Johan Fevery

Diagnosis and management of primary sclerosing cholangitis

Preamble This guideline has been approved by the American Association for the Study of Liver Diseases and represents the position of the Association. These recommendations provide a data-supported approach. They are based on the following: (1) formal review and analysis of the recentlypublished world literature on the topic (Medline search); (2) American College of Physicians Manual for Assessing Health Practices and Designing Practice Guidelines1; (3) guideline policies, including the AASLD Policy on the Development and Use of Practice Guidelines and the American Gastroenterological Association Policy Statement on Guidelines2; and (4) the experience of the authors in the specified topic. Intended for use by physicians, these recommendations suggest preferred approaches to the diagnostic, therapeutic and preventative aspects of care. They are intended to be flexible, in contrast to standards of care, which are inflexible policies to be followed in every case. Specific recommendations are based on relevant published information. To more fully characterize the available evidence supporting the recommendations, the AASLD Practice Guidelines Committee has adopted the classification used by the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) workgroup with minor modifications (Table 1).3 The strength of recommendations in the GRADE system are classified as strong (class 1) or weak (class 2). The quality of evidence supporting strong or weak recommendations is designated by one of three levels: high (level A), moderate (level B), or low-quality (level C).

The clinicopathological and prognostic relevance of cytokeratin 7 and 19 expression in hepatocellular carcinoma. A possible progenitor cell origin

Aims:  Cytokeratin (CK) 7 and CK19 expression, present in hepatic progenitor cells (HPCs) and in cholangiocytes but not in normal hepatocytes, has been reported in some hepatocellular carcinomas (HCCs); however, the incidence and relevance of this expression in HCC in Caucasians is not known. Therefore, our aim was to study the occurrence and clinicopathological characteristics of HCC expressing CK7 and/or CK19 in 109 Caucasian patients.

Early administration of somatostatin and efficacy of sclerotherapy in acute oesophageal variceal bleeds: the European Acute Bleeding Oesophageal Variceal Episodes (ABOVE) randomised trial

BACKGROUND Sclerotherapy is widely used for acute variceal bleeding, although in emergencies bleeding makes it difficult to obtain the clear view required for safe and effective treatment. We investigated whether early administration of somatostatin would improve the efficacy of sclerotherapy. METHODS In this double-blind, prospective trial, patients who had cirrhosis with upper-gastrointestinal bleeding were randomly assigned natural somatostatin (6 mg per 24 h) or placebo for 120 h. In addition, intravenous bolus doses of somatostatin (250 micrograms) or placebo were injected after the start of the infusion, before emergency endoscopy or sclerotherapy, and when active bleeding was observed. The primary endpoint was treatment failure, defined as the occurrence during the infusion period of at least one of: excess transfusion of blood products, haematemesis, haemodynamic instability, need for rescue therapy, or death. FINDINGS 205 patients were enrolled: 101 received somatostatin and 104 received placebo. Treatment failed in 35 somatostatin and 57 placebo recipients (p = 0.004); death or use of rescue therapy occurred in nine and 19 patients, respectively (p = 0.05). The mean quantity of blood products transfused over 120 h (adjusted for baseline haemoglobin) was 2.64 (SD 0.35) units in the somatostatin group versus 3.62 (0.35) units in the placebo group (p = 0.05). At endoscopy, active bleeding from oesophageal varices was less frequent (27 vs 42 patients, p = 0.012) and the sclerotherapy procedure was easier (2.8 vs 4.7 cm, p = 0.0027) in the somatostatin than in the placebo group. INTERPRETATION Early administration of natural somatostatin continued for 120 h, combined with additional bolus injections, is more effective than placebo in the overall control of acute variceal haemorrhage in patients with cirrhosis undergoing sclerotherapy.

Effect of the molecular adsorbent recirculating system and Prometheus devices on systemic haemodynamics and vasoactive agents in patients with acute-on-chronic alcoholic liver failure

