Rolf Hultcrantz

Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis.

BACKGROUND/AIMS--The course of primary sclerosing cholangitis (PSC) is highly variable and unpredictable. This study describes the natural history and outcome of PSC. These data were used to construct a prognostic model for patients with PSC. METHODS--A total of 305 Swedish patients with PSC were studied. The median follow up time was 63 (1-194) months and all patients could be traced for follow up. Some 79 patients died or had a liver transplant. The prognostic significance of clinical, biochemical, and histological findings at the time of diagnosis were evaluated using multivariate analysis. RESULTS--The estimated median survival from time of diagnosis to death or liver transplantation was 12 years. Cholangiocarcinoma was found in 24 (8%) of the patients and 134 (44%) of the patients were asymptomatic at the time of diagnosis. The estimated survival rate was significantly higher in the asymptomatic group (p < 0.001). However, 29 (22%) of the asymptomatic patients became symptomatic during the study period. It was found that age, serum bilirubin concentration, and histological stage at the time of diagnosis were independent predictors of a bad prognosis. These variables were used to construct a prognostic model. CONCLUSIONS--This prognostic model developed from a large homogeneous population of PSC patients should be of value for the timing of transplantation and patient counselling in PSC.

Hepatic and extrahepatic malignancies in primary sclerosing cholangitis

BACKGROUND/AIMS To 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. METHODS The 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. RESULTS Median 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. CONCLUSIONS In 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.

Decreased survival of subjects with elevated liver function tests during a 28‐year follow‐up

The long‐term survival of subjects with nonalcoholic fatty liver disease (NAFLD) in comparison with both individuals with elevated transaminases attributable to other causes and the general poulation is poorly characterized. This study was undertaken to determine the frequency of NAFLD in a cohort of subjects who underwent liver biopsy from 1980 to 1984 because of elevated liver enzymes, and to assess mortality among subjects with NAFLD in comparison with the general Swedish population. The 256 subjects (61% men) had a mean age of 45 ± 12 years at the inclusion. Liver biopsies were blindly scored for NAFLD and nonalcoholic steatohepatitis (NASH). Causes of death were ascertained from the national Swedish Cause of Death Registry. Fatty liver was detected in 143 of the 256 subjects, including 25 (10%) with alcoholic fatty liver disease and 118 (46%) exhibiting NAFLD. Of those, 51 (20%) were classified as NASH and 67 (26%) as nonalcoholic bland steatosis. Cirrhosis was present in 9% at inclusion. During the follow‐up period, 113 (44%) of the total population and 47 (40%) of the 118 subjects diagnosed with NAFLD died. Of the 113 deaths, 37 were of cardiovascular disease and 16 of liver diseases. Compared with the total Swedish population, adjusted for sex, age, and calendar period, subjects with NAFLD exhibited a 69% increased mortality (standardized mortality ratio [SMR] = 1.69; 95% confidence interval [CI], 1.24–2.25); subjects with bland steatosis, a 55% increase (SMR, 1.55; 95% CI, 0.98–2.32; P = 0.062); and subjects with NASH, 86% (SMR, 1.86; 95% CI, 1.19–2.76; P = 0.007). Conclusion: Patients with NASH are at increased risk of death compared with the general population. Liver disease is the third most common cause of death among patients with NAFLD. (HEPATOLOGY 2009.)

Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world, strongly associated with insulin resistance and the metabolic syndrome. Nonalcoholic steatohepatitis, i.e., fatty liver accompanied by necroinflammatory changes, is mostly defined by the NAFLD activity score (NAS). The aim of the current study was to determine disease‐specific mortality in NAFLD, and evaluate the NAS and fibrosis stage as prognostic markers for overall and disease‐specific mortality. In a cohort study, data from 229 well‐characterized patients with biopsy‐proven NAFLD were collected. Mean follow‐up was 26.4 (±5.6, range 6‐33) years. A reference population was obtained from the National Registry of Population, and information on time and cause of death were obtained from the Registry of Causes of Death. NAFLD patients had an increased mortality compared with the reference population (hazard ratio [HR] 1.29, confidence interval [CI] 1.04‐1.59, P = 0.020), with increased risk of cardiovascular disease (HR 1.55, CI 1.11‐2.15, P = 0.01), hepatocellular carcinoma (HR 6.55, CI 2.14‐20.03, P = 0.001), infectious disease (HR 2.71, CI 1.02‐7.26, P = 0.046), and cirrhosis (HR 3.2, CI 1.05‐9.81, P = 0.041). Overall mortality was not increased in patients with NAS 5‐8 and fibrosis stage 0‐2 (HR 1.41, CI 0.97‐2.06, P = 0.07), whereas patients with fibrosis stage 3‐4, irrespective of NAS, had increased mortality (HR 3.3, CI 2.27‐4.76, P < 0.001). Conclusion: NAFLD patients have increased risk of death, with a high risk of death from cardiovascular disease and liver‐related disease. The NAS was not able to predict overall mortality, whereas fibrosis stage predicted both overall and disease‐specific mortality. (Hepatology 2015;61:1547–1554)

