Rolf Olsson

Hepatic and extrahepatic malignancies in primary sclerosing cholangitis

BACKGROUND/AIMSnTo assess the risk of hepatic and extrahepatic malignancies in a large cohort of Swedish primary sclerosing cholangitis (PSC) patients compared with that of the general Swedish population.nnnMETHODSnThe study cohort comprised 604 PSC patients identified between 1970 and 1998. Follow-up was provided through linkages to the Swedish Cancer and Death registries. Cumulative incidence of malignancies and standard incidence ratio were calculated with the incidence rates in the Swedish population, taking into account: sex, age and calendar year as comparison group.nnnRESULTSnMedian time of follow-up was 5.7 years (range 0-27.8). Seventy-nine percent had concomitant inflammatory bowel disease. The cause of death was cancer in 44%. The frequency of hepatobiliary malignancies was 13.3% (81/604). Thirty-seven percent (30/81) of all hepatobiliary malignancies were diagnosed less than 1 year after the diagnosis of PSC. The risk for hepatobiliary malignancy was increased 161 times, for colorectal carcinoma 10 times and for pancreatic carcinoma 14 times, compared with that of the general population.nnnCONCLUSIONSnIn this national-based study including the largest cohort of PSC patients ever presented, the frequency of cholangiocarcinoma is 13%. The risk of hepatobiliary carcinoma is constant after the first year after PSC diagnosis with an incidence rate of 1.5% per year. The risk of pancreatic carcinoma is increased 14 times compared with the general Swedish population. These results are suggestive of an increased risk of pancreatic carcinoma in patients with PSC.

Outcome and prognostic markers in severe drug‐induced liver disease

The combination of high aminotransferases (hepatocellular injury) and jaundice has been reported to lead to a mortality rate of 10% to 50% for different drugs, a phenomenon known as “Hys rule.” However, Hys rule has never been validated, and limited data exist on predictors for outcome in hepatocellular and other forms of drug‐induced liver disease. All reports of suspected hepatic adverse drug reactions received by the Swedish Adverse Drug Reactions Advisory Committee (1970‐2004) were reviewed. Cases with bilirubin levels 2 or more times the upper limit of normal (ULN) were analyzed. A total of 784 cases were retrieved—409 with hepatocellular injury, 206 with cholestatic injury, and 169 with mixed liver injury. The mortality/transplantation rate was 9.2%, and bilirubin (median 18.7 × ULN [IQR 12.6‐25]; range 4.5‐42) was higher (P < .0001) in the deceased/transplant recipients compared with the surviving patients (median 5.5 × ULN [IQR 3.3‐9.5]; range 2.0‐38). A total of 7.8% with cholestatic and 2.4% with a mixed pattern died. The mortality rate in hepatocellular injury for different drugs varied from 40% (6 of 15) for halothane to 0% (0 of 32) for erythromycin, in total 12.7%. Using logistic regression analysis, age, aspartate aminotransferase (AST) and bilirubin were found to independently predict death or liver transplantation in the hepatocellular group, whereas among patients with cholestatic/mixed liver injury, bilirubin was the only independent predictor. In conclusion, hepatocellular jaundice has a high but variable mortality rate, depending on the drug involved. The AST and bilirubin levels are the most important predictors of death or liver transplantation. (HEPATOLOGY 2005;42:481–489.)

The natural history of small-duct primary sclerosing cholangitis.

BACKGROUND & AIMSnThe long-term prognosis of patients with small-duct primary sclerosing cholangitis (PSC) remains incompletely characterized. We aimed at determining the natural history and long-term outcomes of a large number of patients with small-duct PSC.nnnMETHODSnData from 83 patients with well-characterized small-duct PSC from several medical institutions in Europe and the United States were combined. Each patient with small-duct PSC was randomly matched to 2 patients with large-duct PSC by age, gender, calendar year of diagnosis, and institution.nnnRESULTSnThe median age at diagnosis in both groups was 38 years (61% males). Nineteen (22.9%) of the 83 patients with small-duct PSC progressed to large-duct PSC in a median of 7.4 (interquartile range [IQR], 5.1-14) years. One patient with small-duct PSC who progressed to large-duct PSC was diagnosed with cholangiocarcinoma but after progression to large-duct PSC; 20 patients with large-duct PSC developed cholangiocarcinoma. Patients with small-duct PSC had a significantly longer transplantation-free survival compared with large-duct PSC patients (13 years [IQR, 10-17] vs 10 years [IQR, 6-14], respectively; hazard ratio, 3.04; 95% confidence interval: 1.82-5.06; P < .0001). Two patients with small-duct PSC who underwent liver transplantation had recurrence of small-duct PSC in the graft 9 and 13 years, respectively, after transplantation.nnnCONCLUSIONSnSmall-duct PSC is a disease of progressive potential but associated with a better long-term prognosis as compared with large-duct PSC. Small-duct PSC may recur after liver transplantation. Cholangiocarcinoma does not seem to occur in patients with small-duct PSC, unless the disease has progressed to large-duct PSC.

