Niels Tygstrup

Aspects of the Natural History of Gastrointestinal Bleeding in Cirrhosis and the Effect of Prednisone

The natural history of gastrointestinal bleeding in cirrhosis has been studied using prospectively collected data of 532 patients included in a randomized clinical trial with a regular follow-up of up to 12 yr. Of the total 199 patients who experienced gastrointestinal bleeding, 95 (48%) bled from esophageal or gastric varices, 67 (34%) bled from peptic ulcer or gastritis, and 37 (18%) had either insufficient evidence of the source (33) or mixed sources (4). In the total group of patients the cumulative percentage of patients in whom varices had been demonstrated of patients in whom varices had been demonstrated by radiography increased from 12 to 90 in 10 yr, while that of bleeding from varices increased from 7 to 40. In 104 patients who bled for the first time during the trial period (trial bleeding patients) the median number of bleeding episodes was one (range 1-8). In these patients the fatality from bleeding from varices was 82%. The risk of rebleeding from varices was 81%, and 4 yr after the first bleeding the cumulative survival had decreased to less than 10%. Rebleeding was significantly less frequent and survival significantly higher in patients bleeding from sources other than varices. Prednisone reduced the occurrence rate of varices, bleeding from varices, and death from bleeding varices in nonalcoholic females without ascites, 40% of whom fulfilled the histologic criteria of chronic active hepatitis. Prednisone significantly increased the occurrence rate of varices inpatient with ascites and of bleeding from varices in alcoholic patients. Prednisone significantly increased the occurrence rate of peptic ulcer in males and in patients without chronic active hepatitis.

Transit-amplifying ductular (oval) cells and their hepatocytic progeny are characterized by a novel and distinctive expression of delta-like protein/preadipocyte factor 1/fetal antigen 1.

Hepatic regeneration from toxic or surgical injury to the adult mammalian liver, endorses different cellular responses within the hepatic lineage. The molecular mechanisms determining commitment of a cell population at a specific lineage level to participate in liver repair as well as the fate of its progeny in the hostile environment created by the injury are not well defined. Based on the role of the Notch/Delta/Jagged system in cell fate specification and recent reports linking Notch signaling with normal bile duct formation in mouse and human liver, we examined the expression of Notch1, Notch2, Notch3, Delta1, Delta3, Jagged1, and Jagged2, and delta-like protein/preadipocyte factor 1/fetal antigen 1 (dlk) in four well-defined experimental rat models of liver injury and regeneration. Although Delta3 and Jagged2 were undetectable by reverse transcriptase-polymerase chain reaction and Northern blot, we observed the most significant up-regulation of all other transcripts in the 2-acetylaminofluorene-70% hepatectomy (AAF/PHx) model, in which liver mass is restored by proliferation and differentiation of transit-amplifying ductular (oval) cells. The most profound change was observed for dlk. Accordingly, immunohistochemical analyses in the AAF/PHx model showed a specific expression of dlk in atypical ductular structures composed of oval cells. Delta-like protein was not observed in proliferating hepatocytes or bile duct cells after partial hepatectomy or ligation of the common bile duct whereas clusters of dlk immunoreactive oval cells were found in both the retrorsine and the AAF/PHx models. Finally, we used dlk to isolate alpha-fetoprotein-positive cells from fetal and adult regenerating rat liver by a novel antibody panning technique.

Cyclosporin a treatment in primary biliary cirrhosis: Results of a long-term placebo controlled trial

BACKGROUND Effective treatment for primary biliary cirrhosis (PBC) resulting in slower progression and improved survival remains elusive. Cyclosporin A (CyA), which has been so effective in preventing human allograft rejection, has shown promise in small numbers of patients in early studies. METHODS Three hundred forty-nine patients with PBC were randomized to receive CyA, 3 mg.kg-1.day-1, or placebo in a multicenter study with follow-up for 6 years. The end point was death or liver transplantation. RESULTS Cox multivariate analysis showed time from entry to death or transplantation was significantly prolonged (by up to 50%) in the CyA-treated group. Liver-related mortality was also significantly lower. However, a univariate analysis of survival showed no statistical differences between the two groups. Biochemical liver indices deteriorated more slowly in the CyA-treated group, but serum creatinine concentration was elevated > 150 mumol/L in 9%, necessitating permanent discontinuation in half of these. A reduction in the dose of CyA was required in 11% because of hypertension. CONCLUSIONS CyA has some therapeutic potential in primary biliary cirrhosis, providing blood pressure and renal function are closely monitored.

