Ductular reaction and hepatocyte ballooning identify patients with fibrosing cholestatic hepatitits after liver transplantation.

INTRODUCTION: Diagnosis of severe hepatitis C recurrence is based on analytical and histological criteria but there is little information about their correlation. AIM: To assess the accuracy of laboratory criteria for the diagnosis of fibrosing cholestatic hepatitis (FCH). PATIENTS AND METHODS: Retrospective analysis of prospectively collected data form HCV positive patients who underwent liver transplantation (LT) between 2000 and 2014 in two European university hospitals. Patients were classified according to laboratory criteria such as FCH, cholestatic hepatitis (CH) and non-cholestatic acute hepatitis (NCAH). Histological characteristics were also evaluated. RESULTS: Seventy patients with acute HCV recurrence within the first year after LT with an available liver biopsy were included in the study. Most patients were male (70%) with a median age of 58 years (50-64) and infected with genotype 1b (71.4%). Median time from LT to diagnosis of recurrence was 2.96 months (2.1-5.3). Thirty-nine patients were classified as FCH, 21 as CH and 10 as NCAH. Marked hepatocyte ballooning and ductular reaction were associated with the presence of FCH with an OR of 4.66 (p=0.047) and 20.58 (p=0.025), respectively. Considering liver biopsy as the gold standard, the sensitivity, specificity, positive and negative predictive values of the analytical criteria were 0.8, 0.5, 0.3 and 0.9, respectively. However, correlation between histological and analytical criteria was poor (k=0.033). DISCUSSION: Analytical criteria may be used to rule out the presence of FCH, but a biopsy is mandatory to confirm the diagnosis. Ductular reaction and hepatocyte ballooning were independent predictors of FCH.

Post-transplant cholangiopathy: Classification, pathogenesis, and preventive strategies.

Biliary complications are the most frequent cause of morbidity, re-transplantation, and even mortality after liver transplantation. In general, biliary leakage and anastomotic and non-anastomotic biliary strictures (NAS) can be recognized. There is no consensus on the exact definition of NAS and different names and criteria have been used in literature. We propose to use the term post-transplant cholangiopathy for the spectrum of abnormalities of large donor bile ducts, that includes NAS, but also intraductal casts and intrahepatic biloma formation, in the presence of a patent hepatic artery. Combinations of these manifestations of cholangiopathy are not infrequently found in the same liver and ischemia-reperfusion injury is generally considered the common underlying mechanism. Other factors that contribute to post-transplant cholangiopathy are biliary injury due to bile salt toxicity and immune-mediated injury. This review provides an overview of the various types of post-transplant cholangiopathy, the presumed pathogenesis, clinical implications, and preventive strategies.

Improved classification of indeterminate biliary strictures by probe-based confocal laser endomicroscopy using the Paris Criteria following biliary stenting.

BACKGROUND AND AIMS: Probe-based confocal laser endomicroscopy (pCLE) using the Miami Criteria has improved classification of indeterminate biliary strictures. However, previous biliary stenting may result in their misclassification as malignant strictures. Inflammatory criteria were added to form the Paris Classification to prevent this misclassification and reduce false positives. The aim of this study was to assess if the Paris Classification was more accurate than the Miami Classification in classifying indeterminate biliary strictures after biliary stenting. METHODS: This was a retrospective observational study involving 21 patients with indeterminate biliary strictures from whom 27 pCLE video sequences were obtained (20 benign and seven malignant). Patients with and without prior biliary stenting underwent pCLE. Two investigators classified the strictures as malignant or benign using the Miami and Paris Classifications. Diagnostic accuracy, sensitivity (Se), and specificity (Sp) of endoscopic retrograde-guided pCLE were compared with final histopathology. RESULTS: In those without biliary stenting, the Miami Criteria resulted in Se 88%, Sp 75%, positive predictive value (PPV) 64%, negative predictive value (NPV) 92%, and accuracy 79%, while the Paris Classification resulted in Se 63%, Sp 88%, PPV 71%, NPV 82%, and accuracy 79%. In those with prior biliary stenting, the Miami Criteria resulted in Se 88%, Sp 36%, PPV 23%, NPV 93%, and accuracy 45%, while the Paris Classification resulted in Se 63%, Sp 73%, PPV 31%, NPV 91%, and accuracy 71%. The kappa statistic was 0.56. CONCLUSION: The Paris Classification improved specificity and accuracy of biliary stricture classification in those who had been previously stented and decreased the rate of misclassification of benign strictures as malignant.