Hepatic Findings in Long-Term Clinical Trials of Ximelagatran

AbstractObjective: In clinical trials, the efficacy and safety of the oral direct thrombin inhibitor ximelagatran have been evaluated in the prevention or treatment of thromboembolic conditions known to have high morbidity and mortality. In these studies, raised aminotransferase levels were observed during long-term use (>35 days). The aim of this analysis is to review the data regarding these hepatic findings in the long-term trials of ximelagatran.n Patients and methods: The prospective analysis included 6948 patients randomised to ximelagatran and 6230 patients randomised to comparator (warfarin, low-molecular weight heparin followed by warfarin or placebo). Of these, 6931 patients received ximelagatran for a mean of 357 days and 6216 patients received comparator for a mean of 389 days. An algorithm was developed for frequent testing of hepatic enzyme levels. A panel of four hepatologists analysed all cases of potential concern with regard to causal relation to ximelagatran treatment using an established evaluation tool (Roussel Uclaf Causality Assessment Method [RUCAM]).n Results: An elevated alanine aminotransferase (ALT) level of >3 × the upper limit of normal (ULN) was found in 7.9% of patients in the ximelagatran group versus 1.2% in the comparator group. The increase in ALT level occurred 1–6 months after initiation of therapy and data were available to confirm recovery of the ALT level to <2 × ULN in 96% of patients, whether they continued to receive ximelagatran or not. There was some variability in the incidence of ALT level elevation between indications, those with simultaneous acute illnesses (acute myocardial infarction or venous thromboembolism) having higher incidences. Combined elevations of ALT level of >3 × ULN and total bilirubin level of >2 × ULN (within 1 month of the ALT elevation), regardless of aetiology, were infrequent, occurring in 37 patients (0.5%) treated with ximelagatran, of whom one sustained a severe hepatic illness that appeared to be resolving when the patient died from a gastrointestinal haemorrhage. No death was observed directly related to hepatic failure caused by ximelagatran.n Conclusion: Treatment with ximelagatran has been associated with mainly asymptomatic elevation of ALT levels in a mean of 7.9% of patients in the long-term clinical trial programme and nearly all of the cases occurred within the first 6 months of therapy. Rare symptomatic cases have been observed. An algorithm has been developed for testing ALT to ensure appropriate management of patients with elevated ALT levels. Regular ALT testing should allow the clinical benefits of ximelagatran to reach the widest population of patients while minimising the risk of hepatic adverse effects.

The AST/ALT ratio as an indicator of cirrhosis in patients with PBC

Abstract: Objectives: A non‐invasive, simple and non‐expensive test to predict cirrhosis would be highly desirable. The aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio has been proven to be such an indicator of cirrhosis in alcoholic liver disease, hepatitis C.

Small intestinal motility disturbances and bacterial overgrowth in patients with liver cirrhosis and portal hypertension

OBJECTIVES:Altered small bowel motility and a high prevalence of small intestinal bacterial overgrowth (SIBO) has been observed in patients with liver cirrhosis. Our aim was to explore the relationship between motility abnormalities, portal hypertension, and SIBO.METHODS:Twenty-four patients with liver cirrhosis were included. Twelve had portal hypertension (PH) and 12 had liver cirrhosis (LC) alone. Child-Pugh score was the same in the groups. Antroduodenojejunal pressure recordings were performed, and noninvasive variceal pressure measurements were undertaken. Thirty-two healthy volunteers served as a reference group. Bacterial cultures were obtained from jejunal aspirates.RESULTS:The PH group had a higher proportion of individual pressure waves that were retrograde in the proximal duodenum during phase II (52% vs 13% vs 8% of propagated contractions; p < 0.001) as well as postprandially (49% vs 18% vs 13%; p < 0.01) compared with LC and controls, respectively. Long clusters were more common in PH than in controls (9.1 ± 2.1 vs 4.9 ± 0.8; p < 0.05), and a higher motility index in phase III in the proximal and distal duodenum was seen in the PH as compared with the other groups. The mean variceal pressure was 21 ± 1 mm Hg. Motor abnormalities were not correlated to the level of variceal pressure. Thirty-three percent of the patients in the PH group but none in the LC group had SIBO.CONCLUSIONS:Abnormal small bowel motility and SIBO is common in patients with liver cirrhosis with concomitant portal hypertension. Portal hypertension per se might be significantly related to small bowel abnormalities observed in patients with liver cirrhosis.