DETERMINATION OF THE HEPATIC ARTERIAL BLOOD FLOW AND OXYGEN SUPPLY IN MAN BY CLAMPING THE HEPATIC ARTERY DURING SURGERY

The function of the hepatic artery has been extensively studied in animals (1-5). Great differences have been found from one species to another (6, 7), and our knowledge of the significance of the arterial blood supply to the human liver is limited mainly to observations of the late effect of occlusion of the hepatic artery (8) or of the portal vein (9, 10). As these events are followed by compensatory changes in the hepatic circulation (11, 12), no definite conclusions regarding the physiological role of the hepatic artery can be made on this basis. It might be expected that acute, transitory interruption of the blood flow through the hepatic artery minimizes this compensation and thus gives a clearer picture of the function of the artery.

Updating Prognosis and Therapeutic Effect Evaluation in Cirrhosis with Cox's Multiple Regression Model for Time-Dependent Variables

A multivariate Cox regression analysis with time-dependent variables has been performed on the data of 415 patients with cirrhosis included in a controlled clinical trial of 10-15 mg prednisone daily versus placebo. The analysis showed that a poor prognosis was associated with a low prothrombin index, marked ascites, GI bleeding, high age, high daily alcohol consumption, high bilirubin and alkaline phosphatase and low albumin values, little liver connective tissue inflammation, and poor nutritional status. Prothrombin index and ascites showed significant interaction with the treatment in such a manner that high prothrombin index and absence of ascites were associated with a beneficial effect of prednisone, whereas low prothrombin index and presence of ascites were associated with a harmful effect of prednisone treatment. The final model was validated in independent patients by comparing their actual survival with that predicted from the model, using a split-sample testing technique. The prognostic factors were combined with an index that can be used to update prognosis whenever changes occur in the clinical status of a patient during the course of the disease. The probability of surviving the next 3 or 6 months can be estimated from the prognostic index at any time during the course. The index may be of value for the correct timing of special therapeutic procedures such as liver transplantation.

Updating prognosis in primary biliary cirrhosis using a time-dependent Cox regression model

BACKGROUND The precision of current prognostic models in primary biliary cirrhosis (PBC) is rather low, partly because they are based on data from just one time during the course of the disease. The aim of this study was to design a new, more precise prognostic model by incorporating follow-up data in the development of the model. METHODS We have performed Cox regression analyses with time-dependent variables in 237 PBC patients followed up regularly for up to 11 years. The validity of the obtained models was tested by comparing predicted and observed survival in 147 independent PBC patients followed for up to 6 years. RESULTS In the obtained model the following time-dependent variables independently indicated a poor prognosis: high bilirubin, low albumin, ascites, gastrointestinal bleeding, and old age. When including histological variables, cirrhosis, central cholestasis, and low immunoglobulin (Ig)M also indicated a poor prognosis. The survival predicted by the models agreed well with the survival observed in the independent PBC patients. The time-dependent models predicted better than our previously published time-fixed model. CONCLUSIONS Using the time-dependent Cox models, one can estimate a more precise probability of surviving the next 1, 3, or 6 months for any given patient at any time during the course of the disease. This may improve monitoring of PBC patients.

Remarkable heterogeneity displayed by oval cells in rat and mouse models of stem cell-mediated liver regeneration.