IntroductionPatients with acute-on-chronic liver failure show an aggravated hyperdynamic circulation. We evaluated, in a controlled manner, potential changes in systemic haemodynamics induced by the molecular adsorbent recirculating system (MARS) and the Prometheus system liver detoxification devices in a group of patients with acute-on-chronic liver failure.MethodsEighteen patients (51.2 ± 2.3 years old; Child–Pugh score, 12.5 ± 0.2; Maddrey score, 63.1 ± 5.0; hepatic venous pressure gradient, 17.6 ± 0.9 mmHg) with biopsy-proven alcoholic cirrhosis and superimposed alcoholic hepatitis were either treated with standard medical therapy (SMT) combined with MARS (n = 6) or Prometheus (n = 6) or were treated with SMT alone (n = 6) on three consecutive days (6 hours/session). Liver tests, systemic haemodynamics and vasoactive substances were determined before and after each session.ResultsGroups were comparable for baseline haemodynamics and levels of vasoactive substances. Both MARS and Prometheus decreased serum bilirubin levels (P < 0.005 versus SMT), the Prometheus device being more effective than MARS (P = 0.002). Only MARS showed significant improvement in the mean arterial pressure (Δchange, +9 ± 2.4 mmHg versus -0.3 ± 2.4 mmHg with Prometheus and -5.2 ± 2.1 mmHg with SMT, P < 0.05) and in the systemic vascular resistance index (Δchange, +131.5 ± 46.2 dyne.s/cm5/m2 versus -92.8 ± 85.2 dyne.s/cm5/m2with Prometheus and -30.7 ± 32.5 dyne.s/cm5/m2 with SMT; P < 0.05), while the cardiac index and central filling remained constant. This circulatory improvement in the MARS group was paralleled by a decrease in plasma renin activity (P < 0.05), aldosterone (P < 0.03), norepinephrine (P < 0.05), vasopressin (P = 0.005) and nitrate/nitrite levels (P < 0.02).ConclusionThe MARS device, and not the Prometheus device, significantly attenuates the hyperdynamic circulation in acute-on-chronic liver failure, presumably by a difference in removal rate of certain vasoactive substances. These findings suggest conspicuous conceptual differences among the albumin dialysis devices.

Improvement of autoimmune hepatitis during pregnancy followed by flare-up after delivery.

OBJECTIVES:Pregnancy in autoimmune hepatitis has been a rare event, but it has become more frequent with improved therapy. The present study aimed to analyze the consequences for mother and child in patients with autoimmune hepatitis.METHODS:Fourteen pregnancies have been followed in five patients with autoimmune chronic hepatitis (AIH) and in one with autoimmune sclerosing cholangitis (overlap AIH-PSC).RESULTS:Features of AIH improved markedly from the second trimester of pregnancy onward, allowing a decrease in immunosuppressive therapy. After delivery (or stillbirth in one patient), the activity of the autoimmune disease flared up rapidly in 12 of 14 events.CONCLUSIONS:Pregnancy induces a state of immune tolerance with improvement of the liver tests in AIH. This could result from a transition of TH1 to TH2 predominance during pregnancy. A flare-up often occurs after delivery. Preemptive increase of the immunosuppressive therapy is therefore advocated consecutive to delivery. Azathioprine use seems to be safe during pregnancy.

Unconjugated Bilirubin and an Increased Proportion of Bilirubin Monoconjugates in the Bile of Patients with Gilbert's Syndrome and Crigler-Najjar Disease

Bilirubin pigments were studied in the bile of 20 normal adults, 25 patients with Gilberts syndrome, 9 children with Crigler-Najjar disease, and 6 patients with hemolysis, to determine how a deficiency of hepatic bilirubin UDP-glucuronosyltransferase would affect the end products of bilirubin biotransformation. In the bile from patients with Gilberts syndrome, a striking increase was found in the proportion of bilirubin monoconjugates (48.6+/-9.8% of total conjugates) relative to that in normal bile (27.2+/-7.8%). This increase was even more pronounced in children with Crigler-Najjar disease, in whom, even in the most severe cases, glucuronide could always be demonstrated in the bile. Furthermore, unconjugated bilirubin-IXalpha was unquestionably present in the bile of these children and amounted to 30-57% of their total bilirubin pigments (<1% in the controls). It was not possible to predict from the biliary bilirubin composition whether a child would respond to phenobarbital therapy or not. Bile composition was normal in patients with hemolysis, except when there was associated deficiency of hepatic glucuronosyltransferase. Therefore, the observed alterations were not a simple consequence of unconjugated hyperbilirubinemia. The present findings suggest that Crigler-Najjar disease represents a more pronounced expression than Gilberts syndrome of a common biochemical defect. Hepatic bilirubin UDP-glucuronosyltransferase deficiency leads to decreased formation of diconjugates with an ensuing increase in the proportion of bilirubin monoconjugates in bile; in the most severe cases, an elevated content of biliary unconjugated bilirubin is also found.

Bilirubin in clinical practice: a review

Bilirubin is an endogenous compound that can be toxic under certain conditions but, on the other hand, mild unconjugated hyperbilirubinaemia might protect against cardiovascular diseases and tumour development. Serum bilirubin levels are often enhanced under a variety of clinical conditions. These are discussed and the mechanisms are outlined.

Long-term follow-up of chronic active hepatitis of moderate severity.

