Chronic Cholestatic Diseases Research Articles

Primary Biliary Cholangitis and Primary Sclerosing Cholangitis Therapy Landscape.

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are rare, chronic cholestatic diseases that can progress to liver failure. The goals of treatment are to halt the progression of liver disease to cirrhosis and/or liver failure, and alleviate symptoms associated with these diseases. Ursodeoxycholic acid (UDCA) has historically been the first-line treatment for PBC, with obeticholic acid (OCA) and fibrates used as second-line or adjunctive therapies. However, the treatment landscape is rapidly expanding. Recently, two new second line agents gained FDA approval for the treatment of PBC, and several other therapies remain under investigation with promising results. While significant progress has been made in development of therapies for PBC, there are no current approved treatments for PSC other than liver transplantation although several emerging therapies have shown encouraging results. This review outlines the current and upcoming treatments for PBC and PSC.

Validation of Metallothionein Immunohistochemistry as a Highly Sensitive Screening Test for Wilson Disease

Wilson disease (WD) is a rare autosomal recessive condition with protean clinical manifestations that result from biallelic ATP7B mutations. However, nondestructive tissue tests to be applied clinically to tissue specimens are not widely available to effectively assess patients for possible WD. Previously, we showed that metallothionein (MTH) immunohistochemistry (IHC) has a high sensitivity and specificity for WD diagnosis and, thus, represents a potentially powerful diagnostic tool that can be used in routine histologic sections. This study aimed to validate this finding in a large cohort of bona fide patients with WD and to correlate metallothionein expression with other histologic features. We identified 91 cases of WD, which included 28 needle biopsies and 64 explants from 14 centers worldwide. Histologic features were evaluated, and a histopathological pattern was assigned to each case. All cases were evaluated with Masson trichrome and MTH IHC (clone UC1MT, Abcam) using a previously published technique. Liver tissues from chronic cholestatic diseases (n = 42) were used as controls. The median age of the cohort was 28.5 years. Of the 91 total cases, 83 were positive for MTH immunostain. In the controls, all 42 cases were negative for MTH immunostain. The sensitivity and specificity of MTH immunostain for WD were 91.20% and 100%, respectively. MTH IHC is a highly sensitive and specific cost-effective screening tool for WD. It can be used for patients across age groups, varied histologic patterns, and fibrosis stages. This marker could prove to be a valuable tool in the evaluation of patients with possible WD.

JiaGaSongTang improves chronic cholestasis via enhancing FXR-mediated bile acid metabolism

BackgroundBile acid (BA) enterohepatic circulation disorders are a main feature of chronic cholestatic diseases. Promoting BA metabolism is thus a potential method of improving enterohepatic circulation disorders, and treat enterohepatic inflammation, oxidative stress and fibrosis due to cholestasis. PurposeTo investigate the effect of JiaGaSongTang (JGST) and its blood-absorbed ingredient 6-gingerol on α-naphthylisothiocyanate (ANIT)-induced chronic cholestasis, as well as elucidate the underlying regulatory mechanism. MethodsChronic cholestasis was induced in mice via subcutaneous injection of ANIT (50 mg/kg) every other day for 14 d. Treatment groups were administered JGST orally daily. Damage to the liver and intestine was observed using histopathological techniques. Biochemical techniques were employed to assess total BA (TBA) levels in the serum, liver, and ileum samples. Liquid chromatograph-mass spectrometry/mass spectrometry (LC-MS/MS) was used to analyze fecal BA components. Bioinformatic methods were adopted to screen the core targets and pathways. The blood-absorbed ingredients of JGST were scrutinized via LC-MS/MS. The effects of the major JGST ingredients on farnesoid X receptor (FXR) transactivation were validated using dual luciferase reporter genes. Lastly, the effects of the FXR inhibitor, DY268, on JGST and 6-gingerol pharmacodynamics were observed at the cellular and animal levels. ResultsJGST ameliorated pathological impairments in the liver and intestine, diminishing TBA levels in the serum, liver and gut. Fecal BA profiling revealed that JGST enhanced the excretion of toxic BA constituents, including deoxycholic acid. Bioinformatic analyses indicated that JGST engaged in anti-inflammatory mechanisms, attenuating collagen accumulation, and orchestrating BA metabolism via interactions with FXR and other pertinent targets. LC-MS/MS analysis identified six ingredients absorbed to the bloodstream, including 6-gingerol. Surface plasmon resonance (SPR) and dual luciferase reporter gene assays confirmed the abilities of 6-gingerol to bind to FXR and activate its transactivation. Ultimately, in both cellular and animal models, the therapeutic efficacy of JGST and 6-gingerol in chronic cholestasis was attenuated in the presence of FXR inhibitors. ConclusionThe findings, for the first time, demonstrated that 6-gingerol, a blood-absorbed ingredient of JGST, can activate FXR to affect BA metabolism, and thereby attenuate ANIT-induced liver and intestinal injury in chronic cholestasis mice model via inhibition of inflammation, oxidative stress, and liver fibrosis, in part in a FXR-dependent mechanism.