Clinical Application of Six Current Classification Systems for Iatrogenic Bile Duct Injuries after Cholecystectomy.

BACKGROUND/AIMS: Due to being a severe complication, iatrogenic bile duct injury is still a challenging issue for surgeons in gallbladder surgery. However, a commonly accepted classification describing the type of injury has not been available yet. This study aims to evaluate ability of six current classification systems to discriminate bile duct injury patterns. METHODOLOGY: Twelve patients, who were referred to our clinic because of iatrogenic bile duct injury after laparoscopic cholecystectomy were reviewed retrospectively. We described type of injury for each patient according to current six different classifications. RESULTS: 9 patients underwent definitive biliary reconstruction. Bismuth, Strasberg-Bismuth, Stewart-Way and Neuhaus classifications do not consider vascular involvement, Siewert system does, but only for the tangential lesions without structural loss of duct and lesion with a structural defect of hepatic or common bile duct. Siewert, Neuhaus and Stewart-Way systems do not discriminate between lesions at or above bifurcation of the hepatic duct. CONCLUSION: The Hannover classification may resolve the missing aspects of other systems by describing additional vascular involvement and location of the lesion at or above bifurcation.

Refined probe-based confocal laser endomicroscopy classification for biliary strictures: the Paris Classification.

BACKGROUND: Most modalities for tissue confirmation during endoscopic retrograde cholangiopancreatography (ERCP) suffer from low sensitivity and poor diagnostic accuracy. Probe-based confocal laser endomicroscopy (pCLE) was prospectively evaluated in a multicenter registry including 102 patients with indeterminate strictures and demonstrated excellent sensitivity (98 %). Yet, several false-positive cases were induced by benign inflammatory conditions resulting in a specificity of 67 %. AIMS: To evaluate the diagnostic performance of pCLE for the diagnosis of indeterminate biliary stricture; and to propose interpretation criteria for benign inflammatory conditions to reduce the number of false positives. METHODS: Sixty cases from the prospective registry were reviewed retrospectively (27 malignant, 33 benign) by a panel of three biliary endoscopists. Each case's clinical history, ERCP impression, and corresponding pCLE sequences was used to score image quality, propose presumptive diagnoses, and rate level of diagnostic confidence. RESULTS: Using the Miami Classification (MC), the overall accuracy in retrospectively diagnosing malignancy in those 60 cases was 85 versus 78 % for the prospective analysis, reducing the number of false positives from 12 to 8. A second review of the false-positive cases' pCLE sequences (benign inflammatory) helped refine the existing classification by identifying four descriptive criteria specific to benign inflammatory conditions (Paris Classification): Vascular congestion, dark granular patterns with scales, increased inter-glandular space, and thickened reticular structure. CONCLUSIONS: The Paris Classification is a refinement of the existing Miami Classification to improve the accuracy of pCLE for diagnosing benign inflammatory strictures. Prospective multicenter studies are needed to further validate this refined classification criteria.

[10 years of cholelithiasis classification (Central Scientific Research Institute of Gastroenterology): highlights of scientific and practical applications].

Clinical classification of cholelithiasisis presented, which includes 4 stages: stage without calculi, stage of formed gallstones, chronic calculous cholecystitis and complications. Sonographic description of main versions of biliary sludge, its causes and therapy efficacy are also given.

Portal cholangiopathy: radiological classification and natural history.

BACKGROUND/AIM: Portal cholangiopathy (PC) is identified in over 80% of patients with portal vein thrombosis (PVT), but the true impact of this condition is not well known. This study investigated the relationship between cholangiographic abnormalities and clinical symptoms and their evolution over time. PATIENTS/METHODS: 67 consecutive patients with non-tumoral non-cirrhotic PVT following a standardised diagnostic protocol were studied. Findings at magnetic resonance angiography and cholangiography (MRA/MRC) were classified as no PC, grade I PC (minimal irregularities), grade II PC (stenosis without dilation) and grade III PC (stenosis with dilation). These changes were related to the presence of symptoms. RESULTS: 22 patients were diagnosed with acute PVT and 45 presented with chronic PVT. Overall, 52 patients had PC (6 grade I, 12 grade II and 34 grade III). 14 patients developed symptoms, all of whom had grade III PC. 30% of patients with acute PVT developed grade III PC within 1 year. In those without grade III PC, follow-up MRC showed no progression of the biliary lesions to grade III. The 5-year probability of developing symptoms of PC after acute PVT was 19%. In 45 patients with chronic PVT, MRA/MRC showed grade III PC in 26. In those without grade III PC, no progression of PC was observed at further follow-up MRC. The prevalence of symptoms of PC in these patients was 22%. CONCLUSIONS: PC is a frequent complication that develops and stabilises early after PVT and becomes symptomatic in its more severe form (grade III). These data suggest that follow-up MRA/MRC is not mandatory and strategies to prevent the development of symptoms of PC should be tested in patients with grade III PC.

