporary association with administration of medications; ruling out other causes of liver injury. Results. 114 children with tuberculosis, aged 3 to 14, were examined. Drug-induced liver injury during the anti-TB therapy was diagnosed in 77 (67.5%) children. In almost half of the cases (37 children, 48%), the liver injury was asymptomatic and was diagnosed with a biochemical blood test. The most common clinical manifestation of pathology include dyspeptic syndrome (in 42.9% of children), less frequent one is abdominal pain syndrome (in 29.9%). The most common biochemical variant of drug-induced liver injury (in 64% of children) was a mixed variant (increased levels of transaminases and bilirubin). Also cytolytic syndrome was pronounced in 54% (in 31 of 57 children) of cases. Conclusions. Drug-induced liver injury during the administration of potentially hepatotoxic drugs should be actively detected by a control biochemical blood test every 2 weeks. Early detection of minimal clinical and laboratory symptoms of liver injury in patients with tuberculosis and timely initiation of treatment will allow controlling quickly liver injury, reducing the number of cases of cancellation of TB treatment, improving the outcome and prognosis for both tuberculosis and hepatic conditions.

Is obesity rather than the dietary supplement used for weight reduction the cause of liver injury?

Acute liver injury has been attributed to dietary supplements (DS) used for weight loss, but their causal role was much questioned, and obesity as an alternative cause of the liver injury remained unclear. A comprehensive search of the Medline database was conducted with terms that included “DS,” “liver injury,” “obesity,” “obesity‐related liver diseases,” and “nonalcoholic steatohepatitis.” For each term, we focused on the first 50 publications. We undertook a manual search to identify additional reports. Underlying liver diseases and other health issues are common in patients taking DS for weight reduction. These include obesity or morbid obesity, as well as complex metabolic disorders complicated by excess morbidity and mortality due to associated liver diseases. Among these are nonalcoholic fatty liver disease with potential progression to nonalcoholic steatohepatitis and cirrhosis, often classified as cryptogenic with a rare risk of hepatocellular carcinoma. With the exception of hepatocellular carcinoma, these obesity‐related liver diseases were observed to varying degrees in patients, and some even required a liver transplant. This raises the question whether the liver injury that occurred in these patients is due to DS consumed for weight loss or to the underlying obesity‐related liver diseases. This analysis showed that, in many instances, the causal role of obesity has been neglected. Obesity‐associated liver diseases should be considered as differential diagnosis of liver injury in obese patients using DS.

Chemical Analysis of Weight Loss Herbal Supplement Safe Lean™ Associated With Acute Liver Injury – A Concern for Spurious Drug, Misbranding and Adulteration

Liver injury due to herbal and dietary supplements are well described in literature and its incidence has been on the rise in the past decade. Labelling an herbal product as non-medicinal and as a supplement precludes protocols needed for testing, trials and marketing criteria. This has led to rampant use of clinically unproven multi-herb-based drugs use for a myriad of lifestyle diseases. In this report, we discuss a new dietary weight loss supplement, Safe Lean™ that was found to be the cause of liver injury in a young obese woman, that resolved after discontinuation, and discuss current literature on component, toxicology and chemical analysis of the offending drug.

Herb-Induced Liver Injury: A Global Concern.

Chinese medicine and herb medicine though used to treat liver diseases are an important cause of liver injury. Many phytochemicals have the potential to injure the liver, some in a dose-related fashion and more often in an idiosyncratic fashion, meaning occurrence is uncommon to rare in the population using these treatments. As is the case with pharmaceuticals, the phytochemicals are usually tolerated despite either no or mild transient subclinical injury but rarely in some susceptible patients cause moderate to severe liver injury which is likely mediated by the adaptive immune system.

Development and Validation of a Test to Identify Drugs That Cause Idiosyncratic Drug-Induced Liver Injury

Idiosyncratic drug-induced liver injury (iDILI) is one of the most challenging diagnoses in hepatology. It is frequently impossible to identify the agent that has caused iDILI in patients who take multiple medicines. We developed an invitro method to identify drugs that cause liver injury in patients, based on drug toxicity to monocyte-derived hepatocyte-like (MH) cells from patient blood samples. We then collected data on patients who were re-exposed to drugs found to be toxic in the MH test to validate test performance. We performed a prospective study of patients referred to the University Hospital in Munich,Germany, with acute liver injury believed to be caused by medications (300 patients were enrolled in the study and we present data from 40 patients with iDILI and re-exposure to implicated drugs). We collected data from patients on medical history, laboratory testand imaging results, findings from biopsy analyses, and medications taken. Blood samples were collected from all patients and MH cells were isolated and cultured for 10days. MH cells were then incubated with drugs to which each patient had been exposed, and toxicity was measured based on release of lactate dehydrogenase. Agents found to be toxic to MH cells were considered as candidates for the cause of liver injury. Patients were followed up for up to 6 months after liver injury and data on drug re-exposures and subsequent liver damage within the following 3 to 24 months were associated with findings from MH tests. Our test identified 10 drugs that were toxic to MH cells from 13 patients (amoxicillin/clavulanateto cells from 2 patients; diclofenac to cells from 2 patients; methylprednisolone to cells from 2 patients; and atorvastatin, metamizole, pembrolizumab, piperacillin/tazobactam, moxifloxacin, duloxetine, or sertraline each to cells from 1 patient). Thirteen patients had a recurrence of liver injury after inadvertent re-exposure to a single drug, and the MH test correctly identified 12 of the 13 drugs that caused these liver re-injury events. All 86 drugs that were not toxic to MH cells in our assay were safely resumed by patients and were not associated with liver re-injury in 27 patients. Therefore, the MH test identifies drugs that cause liver injury with 92.3% sensitivity and 100% specificity (1 false-negative and 12 true-positive results). We developed a test to identify drugs that cause liver injury in patients based on their toxicity to MH cells isolated from patients with DILI. We validated results from the assay and found it to identify drugs that cause DILI with 92.3% sensitivity and 100% specificity. The MH cell test could be a tool to identify causes of iDILI, even in patients taking multiple medications. ClinicalTrials.gov no: NCT02353455.