Secondary bile acids and the biliary epithelia: The good and the bad.

The biliary tract has been considered for several decades a passive system just leading the hepatic bile to the intestine. Nowadays several researches demonstrated an important role of biliary epithelia (i.e. cholangiocytes) in bile formation. The study of biliary processes therefore maintains a continuous interest since the possible important implications regarding chronic cholestatic human diseases, such as primary biliary cholangitis or primary sclerosing cholangitis. Bile acids (BAs), produced by the liver, are the most represented organic molecules in bile. The physiologic importance of BAs was initially attributed to their behavior as natural detergents but several studies now demonstrate they are also important signaling molecules. In this minireview the effect of BAs on the biliary epithelia are reported focusing in particular on secondary (deriving by bacterial manipulation of primary molecules) ones. This class of BAs is demonstrated to have relevant biological effects, ranging from toxic to therapeutic ones. In this family ursodeoxycholic and lithocholic acid present the most interesting features. The molecular mechanisms linking ursodeoxycholic acid to its beneficial effects on the biliary tract are discussed in details as well as data on the processes leading to lithocholic damage. These findings suggest that expansion of research in the field of BAs/cholangiocytes interaction may increase our understanding of cholestatic diseases and should be helpful in designing more effective therapies for biliary disorders.

Secondary sclerosing cholangitis and IgG4-sclerosing cholangitis - A review of cholangiographic and ultrasound imaging.

Sclerosing cholangitis (SC) represents a spectrum of chronic progressive cholestatic diseases of the intrahepatic and/or extrahepatic biliary system characterized by patchy inflammation, fibrosis, and stricturing. Primary and secondary SC must be distinguished given the different treatment modalities, risks of malignancy, and progression to portal hypertension, cirrhosis, and hepatic failure. This review focuses on secondary SC and the pathogenic mechanisms, risk factors, clinical presentation, and novel imaging modalities that help to distinguish between these conditions. We explore the detailed use of cholangiography and ultrasound imaging techniques.

Abstract PO026: Bile acid signaling remodels the iCCA immune microenvironment

Abstract Intrahepatic cholangiocarcinoma (iCCA) primarily arises from the transformation of cholangiocytes (epithelial cells of the bile ducts), is diagnosed at late stage and has a dismal prognosis (average 5-year survival after resection is 32%). An alarming increase in its incidence over the past decades and the scarce treatment options available urges for the development of novel therapeutic strategies to tackle this malignancy. Immunotherapy has had limited success in iCCA. Possible explanations are that iCCA immune microenvironment is poor in CD8+ T cells and rich in immunosuppressive innate immune cells. The immune landscape of iCCA is determined by the aetiology of the liver insult (e.g. viral, cholestatic) and these different iCCA immune landscapes have not yet been characterized. Therefore, in depth studies on the immunobiology of iCCA are essential to develop new immunotherapy strategies where innate immune cells play a prominent role. We hypothesized that bile acids (BA) are a potential, valid therapeutic target for iCCA, as they strongly influence liver immune microenvironment and proliferation. This idea is supported by the fact that BA have an immunomodulatory role through inhibition of NF-KB and reduction of macrophage production of pro-inflammatory cytokines, suppressing cholangiocyte transformation in iCCA. Since BA and derivatives have recently been approved for the treatment of human chronic cholestatic diseases and primary sclerosis cholangitis, but have not yet been tested to treat iCCA, the proposed project might directly offer evidence for a second use of these drugs in patients with iCCA. Using novel preclinical mouse models of iCCA and human iCCA samples, our objective is to develop new therapeutic strategies for iCCA treatment based on BA signalling, that would impair tumour growth and foster the immune response against the tumour. In order to investigate the effects that BA can exert in tumour initiation and development, we adopted a iCCA mouse model based on the hydrodynamic tail-vein delivery of genetic elements specifically in hepatocytes, which differentiate into cholangiocytes and ultimately leads to the development of iCCA, while conserving a competent immune system. We found that by feeding the animals with an endogenous BA-enriched diet (BA diet), we reduced the overall tumor burden and strikingly increased overall survival. The positive response to the BA diet was associated to an inhibition of tumor proliferation and a robust increase in the abundance and activation of inflammatory monocytes and T cells. Our preliminary results indicate that mimicking the effect of BA could represent a novel immunotherapeutic strategy for iCCA. We will present these data as well as ongoing studies including fluorescence-activated cell sorting and single-cell RNA seq sequencing, focused on understanding the cooperation between different immune cell types that foster response against the tumor. Citation Format: María García-Beccaria, Mirian Fernández-Vaquero, Maria Reich, Dominik Pfister, Diran Herebian, Benjamin Goeppert, Darjus Felix Tschaharganeh, Verena Keitel, Mathias Heikenwälder. Bile acid signaling remodels the iCCA immune microenvironment [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO026.