Liver Investigation in 149 Asymptomatic Patients with Moderately Elevated Activities of Serum: Aminotransferases

The accidental finding of raised levels of serum aminotransferase levels may lead to extensive investigations of the liver in apparently healthy people. To identify diagnostic groups and their need for investigations, we have evaluated the results of all investigative procedures carried out in 149 asymptomatic patients with persistently raised serum levels of aminotransferases. Fatty liver was found in 64%. These patients often had a high body weight. A high alcohol intake and diabetes mellitus were also noted. Chronic active or persistent hepatitis was found in 20% of the patients. Six per cent had cirrhosis, 4% had alpha 1-antitrypsin deficiency, and 3.5% had hemochromatosis. Apart from ferritin, alpha 1-antitrypsin, and markers for hepatitis B, blood tests were of little value for distinguishing among different diagnostic groups. This was the case also for the imaging procedures, and neither liver scintigraphy nor ultrasonography was a reliable source of diagnostic information. The results of our study indicate that diagnosis in this group of patients cannot be made without liver biopsy.

Budesonide Induces Remission More Effectively Than Prednisone in a Controlled Trial of Patients With Autoimmune Hepatitis

BACKGROUND & AIMS Autoimmune hepatitis (AIH) is a chronic liver disease associated with cirrhosis and liver failure. Corticosteroid therapy induces long-term remission but has many side effects. We compared the effects of budesonide (a steroid that is rapidly metabolized, with low systemic exposure) and prednisone, both in combination with azathioprine. METHODS We performed a 6-month, prospective, double-blind, randomized, active-controlled, multicenter, phase IIb trial of patients with AIH without evidence of cirrhosis who were given budesonide (3 mg, three times daily or twice daily) or prednisone (40 mg/d, tapered to 10 mg/d); patients also received azathioprine (1-2 mg/kg/d). Treatment was followed by a 6-month, open-label phase during which all patients received budesonide in addition to azathioprine. The primary end point was complete biochemical remission, defined as normal serum levels of aspartate aminotransferase and alanine aminotransferase, without predefined steroid-specific side effects, at 6 months. RESULTS The primary end point was achieved in 47/100 patients given budesonide (47.0%) and in 19/103 patients given prednisone (18.4%) (P < .001; 97.5% 1-side confidence interval [CI] = 16.2). At 6 months, complete biochemical remission occurred in 60% of the patients given budesonide versus 38.8% of those given prednisone (P = .001; CI: 7.7); 72.0% of those in the budesonide group did not develop steroid-specific side effects versus 46.6% in the prednisone group (P < .001; CI = 12.3). Among 87 patients who were initially given prednisone and then received budesonide after 6 months, steroid-specific side effects decreased from 44.8% to 26.4% at month 12 (P < .002). CONCLUSIONS Oral budesonide, in combination with azathioprine, induces and maintains remission in patients with noncirrhotic AIH, with a low rate of steroid-specific side effects.

The Myofibroblastic Conversion of Peribiliary Fibrogenic Cells Distinct from Hepatic Stellate Cells Is Stimulated by Platelet-Derived Growth Factor During Liver Fibrogenesis

The origin of myofibroblasts and the factors promoting their differentiation during liver fibrogenesis remain uncertain. During biliary-type fibrogenesis, the proliferation and chemoattraction of hepatic stellate cells (HSC) toward bile ducts is mediated by platelet-derived growth factor (PDGF), while myofibroblastic conversion of peribiliary cells distinct from HSC also occurs. We herein examined the phenotype of these peribiliary myofibroblasts as compared with myofibroblastic HSC and tested whether their differentiation was affected by PDGF. Biliary-type liver fibrogenesis was induced by common bile duct ligation in rats. After 48 hours, periductular fibrosis in portal tracts colocalized with smooth muscle α-actin–immunoreactive myofibroblasts, the majority of which were desmin negative. Simultaneously, in sinusoids, desmin immunoreactivity was induced in a large number of HSC, which were smooth muscle α-actin negative. Cultures of peribiliary myofibroblasts were expanded from isolated bile duct segments and compared with myofibroblastic HSC. Peribiliary myofibroblasts outgrowing from bile duct segments expressed smooth muscle α-actin, α1 (I) collagen mRNA, and PDGF receptor-β subunit. Desmin immunoreactivity gradually decreased in cultured peribiliary myofibroblasts, contrasting with constant labeling of all myofibroblastic HSC. In addition, IL-6 expression in peribiliary myofibroblasts was up to 100-fold lower than in myofibroblastic HSC, whereas the expression of the complement-activating protease P100 in both cell types showed little difference and that of the extracellular matrix component fibulin 2 was similar. The expression of smooth muscle α-actin protein in cultured peribiliary myofibroblasts was stimulated by PDGF-BB and inhibited by STI571, a PDGF receptor tyrosine kinase inhibitor, whereas in bile duct–ligated rats, the administration of STI571 caused a significant decrease in peribiliary smooth muscle α-actin immunoreactivity, and to a lesser extent, a decrease in peribiliary fibrosis. These results indicate that peribiliary cells distinct from HSC undergo a PDGF-mediated conversion into myofibroblasts expressing IL-6 at lower levels than myofibroblastic HSC and contribute to the initial formation of biliary-type liver fibrosis.