[Current management of benign and malignant bile duct strictures]. / Manejo de las estenosis benignas y malignas de las vías biliares.

Benign and malignant bile duct strictures require multidisciplinary management. The radiologist, endoscopist and surgeon must assess the general conditions of the patient, as well as the etiology of the stenosis and the therapeutic options (palliative, temporal, or definitive). Stenotic injuries that maintain bilioenteric continuity are susceptible to radiologic and/or endoscopic treatment, specially benign lesions, usually appearing in the postsurgical period. Injuries with loss of continuity require surgical management in almost every case. Iatrogenic bile duct injuries with preserved continuity (Strasberg A and D) may be treated by endoscopy. Types B and C, in which a liver segment loses communication with the remaining bile tree, need surgical repair and/or resection. Complete sections of the bile ducts require surgical intervention, with hepatojejunostomy being the best choice. The use of metallic endoluminal stents is almost prohibited in these types of injuries. Benign, non-iatrogenic injuries (sclerosing cholangitis, autoimmune cholangiopathy) require surgical intervention in rare occasions. Malignant injuries are extremely aggressive and only a small percentage (less than 15%) is candidate for curative resection, which unfortunately does not preclude recurrence.

Application of a new histological staging and grading system for primary biliary cirrhosis to liver biopsy specimens: Interobserver agreement.

Recently the authors proposed a new staging and grading system for primary biliary cirrhosis (PBC) that takes into account necroinflammatory activity and histological heterogeneity. Herein is proposed a convenient version of this system. Scores for fibrosis, bile duct loss, and chronic cholestasis were combined for staging: stage 1, total score of 0; stage 2, score 1-3; stage 3, score 4-6; and stage 4, score 7-9. Cholangitis activity (CA) and hepatitis activity (HA) were graded as CA0-3, and HA0-3, respectively. Analysis of interobserver agreement was then conducted. Digital images of 62 needle liver biopsy specimens of PBC were recorded as virtual slides on DVDs that were sent to 28 pathologists, including five located overseas. All participants were able to apply this version in all 62 cases. For staging, kappa was 0.385 (fair agreement) and the concordance rate was 63.9%. For necroinflammatory activity, the kappa and concordance rate were 0.110 (slight agreement) and 36.9% for CA, and 0.197 (slight agreement) and 47% for HA, respectively. In conclusion, this new staging and grading system for PBC seems to be more convenient and practical than those used at present, but more instruction and guidance are recommended for the grading of necroinflammatory activity in practice.

Advances in drug-induced cholestasis: Clinical perspectives, potential mechanisms and in vitro systems.

Despite growing research, drug-induced liver injury (DILI) remains a serious issue of increasing importance to the medical community that challenges health systems, pharmaceutical industries and drug regulatory agencies. Drug-induced cholestasis (DIC) represents a frequent manifestation of DILI in humans, which is characterised by an impaired canalicular bile flow resulting in a detrimental accumulation of bile constituents in blood and tissues. From a clinical point of view, cholestatic DILI generates a wide spectrum of presentations and can be a diagnostic challenge. The drug classes mostly associated with DIC are anti-infectious, anti-diabetic, anti-inflammatory, psychotropic and cardiovascular agents, steroids, and other miscellaneous drugs. The molecular mechanisms of DIC have been investigated since the 1980s but they remain debatable. It is recognised that altered expression and/or function of hepatobiliary membrane transporters underlies some forms of cholestasis, and this and other concomitant mechanisms are very likely in DIC. Deciphering these processes may pave the ways for diagnosis, prognosis and prevention, for which currently major gaps and caveats exist. In this review, we summarise recent advances in the field of DIC, including clinical aspects, the potential mechanisms postulated so far and the in vitro systems that can be useful to investigate and identify new cholestatic drugs.