Involvement of Autophagy in Ageing and Chronic Cholestatic Diseases.

Autophagy is a “housekeeping” lysosomal degradation process involved in numerous physiological and pathological processes in all eukaryotic cells. The dysregulation of hepatic autophagy has been described in several conditions, from obesity to diabetes and cholestatic disease. We review the role of autophagy, focusing on age-related cholestatic diseases, and discuss its therapeutic potential and the molecular targets identified to date. The accumulation of toxic BAs is the main cause of cell damage in cholestasis patients. BAs and their receptor, FXR, have been implicated in the regulation of hepatic autophagy. The mechanisms by which cholestasis induces liver damage include mitochondrial dysfunction, oxidative stress and ER stress, which lead to cell death and ultimately to liver fibrosis as a compensatory mechanism to reduce the damage. The stimulation of autophagy seems to ameliorate the liver damage. Autophagic activity decreases with age in several species, whereas its basic extends lifespan in animals, suggesting that it is one of the convergent mechanisms of several longevity pathways. No strategies aimed at inducing autophagy have yet been tested in cholestasis patients. However, its stimulation can be viewed as a novel therapeutic strategy that may reduce ageing-dependent liver deterioration and also mitigate hepatic steatosis.

Malnutrition in Pediatric Chronic Cholestatic Disease: An Up-to-Date Overview

Despite recent advances, the causes of and effective therapies for pediatric chronic cholestatic diseases remain elusive, and many patients progress to liver failure and need liver transplantation. Malnutrition is a common complication in these patients and is a well-recognized, tremendous challenge for the clinician. We undertook a narrative review of both recent and relevant older literature, published during the last 20 years, for studies linking nutrition to pediatric chronic cholestasis. The collected data confirm that malnutrition and failure to thrive are associated with increased risks of morbidity and mortality, and they also affect the outcomes of liver transplantation, including long-term survival. Malnutrition in children with chronic liver disease is multifactorial and with multiple potential nutritional deficiencies. To improve life expectancy and the quality of life, patients require careful assessments and appropriate management of their nutritional statuses by multidisciplinary teams, which can identify and/or prevent specific deficiencies and initiate appropriate interventions. Solutions available for the clinical management of these children in general, as well as those directed to specific etiologies, are summarized. We particularly focus on fat-soluble vitamin deficiency and malnutrition due to fat malabsorption. Supplemental feeding, including medium-chain triglycerides, essential fatty acids, branched-chain amino acids, and the extra calories needed to overcome the consequences of anorexia and high energy requirements, is reviewed. Future studies should address the need for further improving commercially available and nutritionally complete infant milk formulae for the dietary management of this fragile category of patients. The aid of a specialist dietitian, educational training regarding nutritional guidelines for stakeholders, and improving family nutritional health literacy appear essential.