The effect of antiviral therapy on serum lipid profiles in chronic hepatitis C.

BackgroundLow lipid profile is associated with hepatitis C virus (HCV) infection. Chronic HCV infection is the main cause of liver injury and serum lipid levels during antiviral treatment. We aimed to evaluate the effect of antiviral treatment on the change of lipid profiles during HCV treatment.MethodsTotal 863 patients who complete the interferon-based therapy in Kaohsiung Medical University Hospital were included in this study. The lipid profile measured and evaluated in baseline and after 6 months of the treatment.ResultsSustained virological response (SVR) was achieved in 81.2% of all patients. The baseline triglycerides (TG) levels in the SVR group and non SVR groups were similar. The TG levels at 6 months after cessation of the treatment was significantly elevated in SVR group (102.9±57.0 mg/dL, p=0.0001) but did not elevated in non SVR group (94.5±45.6 mg/dL, p=0.690) compared with baseline TG levels. After adjusting patients by four indexes for fibrosis (FIB4) in cut-off point 3.25, serum TG levels significantly increased in low FIB4 group (103.2±57.9 mg/dL, p=0.0001) but not in high FIB4 group (98.1±49.6 mg/dL, p=0.095) after 6 months end of the treatment. Serum TG level was increased greater in patients who had low FIB4 score and patients who achieved SVR (baseline 89.1±34.8 mg/dL; 6 months after treatment 104.3±59.3 mg/dL, paired T test p=0.0001).ConclusionThe clearance of the HCV RNA is the main determinant of the increase of lipids after PegIFN/RBV treatment. However advanced fibrosis also has an effect in increase of lipids after the treatment.

Drug-Induced Liver Injury—Perspectives from Pathology

Drug-induced liver injury (DILI) may be caused by prescription or over-the-counter medications, herbals and nutritional supplements, or environmental agents. This review provides an overview of (1) pathogenetic mechanisms and risk factors, (2) biochemical classification, (3) diagnostic approach, (4) role of liver biopsy, and (5) narratives on commoner agents that cause DILI. DILI is increasingly seen in contemporary practice due to increased usage of medications in general, introduction of newer agents for treatment of cancers and autoimmune diseases, and increasing consumption of herbals and nutritional supplements. Drug-induced liver injury is a significant cause of liver disease worldwide. No clinical, biochemical, or histological feature is specific for the diagnosis of DILI, which can mimic every pattern of liver injury and is in the differential diagnosis of every patient with liver disease. The diagnosis of DILI relies on (1) establishing a temporal association between clinical disease and initiation of the suspected drug, followed in the majority of cases by clinical improvement and disease resolution on its withdrawal and (2) exclusion of competing causes of liver injury. Herbals and nutritional supplements are particularly interesting as these are generally regarded as “safe, natural” compounds by an increasingly health-conscious population. Establishing a temporal relationship is often challenging as the patient may be taking multiple supplements simultaneously and is usually unclear about timing of initiation and withdrawal of the agents. Additionally, these agents change in potency and composition depending on the harvest conditions of the constituent botanicals.

Clinical and prognostic associations of liver volume determined by computed tomography in acute liver failure.

Liver volume (LV) can be non-invasively determined from the analysis of computed tomography (CT) images, and in patients with acute liver injury (ALI) or failure (ALF), it can reflect the balance of structural collapse with hepatic regeneration. We examined its relation to cause of liver injury, measures of liver function and histopathological findings, and utility in prediction of complications and mortality. Two hundred and seventy-three patients with ALF/ALI admitted to a specialist intensive care unit were studied. One hundred and ninety-nine patients (73%) had non-acetaminophen (NA) aetiologies and 74 (27%) had acetaminophen-induced disease. LV and proportion of predicted LV (PLV%) were determined from admission CT imaging. LV and PLV% showed marked variation when aetiologic groups were compared (P<.0001), including loss in cases with indeterminate cause (LV 939cm3 [IQR 680-1259], PLV% 56% [42-84]) and increase in Budd-Chiari syndrome (1891cm3 [1601-2094], 121% [111-131]). Progression to high-grade encephalopathy was more common with smaller LV and PLV. A<1000cm3 threshold identified NA patients who later developed it with 93% (95%CI 83-98) specificity and odds ratio 10.6 (3.3-34.5) at median 5days prior to onset, and risk of death in those with NA-drug-induced (DILI) or indeterminate disease with 91% (71-99) specificity and 63% (50-75) sensitivity. In patients with ALF/ALI, LV shows marked variation by the cause of disease, and in prognostic importance. In indeterminate and DILI cases, loss of volume to <1000cm3 may indicate irreversible liver injury and regenerative failure and serve as an early clinical predictor for the development of high-grade encephalopathy and death.