The experimental protocols used in the investigation of stem cell–mediated liver regeneration in rodents are characterized by activation of the hepatic stem cell compartment in the canals of Hering followed by transit amplification of oval cells and their subsequent differentiation along hepatic lineages. Although the protocols are numerous and often used interchangeably across species, a thorough comparative phenotypic analysis of oval cells in rats and mice using well‐established and generally acknowledged molecular markers has not been provided. In the present study, we evaluated and compared the molecular phenotypes of oval cells in several of the most commonly used protocols of stem cell–mediated liver regeneration—namely, treatment with 2‐acetylaminofluorene and partial (70%) hepatectomy (AAF/PHx); a choline‐deficient, ethionine‐supplemented (CDE) diet; a 3,5‐diethoxycarbonyl‐1,4‐dihydro‐collidin (DDC) diet; and N‐acetyl‐paraaminophen (APAP). Reproducibly, oval cells showing reactivity for cytokeratins (CKs), muscle pyruvate kinase (MPK), the adenosine triphosphate–binding cassette transporter ABCG2/BCRP1 (ABCG2), alpha‐fetoprotein (AFP), and delta‐like protein 1/preadipocyte factor 1 (Dlk/Pref‐1) were induced in rat liver treated according to the AAF/PHx and CDE but not the DDC protocol. In mouse liver, the CDE, DDC, and APAP protocols all induced CKs and ABCG2‐positive oval cells. However, AFP and Dlk/Pref‐1 expression was rarely detected in oval cells. Conclusion: Our results delineate remarkable phenotypic discrepancies exhibited by oval cells in stem cell–mediated liver regeneration between rats and mice and underline the importance of careful extrapolation between individual species. (HEPATOLOGY 2007;45:1462–1470.)

Double blind controlled trial of d-penicillamine in patients with primary biliary cirrhosis.

One hundred and eighty nine patients with primary biliary cirrhosis were entered into a double blind, placebo controlled randomised trial starting in January 1978 to assess the therapeutic value of d-penicillamine 1200 mg daily. Eighteen of the 98 patients receiving d-penicillamine and 22 of the 91 placebo treated patients died during the study. Thirty six per cent of those on d-penicillamine and 8% of those on placebo were withdrawn from the study. No difference in overall survival was noted between the two groups of patients whether the results were analysed for the entire period of observation or only during the period in which the patients were receiving therapy. The mortality rate of those receiving d-penicillamine in histological stage I to II, however, was one third of that of the placebo group although this difference did not reach statistical significance. Using the occurrence rate ratio as the statistical method of analysis, no effect of d-penicillamine was noted on any clinical, biochemical or histological features examined, except the serum alanine aminotransferase activity which was greater in those on active treatment. In this trial we have been unable to establish any therapeutic benefit from the drug.

Main causes of death in cirrhosis.

The main causes of 436 deaths among 532 patients with cirrhosis followed up for up to 16 years constituted liver failure (24%), liver failure with gastrointestinal bleeding (13%), gastrointestinal bleeding (14%), primary liver cell carcinoma (4%), other liver-related causes (2%), infections (7%), cardiovascular diseases (22%), extrahepatic malignancies (9%), and other non-liver-related causes (5%). Totally, 57% died of liver-related causes. A high frequency of liver-related death was found among patients with a short observation time, high biochemical activity, pronounced change in liver architecture, ascites, and other signs of a poor prognosis at the time of diagnosis. The findings favoured the hypothesis that cirrhosis of the liver is a disease with an initial active and a subsequent inactive phase. Half of the patients were treated with prednisone, but this had no detectable influence on the distribution of causes of or on the frequency of single causes of death as infections or gastrointestinal bleeding. The group of patients responding favourably to prednisone treatment with regard to survival (non-alcoholic women without ascites) showed causes of death not different from those of the total material.

Glucoregulation in acute liver failure

Abstract. Five patients with fatal acute liver failure, given 5 g h‐1 of glucose for the previous 12 h, were investigated by the hyper‐ and euglycaemic glucose ‘clamp’ technique, and the results compared with reported control values. Initial average blood glucose concentration was normal (6·0 mmol l‐1, range 5·0–8·8). Plasma insulin and C‐peptide concentrations were increased about tenfold (1450 pmol l‐1, range 330–4021, and 3000 pmol l‐1, range 670–7650, respectively). The whole body glucose metabolic rate was decreased to about half control values (21 μmol min‐1 kg‐1, range 6–28) and the insulin sensitivity of the glucose metabolism was decreased to about 15% (9·4 m3 min‐1 kg‐1, range 3·6–14·4). The calculated metabolic clearance of insulin was normal (520 ml min‐1 (m2)‐1, range 305–1027) and the calculated systemic delivery rate of insulin was about sixfold increased (1135 pmol min‐1 (m2)‐1, range 474–2010). The initial glucagon concentrations were fifty‐fold increased (550 pmol l, range 72–1309) and not suppressible by glucose and insulin. The patients thus exhibited pronounced insulin insensitivity and hyperinsulinaemia, attributable primarily to pancreatic hypersecretion. The reason for the relation between, and the pathogenetic importance of, these findings is not known.