Keratin 7 expression in hepatic cholestatic diseases

We evaluated keratin 7 (K7) hepatocellular expression in 92 patients with common types of acute and chronic cholestatic diseases caused by bile duct obstruction/destruction or parenchymal lesions [acute hepatitis (n=20), mixed/pure cholestasis (n=16), primary biliary cholangitis-PBC (n=35), primary sclerosing cholangitis-PSC (n=10), vanishing bile duct syndrome (n=3), complete large bile duct obstruction due to space-occupying lesions (n=8)]. K7 immunohistochemical hepatocellular expression and ductular reaction (DR) were semi-quantitatively assessed. Results were correlated with liver enzyme serum levels, cholestasis type, histological features, hepatocellular Ki67 labelling index (LI) and HepPar1 expression. Hepatocellular K7 expression was detected in 87% (81/92) cases and in all cholestatic disease types with lowest incidence in pure/mixed cholestasis and highest in incomplete bile duct obstruction (iBDO), reaching 100% in PSC. K7-positive hepatocytes had low Ki67 LI (0-5%) retaining HepPar1 expression, irrespective of disease type. PSC cases had high K7 hepatocellular expression even with intact bile ducts, a feature that may aid differential diagnosis of cholestatic syndromes. K7 hepatocellular expression significantly correlated with cholestasis type, bile duct loss and fibrosis stage. It was higher in milder acute cholestatic hepatitis showing inverse correlation with hepatocyte proliferation and serum transaminase levels. In iBDO, younger age independently correlated with high K7 expression, while serum GGT levels showed a nearly significant correlation. Correlation with DR findings implied that K7-positive hepatocytes may result through metaplasia. In conclusion, K7 hepatocellular expression is a sensitive though non-specific marker of cholestasis. It may represent a cytoprotective reaction of resting hepatocytes in cholestasis of longer duration especially in younger patients.

A219 EARLY PREDICTORS OF UNFAVORABLE OUTCOME IN NORTH AMERICAN INDIAN CHILDHOOD CIRRHOSIS

Abstract Background North American Indian Childhood Cirrhosis (NAIC) has only been described in the Cree-Ojibway First Nations of Northern Quebec. NAIC presents with transient neonatal jaundice and progresses to biliary cirrhosis often requiring liver transplantation (LT) in childhood. Only 30 patients have been described to date and risk factors associated with an earlier progression to LT have not yet been identified. Moreover, NAIC patients seem to experience more fractures than other cholestatic patients, but this has not been confirmed. Aims With this study, we aimed to identify predictors at 6 months from presentation that might suggest progression to end-stage liver disease as well as evaluate bone health in affected patients. Methods The records of all NAIC patients diagnosed between 2000–2020 were reviewed. Subjects were split into 2 groups based on whether they had undergone LT or not (No_LT) before age 18. Recorded complications included: hepatic encephalopathy (HE), variceal bleeding (VB), ascites, spontaneous bacterial peritonitis (SBP), bacteremia, and pulmonary shunts. Laboratory data (alanine aminotransferase, ALT; total bilirubin, TB) were collected at presentation and follow-up. Bone mineral density (BMD) of the lumbar spine (Z-scores) and number of fractures were compared between groups. NAIC patients were then compared to cohorts with other chronic cholestatic diseases such as biliary atresia (BA, n=24) and Alagille syndrome (AS, n=11). Results A total of 14 patients (M=9, F=5) were diagnosed with NAIC. Average age at presentation was 2.1 months (IQR 1–16.9 months), with 3 patients older than 18 months. Overall, 6 patients were transplanted (avg 8.6±1.7 years), one was listed for LT but died waiting, and 7 remained in a state of compensated cirrhosis. All complications were only observed in the LT group except for VB which also occurred in 2 patients of the No_LT group. Between presentation and 6 months, ALT and TB levels increased more in the LT vs No_LT group (p=ns). There was a greater variation of ALT/TB levels in the LT group (p=0.0047) even once the 3 patients with late referral were excluded (p=0.0381). No patient in the No_LT group had fractures, while 3 did in the LT group. BMD was lower in the LT group vs No_LT group (-2.2±1.2 vs. -1.1±1.3, p=ns). NAIC patients had lower BMD (-1.7±1.3) than those with AS (0.7±0.9, p=0.003) or BA (-0.9±1.4, p=ns) and had a higher prevalence of fractures (21.4% vs. 12.5% for BA and 18.2% for AS patients). Conclusions In patients with NAIC, variation of ALT/TB levels at 6 months from presentation may be used as an early predictor of unfavorable outcome and progression towards end-stage liver disease. Patients who evolved to LT had more complications, higher prevalence of fractures and lower BMD values. Compared to children with BA or AS, NAIC patients had poorer bone health. Funding Agencies None