Cholangitis: a histologic classification based on patterns of injury in liver biopsies.

Inflammatory disorders of the biliary tract present difficult diagnostic problems in liver needle biopsies. The aim of this study was to perform a detailed histologic analysis of liver biopsies from patients with biliary tract disorders, classify them by pattern of inflammation, and determine the accuracy of the histologic classification by clinical follow-up. Percutaneous liver needle biopsies from the surgical pathology files of UmassMemorial Healthcare (UMMHC) from 2000 to 2003 with a diagnosis suggesting a biliary tract process (n = 32) and four biopsies from cases with systemic non-biliary tract disorders were analyzed for multiple histologic features and classified as one of five patterns: acute cholangitis/pericholangitis (ACP), lymphocytic cholangitis (LC), granulomatous (G), ductopenia (D), or non-specific (NS). When compared to the "gold standard" diagnosis based on all clinical data, the concordance between the histologic classification and the clinical diagnosis was: 50% for ACP and bile duct obstruction; 77% for LC and immune-mediated cholangitis NOS; 100% for G and G cholangitis; 100% for D and idiopathic adulthood D; and 50% for NS and non-biliary tract disorders. Our findings suggest that classifying biopsies by pattern of injury is helpful in guiding the subsequent clinical work-up. ACP pattern correlates with bile duct obstruction, infection, and ischemia. LC correlates with serologic studies supporting immune-mediated processes. G pattern suggests further work-up for PBC, drug, tuberculosis, or sarcoidosis. D pattern establishes the clinical diagnosis. NS pattern includes cases of primary sclerosing cholangitis, which cannot be diagnosed by biopsy alone.

Drug- and chemical-induced cholestasis.

Cholestasis resulting from drugs is an increasingly recognized cause of liver disease. It produces a broad clinical-pathologic spectrum of injury that includes simple jaundice, cholestatic hepatitis, and bile duct injury that can mimic extrahepatic biliary obstruction, primary biliary cirrhosis, and sclerosing cholangitis. Although the risk of drug-induced cholestasis leading to a fatal outcome is quite rare, knowledge and recognition of the various forms of cholestatic injury assumes an importance whenever clinicians are confronted with jaundice or other manifestations of liver disease in patients receiving medicinal or chemical agents.

Overview of chronic cholestatic conditions in adults: terminology and definitions.

The cholangiopathies represent diseases and syndromes affecting the biliary system at any site between the canals of Hering and the ampulla of Vater. Hepato-canalicular cholestasis reflects biliary secretory failure of the hepatocyte caused by disturbances of intracellular organelles or damage to the bile canalicular excretory functions. Drug reactions are related especially to antibiotics, phenothiazine derivates and carbamazepine. Immune-mediated cholangiopathies cause destruction and reduction of interlobular bile ducts, and are sometimes called vanishing bile duct diseases. They include primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune cholangitis, chronic hepatic allograft rejection, graft-versus-host disease and chronic cholestatic sarcoidosis. Ischemic (vascular) cholangiopathies include traumatic, hepatic arteritis and mechanical causes. Infectious cholangiopathies usually are associated with the immunosuppressed patient.

Benign biliary strictures: a review of 21 years of experience.

BACKGROUND: The treatment of patients with benign biliary strictures remains a challenge for even the most skilled biliary surgeons. Within the wide range of causes of benign biliary strictures, iatrogenic lesions represent one of the major ones. Biliary reconstruction with Roux-en-Y anastomosis remains the treatment of choice for most cases of benign biliary strictures despite recent reports about endoscopic or percutaneous management that have been quite encouraging. STUDY DESIGN: We retrospectively evaluated 194 patients who underwent surgery for benign biliary strictures over a 21-year period. The biliary strictures were classified into eight different types according to their level. The surgical procedures had been tailored mainly to the site and the extent of the structure as well as the overall status of the patient. RESULTS: Postoperative mortality and morbidity rates were 2.6 percent and 20.1 percent, respectively. The results we obtained were 79.6 percent good, 8.9 percent moderate, and 11.5 percent unsatisfactory. The mean follow-up was 9.3 years. In particular, hepati-cojejunostomy performed in low- and mid-level strictures had the best prognosis (good, 85.5 percent), while high and diffuse strictures had worse results (good, 70 percent), although with only hepaticojejunostomy according to Hepp-Couinaud, this percentage increases to 81 percent. CONCLUSIONS: Correct preoperative assessment of the site and extent of the biliary stricture is important in the choice of the gold-standard surgical procedure. Hepaticojejunostomy and hepaticojejunostomy according to Hepp-Couinaud are the treatments of choice in most instances of benign biliary strictures. Cholangiojejunostomy and hepatic resections are rarely indicated and are performed mostly for highly complicated and intrahepatic strictures. Endoscopic or percutaneous balloon dilation should be reserved for high-risk patients.