A group of patients with only moderately active chronic hepatitis has been studied. The follow-up was long (mean 87 months). All patients except one were treated with prednisone and/or azathioprine. Of the hepatitis B virus positive patients two-thirds developed cirrhosis between the second and fifth year of evolution, while in the hepatitis B negative group this occurred in less than one-third. The transition to cirrhosis was clinically silent. The patients were all allowed to do their normal work except in the terminal stages of cirrhosis. Five patients died of causes related to the disease: three patients with cirrhosis and hepatocellular carcinoma, one with gallbladder carcinoma, and one from bleeding varices. The high incidence of tumour, especially liver-cell carcinoma, may be due to a cumulative effect of the presence of hepatitis B virus, cirrhotic transformation, and immuno-suppression. The other patients are currently in apparently good health.

Portal hypertension: from pathophysiology to clinical practice.

Abstract: Portal hypertension (PHT) is responsible for the more severe and often lethal complications of cirrhosis such as bleeding oesophageal varices, ascites, renal dysfunction and hepatic encephalopathy. Because of the combined impact of these complications, PHT remains the most important cause of morbidity and mortality in patients with cirrhosis. Over the years, it has become clear that a decrease in portal pressure is not only protective against the risk of variceal (re)bleeding but is also associated with a lower long‐term risk of developing complications and an improved long‐term survival. A milestone in therapy was the introduction of non‐selective β‐blockers for the prevention of bleeding and rebleeding of gastro‐esophageal varices. However, in practice, less than half the patients under β‐blockade are protected from these risks, supporting the overall demand for innovation and expansion of our therapeutic armamentarium. Recent advances in the knowledge of the pathophysiology of cirrhotic PHT have directed future therapy towards the increased intrahepatic vascular resistance, which, in part, is determined by an increased hepatic vascular tone. This increased vasculogenic component provides the rationale for the potential use of therapies aimed at increasing intrahepatic vasorelaxing capacity via gene therapy, liver‐selective nitric oxide donors and statines on the one hand, and at antagonizing excessive intrahepatic vasoconstrictor force through the use of endothelin antagonists, angiotensin blockers, α1 adrenergic antagonists or combined α1‐ and non‐selective β‐blockers or somatostatin analogues on the other. The focus of this review is to give an update on the pathophysiology of PHT in order to elucidate these potential novel strategies subsequently.

Bilirubin conjugates in bile of man and rat in the normal state and in liver disease

Conjugates of bilirubin were studied in normal bile of man and rat, and in bile of liver patients. In general human bile was obtained by duodenal intubation. In addition T-tube bile was examined in patients operated on for mechanical obstruction. The bile pigment compositions of duodenal and T-tube bile were similar in two patients where comparison was possible. Obstruction of the bile duct in rats was used as an animal model for obstructive jaundice. Diazotized ethyl anthranilate was used for determination of total conjugated bile pigment and for thin-layer chromatography (t.l.c.) analysis of the derived azopigments. The available t.l.c. procedures are versatile and allow rapid and quantitative analysis. A variety of conjugated azopigments can be distinguished. With chloroform, negligible amounts of unconjugated bilirubin are extracted from bile of man. Therefore, the percentage of monoconjugated bile pigments present in the initial bile sample can be calculated from the percentage of azodipyrrole found after diazotization. Normal bile from man and rat yields similar azopigment patterns. The dominant component is azopigment-delta (azodipyrrole beta-D-monoglucuronoside). Small amounts of azopigments with complex conjugating structures (gamma-azopigments) are present in both cases. Human bile further yields small amounts of azopigments containing xylose or glucose (called azopigments-alpha(2) and -alpha(3), respectively). Monoconjugated bilirubin (estimated from the percentage of azodipyrrole) amounts of 22% of total bile pigments in human bile and to 39% in murine bile. In both, the bulk of bile pigment is bilirubin diglucuronoside. From bile of patients with acquired liver diseases a new azopigment group (beta-azopigment) was derived. The gamma-azopigment group was increased; the delta-azopigment group (containing azodipyrrole beta-D-monoglucuronoside) was decreased. No differentiation was possible between intra- and extrahepatic cholestasis. The percentage of beta-azopigment showed a positive correlation with serum bilirubin concentration (r = 0.6). Recovery of the diseases was accompanied by normalization of the azopigment patterns. In rats, hydrostatic or mechanical obstruction induced increases in beta- and gamma-azopigments and a decrease in delta-azopigment similar to the changes observed in bile of liver patients. Complete normalization was obtained 6 hr after relieving the hydrostatic obstruction (duration 15-21 hr). In contrast, with man after surgery for extrahepatic obstruction, T-tube bile was not normalized when the T-tube was withdrawn (10 days after operation). Hydrostatic obstruction in rats provides an easy model when postobstructive bile pigment composition and parameters have to be investigated. The present investigations stress the importance of the physiopathological state when studying bilirubin conjugation. Hindrance to bile secretion induced heterogeneity of bilirubin conjugates and stimulated the formation of complex structures.