Flavia Mendes

Elevated serum IgG4 concentration in patients with primary sclerosing cholangitis

OBJECTIVES:Biliary strictures, similar to primary sclerosing cholangitis (PSC), have been reported in patients with autoimmune pancreatitis, which is characterized by elevated serum IgG4 levels and responsiveness to corticosteroids. We sought to determine the frequency of elevated IgG4 in patients with PSC and to clinically compare PSC patients with elevated and normal IgG4 levels.METHODS:We measured serum IgG4 in 127 patients with PSC and 87 patients with primary biliary cirrhosis, as disease controls. Demographic, clinical, and laboratory characteristics were compared between the PSC groups with normal and elevated IgG4 (>140 mg/dL).RESULTS:Elevated IgG4 was found in 12 PSC patients (9%) versus one PBC patient (1.1%) (p = 0.017). Patients with elevated IgG4 had higher total bilirubin (p = 0.009), alkaline phosphatase (p = 0.01), and PSC Mayo risk score (p = 0.038), and lower frequency of IBD (p < 0.0001). Importantly, the time to liver transplantation was shorter in patients with elevated IgG4 (1.7 vs 6.5 yr, p = 0.0009). The type of biliary involvement (intrahepatic, extrahepatic, or both) and pancreatic involvement were similar in both groups.CONCLUSIONS:A small proportion of PSC patients had elevated serum IgG4. In these patients parameters of liver disease severity were more pronounced and time to liver transplantation was shorter, suggesting a more severe disease course. It is possible that this subset of patients behaves similarly to autoimmune pancreatitis patients with biliary strictures, and could potentially respond to corticosteroids. Testing PSC patients for IgG4 and treating those with elevated levels with corticosteroids in clinical trials should be considered.

Retreating chronic hepatitis C with daily interferon alfacon‐1/ribavirin after nonresponse to pegylated interferon/ribavirin: DIRECT results

Up to 50% of patients with chronic hepatitis C fail to respond to initial therapy with pegylated interferon (PEG‐IFN) and ribavirin (RBV). With unsuccessful viral eradication, these patients remain at risk for developing progression of their liver disease. Retreatment with PEG‐IFN/RBV yields sustained virologic response (SVR) rates that are under 10%. A wholly synthetic interferon, interferon alfacon‐1 or consensus interferon (CIFN) given with RBV, was evaluated in patients who failed initial PEG‐IFN/RBV therapy. The intent‐to‐treat analysis included 487 patients; 245 received CIFN 9 μg/day and RBV, and 242 received CIFN 15 μg/day and RBV. Within this group of patients, 59.3% had documented advanced fibrosis at baseline liver biopsy (stage F3 or F4). SVR rates were 6.9% (17/245 patients) in the 9 μg group and 10.7% (26/242) in the 15 μg group. In the intent‐to‐treat analysis, SVR rates were higher among patients with a >2‐log10 decrease in hepatitis C virus RNA during prior PEG‐IFN/RBV therapy: 11% (4/38) in the 9 μg group and 23% (7/31) in the 15 μg group. Among patients with lower baseline fibrosis scores (F0‐F3), SVR rates were 7.8% (15/192) in the 9 μg group and 13.1% (23/175) in the 15 μg group. In this same group of patients (F0‐F3), if a >2‐log10 decrease in hepatitis C virus RNA with previous PEG‐IFN/RBV treatment was achieved, SVR rates improved to 10.7% and 31.6% in the 9 μg and 15 μg groups, respectively. CIFN/RBV combination retreatment was safe and well tolerated. Conclusion: Retreatment of PEG‐IFN and RBV nonresponders with CIFN and RBV is safe and efficacious and can be considered a retreatment strategy for patients failing previous therapy with PEG‐IFN/RBV, especially in interferon‐sensitive patients with lower baseline fibrosis scores. (HEPATOLOGY 2009.)

Abnormal Hepatic Biochemistries in Patients With Inflammatory Bowel Disease

OBJECTIVES:The relationship between abnormal hepatic biochemistries and inflammatory bowel disease (IBD) is unclear. We determined the prevalence of abnormal hepatic biochemistries and chronic liver disease in a cohort of IBD patients, and we compared patients with normal and abnormal liver biochemistries.METHODS:Patients with IBD evaluated at our institution between January 1, 2000 and December 31, 2000 were identified. Data on gender, age, IBD subtype, extent and activity, medications, liver disease history, liver biochemistries, and vital status were collected. The χ2 test, Students t-test, and Cox proportional regression were used.RESULTS:We identified 544 patients with available hepatic biochemistries. Abnormal hepatic biochemistries were found in 159 (29%). Defined chronic liver disease was present in 5.8% of patients (primary sclerosing cholangitis in 4.6%). The prevalence of abnormal hepatic biochemistries was 27% for those with active IBD and 36% for those in remission (P = 0.06). Patients with abnormal hepatic biochemistries were less frequently on 5-aminosalicylates (35% vs 51%, P < 0.001), and a smaller proportion was alive at last follow-up (90.4% vs 98.5%, P < 0.0001). The age-adjusted risk of death was 4.8 times higher in patients with abnormal hepatic biochemistries, after excluding patients with any diagnosis of liver disease.CONCLUSIONS:Abnormal hepatic biochemistries were present in nearly one-third of our patients, and surprisingly, they were not associated with IBD activity. Abnormal hepatic biochemistries and chronic liver disease appeared to have a negative impact on vital status. Persistently abnormal hepatic biochemistries should be evaluated, and not attributed to IBD activity.