Chronické cholestatické jaterní choroby, primární biliární cholangitida a primární sklerozující cholangitida

Cholestasis is defined as hepatocyte and cholangiocyte bile excretion failure or failure of bile transport to the duodenum. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis as chronic progressive cholestatic diseases are the common reasons of chronic cholestasis. Altogether with cholestatic laboratory picture the pruritus, liver osteodystrophy and fatigue are associated symptoms in both diseases. All associated symptoms and complications are needed to be diagnosed and treated early. In case of liver cirrhosis complicatons of accompanied portal hypertension should be treated and liver transplantation must be considered in all those patients. Diagnosis of PBC is based on cholestatic laboratory features, animitochondrial antibody positivity or typical histological patern. Most patients are asymptomatic in time of diagnosis. First line therapy is ursodeoxycholic acid. In case of first line therapy failure, the prognosis is unfavourable. In this case, second line therapy must be considered. In case of PSC the diagnosis is based on MRCP finding mainly, laboratory test and liver biopsy in some cases. Progressive inflamatory and fibrosing impairment affecting intrahepatic and extrahepatict biliary ducts and strong association with inflamatory bowel disease, especially ulcerative colitis is typical for PSC. Endoscopic therapy with dilatation of dominant structure is crucial. The effect of pharmacotherapy is still being discussed and ursodeoxycholic acid could be used. During follow up patients are in the risk of bacterial cholangitis and malignant tumor development (cholangiogenic and colorectal carcinoma mainly). In PSC patients the severe pruritus and reccurent bacterial cholangitis could be an indication for the liver transplantation.

Vitamin A deficiency in chronic cholestatic liver disease: Is vitamin A therapy beneficial?

Chronic cholestatic diseases are progressive diseases of the biliary tract that cause hepatic fibrosis and ultimately lead to liver failure. Liver transplantation is the sole curative option currently available, and because of high morbidity and mortality rates of these diseases, new therapeutic approaches are needed. Vitamin A is a nutrient essential for health as it regulates many processes, including epithelial growth and immunological processes. Vitamin A is primarily stored in hepatic stellate cells, and during liver injury, through an unknown mechanism, these cells lose vitamin A and convert into collagen-producing myofibroblasts, which contributes to hepatic fibrosis. Vitamin A deficiencies in chronic cholestatic diseases have been frequently reported, and therefore, retinoid metabolism has attracted a lot of attention. Retinoids have been shown to attenuate or even prevent hepatic fibrosis, and to regulate hepatic immunological response to cholestatic injury in different rodent models of chronic cholestasis. Recently, their potential as therapeutic drugs in primary sclerosing cholangitis patients was analyzed. The aim of this review is to summarize the existing knowledge and hypotheses about vitamin A role and the disease progression in cholestatic liver disease.

Noninvasive diagnostic methods of liver fibrosis in patients with primary biliary cirrhosis and primary sclerosing cholangitis: role of indirect serological markers

Aim of investigation. Considering prognostic value and dynamic nature of liver fibrosis in chronic cholestatic diseases: primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), severity assessment by liver biopsy and/or noninvasive methods should be obligatory component of the investigation plan during patient follow-up to estimate treatment response. The aim of the present study was to evaluate diagnostic value of noninvasive tests based on indirect liver fibrosis serological markers for the estimation of fibrosis severity in PBC and PSC. Materials and methods. Original study was based on retrospective evaluation of 95 patients with PBC and 27 patients with PSC. According to routine laboratory test data and abdominal ultrasound, indexes of AST to ALT ratio (AAR); AST to platelet count ratio (APRI); platelet count to the spleen diameter ratio - PLT/ SPD and Fibrosis-4 score index (FIB-4) were calculated. All patients underwent liver biopsy with fibrosis stage assessment in biopsy specimen (METAVIR scale). Diagnostic value of estimated indexes was evaluated and compared by ROC-analysis with ROC-curve plotting and calculation of the area under the ROC-curve (AUROC). Results. In PBC group (median age Me [interquartile range] was 54 years [49-62]) 50,5% (n=48) of patients had significant liver fibrosis (F≥2) and 21,1% (n=20) - liver cirrhosis (F4). In PSC group (Me=40 [28-50] years) 63% of patients (n=17) had severe fibrosis (F≥2) and 33,4% (n=9) - and liver cirrhosis (F4) respectively. PLT/SPD index provided the highest AUROC values at significant fibrosis (F≥2), severe fibrosis (F≥3) and liver cirrhosis (F4) in PBC group (0,763 [95% CI 0,664- 0,861], 0,764 [0,662-0,866], and 0,805 [0,694-0,915], respectively). However in PSC group, highest AUROC was found for FIB-4 index (0,844 [0,682-1,000], 0,845 [0,698-0,993], and 0,785 [0,594-0,975], respectively). Conclusion. Application of FIB-4 index in PSC allows to reveal significant liver fibrosis stage (F≥2) with high accuracy (80,7%). Efficacy of other indexes (AAR, APRI, and PLT/SPD) in these patients, as well as AAR, APRI, FIB-4, and PLT/SPD indexes in PBC, should be characterized as quite low that makes their clinical application inexpedient.