Increased risk of primary sclerosing cholangitis and ulcerative colitis in first-degree relatives of patients with primary sclerosing cholangitis

BACKGROUND & AIMSnThe importance of genetic factors for the development of primary sclerosing cholangitis (PSC) is incompletely understood. This study assessed the risk of PSC and inflammatory bowel disease (IBD) among first-degree relatives of patients with PSC, compared with the first-degree relatives of a cohort without PSC.nnnMETHODSnSubjects from the national Swedish cohort of PSC patients (n = 678) were matched for date of birth, sex, and region to up to 10 subjects without a diagnosis of PSC (n = 6347). Linkage through general population registers identified first-degree relatives of subjects in both the PSC and comparison cohorts (n = 34,092). Diagnoses among first-degree relatives were identified by using the Inpatient Register.nnnRESULTSnThe risk of cholangitis was statistically significantly increased in offspring, siblings, and parents of the PSC patient cohort, compared with relatives of the comparison cohort, with the hazard ratios and 95% confidence intervals, 11.5 (1.6-84.4), 11.1 (3.3-37.8), and 2.3 (0.9-6.1), respectively. The hazard ratios for ulcerative colitis (UC) among first-degree relatives of all PSC patients was 3.3 (2.3-4.9) and for Crohns disease 1.4 (0.8-2.5). The risk of UC for relatives of PSC patients without IBD was also increased, 7.4 (2.9-18.9).nnnCONCLUSIONSnFirst-degree relatives of patients with PSC run an increased risk of PSC, indicating the importance of genetic factors in the etiology of PSC. First-degree relatives of PSC patients without IBD are also at an increased risk of UC, which might indicate shared genetic susceptibility factors for PSC and UC.

Dominant Strictures in Patients with Primary Sclerosing Cholangitis

BACKGROUND:Repeat endoscopic dilatations of dominant strictures (DS) have been reported to be of benefit in patients with primary sclerosing cholangitis (PSC). We aimed to determine the prevalence of DS in patients with PSC and the spontaneous course of ALP and bilirubin, up to a year from diagnosis in patients with and without DS.METHOD:Cholangiographies from 125 patients with PSC were reevaluated. DS was defined as a stenosis ≤1.5 mm in diameter of the common bile duct (CBD) and/or ≤ 1.0 mm of right (RHD) or left hepatic duct (LHD).RESULTS:A dominant stricture in common bile duct and/or right hepatic duct or left hepatic duct was present in 56 out of 125 (45%) patients. Mean values for alkaline phosphatase were 16 and 15.2 μkat/L and bilirubin values were 42 and 35 μmol/L before cholangiography in patients with and without DS, respectively (NS). The change in ALP and bilirubin observed from the precholangiographic value up to 2 and 12 months afterward was not significantly different in those with and without DS.CONCLUSIONS:Cholestasis in patients with PSC does not seem to be related to the presence of DS. Endoscopic therapy of DS should not be routinely undertaken and randomized studies are needed to clarify its potential benefits.

Bile duct bacterial isolates in primary sclerosing cholangitis: a study of explanted livers

BACKGROUND/AIMSnThe pathogenesis of the inflammatory lesion in primary sclerosing cholangitis is unknown. The clinical picture is characterized by i.a. episodes of fever, the cause of which also remains speculative. Previous studies of bacterial isolates in the liver or bile ducts in primary sclerosing cholangitis have had the shortcoming of possible contamination associated with the sampling. The aim of this study was to investigate whether bile and bile duct tissue, obtained under sterile conditions in connection with liver transplantation, contain bacteria.nnnMETHODSnWe studied bile from bile duct walls and bile collected from the explanted livers of 36 patients with primary sclerosing cholangitis and 14 patients with primary biliary cirrhosis.nnnRESULTSnPositive cultures were obtained from 21 of 36 primary sclerosing cholangitis patients, but from none of the primary biliary cirrhosis patients. The number of bacterial strains was inversely related to the time after the last endoscopic retrograde cholangiography. Treatment with antibiotics or intraductal stent, or the occurrence of fever before liver transplantation did not seem to influence the culture results, whereas antibiotic treatment in connection with endoscopic retrograde cholangiography may possibly have reduced the number of isolates in the cultures. Alpha-haemolytic Streptococci were retrieved as late as 4 years after the last endoscopic retrograde cholangiography. Retrospective analysis of liver laboratory tests after endoscopic retrograde cholangiography did not indicate a deleterious effect of the investigation.nnnCONCLUSIONSnThe data suggest that antibiotics should be given routinely in connection with endoscopic retrograde cholangiography. They also raise the question of a possible role of alpha-haemolytic Streptococci in the progression of primary sclerosing cholangitis.

Colchicine treatment of primary sclerosing cholangitis

BACKGROUND/AIMSnThere is no medical treatment of documented benefit in primary sclerosing cholangitis (PSC). Colchicine has been observed to reduce mortality in primary biliary cirrhosis in one study. The aim of this study was to examine the effect of colchicine in PSC.nnnMETHODSnEighty-four patients with PSC were randomized to receive 1 mg of colchicine daily (n = 44) or placebo (n = 40) in a double-blind 3-year study. The effect of treatment was evaluated through blind scoring of 10 variables in prestudy and poststudy liver biopsy specimens, daily recording of symptoms, and biochemical tests (serum bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, albumin, immunoglobulins, ceruloplasmin, alpha 1-antitrypsin, and plasma prothrombin levels) at 6-month intervals.nnnRESULTSnThere was no evidence of a favorable effect of colchicine on survival, symptoms, serum biochemistry, or liver histology in patients with PSC.nnnCONCLUSIONSnOne milligram of colchicine daily is ineffective in PSC.