A Risk for Hepatocellular Carcinoma Persists Long-term After Sustained Virologic Response in Patients With Hepatitis C-Associated Liver Cirrhosis

BACKGROUND The long-term effect of sustained virologic response (SVR) to antiviral therapy on the risk of developing hepatocellular carcinoma (HCC), liver complications, liver-related death, and overall death in hepatitis C virus (HCV)-infected patients with liver cirrhosis is not fully known. METHODS These risks were evaluated during long-term follow-up in 351 patients with HCV-related cirrhosis. One hundred ten patients with SVR, 193 with non-SVR, and 48 who were untreated were included in a multicenter cohort that was initiated in 2001 and prospectively followed up for a mean of 5.3 (SD, 2.8) years. Complementary follow-up data from national registries were used to minimize the loss of patients during follow-up. RESULTS Six patients with SVR developed HCC at 0.04, 0.64, 2.4, 7.4, 7.4, and 7.6 years, respectively, after achieving SVR. The incidences of HCC, any liver complication, liver-related death, and overall death per 100 person-years were significantly lower in SVR time with 1.0, 0.9, 0.7, and 1.9, compared to 2.3, 3.2, 3.0, and 4.1 in non-SVR and 4.0, 4.9, 4.5, and 5.1 in untreated time. The long-term consequences did not decline significantly after >3 years versus during the first 3 years of follow-up. CONCLUSIONS The risk for HCC, liver decompensation, and death in patients with liver cirrhosis related to HCV was markedly reduced after SVR, but a long-term risk of developing HCC remains for up to 8 years. Cirrhotic patients with HCV who achieve SVR should therefore maintain long-term surveillance for HCC. Future studies aimed to better identify those with remaining long-term risk for HCC are needed.

PDGF-Mediated Chemoattraction of Hepatic Stellate Cells by Bile Duct Segments in Cholestatic Liver Injury

The accumulation of myofibroblasts and fibrosis around proliferating bile ducts in cholestatic liver disease has been attributed to the proliferation and phenotypic modulation of portal fibroblasts, whereas the contribution of hepatic stellate cells remains uncertain. There is increasing evidence to indicate that bile ducts may stimulate chemoattraction of hepatic stellate cells (HSC). In the present study, we undertook dynamic tests to examine such a possibility and to investigate the role of two potential mediators: platelet-derived growth factor-BB (PDGF-BB) and endothelin-1. Cholestasis was induced by bile duct ligation in rats. HSC were isolated from normal rats and culture activated into myofibroblasts expressing PDGF-β receptors. Migration of myofibroblastic HSC was investigated in a Transwell chemotaxis filter assay. As compared with basal conditions, PDGF-BB (100 μg/l) and endothelin-1 (10−8 m) induced a 3-fold and 1.7-fold increase in HSC migration, respectively. Bile duct segments isolated from cholestatic rats triggered a 3-fold increase in migration. This stimulation was significantly more potent than that observed in the presence of normal bile ducts. It was inhibited by neutralizing anti-PDGF antibodies and by STI571 PDGF receptor tyrosine kinase inhibitor, by 60% and 85%, respectively, whereas Bosentan, an endothelin receptor antagonist, had no significant inhibiting effect. In bile duct segments from cholestatic rats PDGF-B chain mRNA was detected at higher levels than in controls, whereas PDGF-BB was immunolocalized in bile duct epithelial cells. The results indicate that chemotaxis of HSC towards bile duct structures may contribute to the development of periductular fibrosis in cholestatic disorders, and that PDGF-BB is the major mediator in this process. In addition, anti-liver fibrogenic properties of STI571 are suggested by potent inhibition of myofibroblastic HSC function.

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

BACKGROUND & AIMS The 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. METHODS Subjects 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. RESULTS The 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). CONCLUSIONS First-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.