Progress of targeting transforming growth factor-β1 small interfering RNA in liver fibrosis.

Liver fibrosis is a common pathological consequence of a variety of chronic stimuli, including viral, autoimmune, drug-induced, cholestatic and metabolic diseases. Fibrosis is driven by a dynamic process involving increased synthesis of matrix components and a failure of physiological mechanisms of matrix turnover. Activation of hepatic stellate cells (HSCs) remains a central event in fibrosis. HSCs are the main source of extracellular matrix (ECM). Transforming growth factor-beta (TGF-Β), which is the fibrogenic master cytokine, can induce the activation of HSCs to produce a large amount of ECM, and is capable of inducing apoptosis of liver cells. RNA interference (RNAi) is a novel gene disruption technology. Studies have shown that small interfering RNA (siRNA) targeting TGF-Β1 may inhibit the activation and proliferation of HSCs, suppress ECM synthesis and block liver fibrosis. TGF-Β1 siRNA-mediated gene silencing therapy provides a new avenue for liver fibrosis. This review summarizes recent progresses in research on HSCs, TGF-Β1 and TGF-Β1 siRNA in liver fibrosis.

Rapidly Deteriorating Cholestatic Hepatitis Requiring Liver Transplantation after the Use of Augmentin in a Patient With Stable Primary Biliary Cirrhosis

Purpose: A 58-year-old male patient with stable, biopsy-proven Primary Biliary Cirrhosis was treated with a 10-day course of Augmentin (Amoxicillin-Sodium Clavulanate) starting on Feburary 20, 2010. Two weeks later, he presented with jaundice and fatigue. His bilirubin rose rapidly over the next 10 days from an initial value of 2.3 to 23.1 mmol/L (direct 19.6 mmol/L). His AST and ALT also rose to 170 and 89 IU/L (normals <37 and 65) and the alkaline phosphatase to 457 U/L (normal<136). A liver biopsy showed established cirrhosis with a paucity of bile ducts, severe intrahepatic cholestasis, and patchy lobular lymphocytic infiltrate, consistent with an acute cholestatic hepatitis superimposed on chronic cholestatic liver disease. His clinical condition worsened over the next 10 days, and he became comatose. His MELD rose to 34. He underwent liver transplantation on May 3, 2010. He had an uneventful post-operative course and returned home approximately 4 weeks later. He continues to follow up and has remained well 2 years post-transplant. Medications such as Augmentin (e.g. erythromycin, estrogens, anabolic steroids) that have been associated with cholestatic hepatitis may be particularly dangerous in patients with pre-existing chronic cholestatic diseases. We believe this is the first case report of such an event, and it should caution clinicians who care for such patients.

Ductal plates in hepatic ductular reactions. Hypothesis and implications. I. Types of ductular reaction reconsidered

This article focuses on the observation that most hepatic ductular reactions (DRs) have ductal plate (DP)-like patterns. Considering old and recent data, it hypothesizes that in DR, dedifferentiation of hepatocytes in ductular metaplasia may lead to the de novo development of liver stem/progenitor cells (LPCs). The three recognized types of DR are reconsidered, and an additional fourth type, DR type 2B, is added. In DR type 1 whose pattern differs from DP, the pre-existing cholangiocytes multiply and adjust the ductal structure in response to micro-environmental changes induced by oedema and inflammation. This DR fails to establish new canaliculo-ductular connections. DRs types 2A, 2B and 3 represent progenitor cell-based reactions in DP configuration which establish canaliculo-ductular connections similar to DPs in embryonic and foetal liver development. DR type 2A occurs in periportal areas in chronic cholestatic and inflammatory diseases and is interpreted as a reaction of LPCs, which either pre-exist or derive from dedifferentiated hepatocytes. DR type 2B occurs in centrolobular areas and zones of parenchymal hypoxia, is induced by hypoxia and corresponds to "ductular metaplasia" like type 2A with a presumably similar cellular origin. DR type 3 relates to the well-recognized activation of LPCs that reside in the canals of Hering. All DRs in DP configuration play a role in progression of fibrosis in chronic liver diseases.