An unusual combination of relapsing and cholestatic hepatitis A in childhood.

Clinical variants of hepatitis A include the prolonged, relapsing and cholestatic forms. Here, the first childhood case of hepatitis A, with a combination of the relapsing and cholestatic forms is presented, a 14-year old boy. In the first phase of the illness, while the AST and ALT levels were declined, th total and direct bilirubin and GGT were increased. The patient was thought to have the cholestatic form of hepatitis A. Du to intense pruritus and high bilirubin levels, ursodeoxycholic acid (UDCA) therapy was started. On the 17th day, the decreased AST and ALT levels began to increase, reaching levels as high as 484 U/L and 862 U/L, respectively. The UDCA treatment was stopped on the 64th day. On the 164th day, all his laboratory parameters were within normal limits, but the anti-HAV IgM was still positive.

Cholestasis in infancy. A review.

The natural history of cholestatic syndromes in infancy remains largely unclarified for lack of sufficient data. Newborn and premature infants are particularly vulnerable to cholestasis because of immaturities in bile-forming mechanisms. Until recently, two board categories of etiologic factors has been thought to be associated with cholestasis in early infancy: mechanical obstruction (almost always extrahepatic), and hepatocellular damage (the "neonatal hepatitis" group). Although in both groups specific etiologic factors have been identified, the majority of cases are currently of unknown etiology. Problems in differential diagnosis are reviewed. In the neonatal period, laboratory screening procedures usually do not uncover cholestatic liver disease until the infants become icteric. It is important to not that patients with liver dysfunction may remain anicteric or become anicteric while cholestasis persists. It is, therefore, important that biochemical markers of cholestasis other than conjugated bilirubin be found.

[Clinical significance of dissociated cholestasis as a biological syndrome (author's transl)]. / Significado clínico del síndrome biológico de colestasis disociada.

The case histories of 1200 patients admitted to our hospital over a 20 month period were reviewed to determine the degree, frequency and cause of dissociated cholestasis as a biological syndrome. Patients were divided into two groups: group I with 80 cases, included all patients whose gamma-GT levels were more than 30 mU/ml and serum-bilirubin less than 1.2 mg/ml, with alkaline phosphatase levels between 90-180 mU/ml. Group II included those with alkaline phosphatase levels higher than 180 mU/ml (57 cases). All over incidence of dissociated cholestasis was 13.82%. Main causes in group I were infectious diseases, mainly pneumonias and urinary infections and congestive cardiac failure. In group II, neoplasias such as Hodgkin's disease and epithelial metastases and obstructions of the biliary tract such as vesicular or choledocal litiasis were the main causes. Transaminase levels underwent variable increases according to the different entities, without there being any difference between the two groups. The physiopathology as well as the anatomopathological aspects which could originate the syndrome are discussed.

[The pathogenetic and diagnostic characteristics of cholestatic forms of viral hepatitis]. / Osoblyvosti patohenezu ta diahnostyky kholestatychnykh form virusnykh hepatytiv.

Some specificities of pathogenesis of cholestatic forms are submitted together with classification of causes of cholestatic syndrome in viral hepatitis. The problems of diagnosis of cholestatic forms of viral hepatitis are highlighted with special reference to specific features of the underlying pathological process, with special emphasis being placed on using those techniques sparing the injured parenchyma of the liver, biochemical and ultrasound ones among their number. Criteria have been established of ultrasound diagnosis for different forms of cholestasis in viral hepatitis.

[Obstructive jaundice in a rupture of echinococcal cysts into the bile ducts]. / Obturatsionnaia zheltukha pri proryve ékhinokokkovykh kist v zhelchnye protoki.

130 patients with obstructive jaundice were examined for break of liver hydatids into the biliary ducts. Types of jaundice and break, frequency of fistula sites and clinical picture are described. The surgical interventions are outlined, and the results of their application are studied.