Genetics of Liver Injury and Fibrosis

Genetic risk factors play critical roles in liver injury and fibrosis, since both initiation and progression of chronic liver diseases differ between individuals challenged by identical environmental factors. Recently genomewide association studies have identified specific novel risk genes for (non-alcoholic) fatty liver disease (adiponutrin), viral hepatitis (interleukin 28B), and chronic cholestatic diseases (interleukin 12). Here, we summarize these studies and provide an inventory of the susceptibility genes. In the future, risk assessment of complex liver diseases might be based on polygenic risk scores or even gene networks. Complimentary to study in humans, experimental crosses of inbred mouse strains contribute to the genetic dissection of gene-gene interaction and gene-environment interactions. The results of these genomewide studies in mice and men might open new avenues for the prevention and treatment of chronic liver injury and the regression of liver fibrosis.

Transient elastography for the diagnosis of liver fibrosis

Transient elastography (FibroScan®) is a noninvasive method proposed for the assessment of liver fibrosis in patients with chronic liver diseases by measuring liver stiffness. It can be easily performed at the bedside or in the outpatient clinic with immediate results and good reproducibility. FibroScan is validated for the diagnosis of significant fibrosis and cirrhosis in chronic hepatitis C, in recurrence of hepatitis C after liver transplantation, in co-infected HIV–HCV patients, in chronic hepatitis B, in chronic cholestatic diseases, in alcoholic disease and in nonalcoholic fatty liver disease. FibroScan is an excellent tool for the early detection of cirrhosis and for the evaluation of portal hypertension, and may have prognostic value in this setting. FibroScan evaluates liver stiffness, which is related to fibrosis, but also inflammation and portal hypertension. Therefore, FibroScan values have to be interpreted according to clinical, biological and morphological data.

Metabolische Störungen bei Leberzirrhose (Teil 1): Hepatische Osteopathie und Malnutrition

Medical treatment of patients with liver cirrhosis consists mainly of symptomatic therapy of associated complications. Apart from the classical complications of cirrhosis, e. g. ascites, portal hypertension or hepatic encephalopathy, other frequent complications are neglected in everyday medicine. The incidence of metabolic disturbances seems to be similar to the prevalence of classical complications of liver cirrhosis, such as portal hypertension or ascites. Osteoporosis is an important manifestation of hepatic osteopathy, especially in chronic cholestatic diseases and in candidates for liver transplantation, which necessitates timely adequate diagnostic test (e. g. osteodensitometry) and treatment (pre-emptive and causal). Malnutrition, especially when related to protein- and energy supply, is very common in patients with liver cirrhosis and has prognostic significance regarding mortality and complication rates. A sufficient daily energy and protein supply should be ensured, one which is higher than that for the normal population. Additional substitution of vitamins and trace elements is indicated when symptoms of deficiency became apparent.

Transplantation hépatique chez l’enfant

Liver transplantations (LT) performed in children aged younger than 16 years account for 6 to 8% of the total number of LT performed yearly in France. Indications for pediatric LT are mainly chronic cholestatic diseases of neonatal onset that lead to biliary cirrhosis; the most common is biliary atresia. Because most children are very young at transplantation (median age of 2 years), LT is performed in most cases with left lateral segments from a deceased donor or a related living donor. This increases the rate of postoperative vascular and biliary complications, compared with whole-liver transplantation. The principal early cause of death is sepsis. Some specific post-LT complications occur more frequently in young children than adolescents or adults: EBV-related post-transplantation lymphoproliferative disease and food allergies in young recipients treated with tacrolimus and acquired renal cystic disease, associated with renal dysfunction, mostly in children treated with cyclosporine. Despite the high rate of early post-LT complications, 10-year survival exceeds 70 to 80% and health-related quality of life is close to normal. Only about 10% of children will require a late retransplantation, mainly for chronic liver graft rejection, which most often results from poor or non-adherence to immunosuppressants, especially during adolescence.