Thyroid dysfunction in primary biliary cirrhosis, primary sclerosing cholangitis and non-alcoholic fatty liver disease

Background/Aims: Primary biliary cirrhosis (PBC) is frequently associated with autoimmune diseases, including thyroid disease, although it is uncertain that this association is higher than in other liver diseases.

Primary sclerosing cholangitis: overview and update

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disorder that most commonly affects middle-aged men. PSC is strongly associated with IBD, and in this setting the risk of colorectal cancer is markedly increased. Cholangiocarcinoma, and its devastating consequences, is another well-recognized complication of PSC. This condition tends to progress to end-stage liver disease, and patients with PSC have reduced survival rates compared with the general population. Despite significant research efforts in this field, the pathogenetic mechanisms of PSC are still incompletely understood, although growing evidence supports the role of genetic and immunologic factors. Effective medical therapy is lacking; liver transplantation is the only curative treatment modality, with excellent outcomes in this patient population.

Mortality attributable to cholestatic liver disease in the United States

In the past 2 decades, important advances have been made in the treatment of cholestatic liver diseases, including primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Whether these new therapies have had demonstrable impact on mortality on a population‐wide scale has not been evaluated. This study describes the age‐specific and sex‐specific mortality rates from PBC and PSC in the United States between 1980 and 1998, based on the Multiple Cause of Death files. Age‐specific and sex‐ specific mortality rates from PBC and PSC were calculated. The multivariable Poisson model was used to evaluate temporal changes in mortality rates. In 1998, the total age‐adjusted and sex‐adjusted PBC‐related mortality rate was 0.24 per 100,000, and the age‐adjusted and sex‐adjusted PSC‐related mortality rate was 0.23 per 100,000. During the observation period, PBC‐related mortality significantly decreased over time in women younger than 65 years, and in men of all age groups, whereas in older women this number increased over time. PSC‐related mortality remained essentially stable, except in men 65 years of age or older. Conclusion: Since the early 1980s, significant changes in mortality from PBC have occurred. The most noticeable change was an increase in the age of death, which indicates prolongation of survival. These changes may be attributable to liver transplantation or ursodeoxycholic acid. In contrast, mortality from PSC remained largely unchanged, highlighting the need for more effective therapeutic strategies. (HEPATOLOGY 2008.)

Primary sclerosing cholangitis

Primary sclerosing cholangitis is a cholestatic liver disease strongly associated with IBD. Considerable advances in the understanding of its pathogenesis have been made. The idea of autoimmunity affecting genetically susceptible individuals is largely accepted; however, much remains to be explained about the origin of this disease. Despite active investigation of different therapeutic modalities with the goal of modifying disease progression, liver transplantation continues to be the only option to provide survival benefit in these patients.

Prevalence and Indicators of Portal Hypertension in Patients With Nonalcoholic Fatty Liver Disease

BACKGROUND & AIMS Little is known about the prevalence and severity of portal hypertension in patients with nonalcoholic fatty liver disease (NAFLD). We investigated the prevalence and noninvasive predictors of portal hypertension in patients with NAFLD. METHODS Signs of portal hypertension, including esophageal varices, splenomegaly, portosystemic encephalopathy, and ascites, were investigated in 354 patients with NAFLD. RESULTS One hundred patients had portal hypertension at the time of NAFLD diagnosis (28.2%), 88 of these patients had septal fibrosis or cirrhosis (88%). Fibrosis stage correlated with presence (r = 0.41, P < .0001) and number of findings (r = 0.48, P = .006) of portal hypertension. Of the 204 patients with no or mild fibrosis (stages, 0-2), 12 patients had portal hypertension (6%); they had a significantly higher grade of steatosis, based on biopsy analysis, compared with the 192 patients without portal hypertension (94%). Thrombocytopenia, hyperbilirubinemia, cirrhosis, and obesity were associated independently with portal hypertension. Esophageal varices were found in 57 of the 128 patients undergoing endoscopic screening (44.5%) and were associated independently with thrombocytopenia, type 2 diabetes, and splenomegaly. CONCLUSIONS Signs of portal hypertension were present in 25% of patients at the time of diagnosis of NAFLD; most had advanced fibrosis or cirrhosis. Portal hypertension can occur in a small proportion of patients with mild or no fibrosis and is associated with the extent of steatosis. Features of advanced liver disease and insulin resistance might identify patients with NAFLD and portal hypertension, and those expected to derive the most benefit from endoscopic screening for esophageal varices.

Recent advances in the treatment of non-alcoholic fatty liver disease

Non-alcoholic steatohepatitis is a liver disease strongly associated with features of the metabolic syndrome. It is part of the disease spectrum of non-alcoholic fatty liver disease, which is now thought to be the most common cause of chronic liver disease in the US and other Western countries. Initially this condition was considered innocuous but it is now recognised as having the potential to progress to cirrhosis and its complications. The role of insulin resistance and oxidative stress in its pathogenesis is increasingly accepted. Current investigations are directed towards a better understanding of the natural history, pathogenesis and development of treatment strategies. Several therapeutic modalities, including antioxidants, insulin-sensitising agents and lipid-lowering agents, have been evaluated for the treatment of these patients, mostly in small clinical trials. Despite promising results, no therapy has demonstrated a proven benefit.

Antimitochondrial antibody-negative primary biliary cirrhosis.

There is a subset of patients who have biochemical and histologic features consistent with primary biliary cirrhosis (PBC) who lack antimitochondrial antibodies (AMA). This entity is usually referred to as AMA-negative PBC or alternatively autoimmune cholangitis. Patients who have AMA-negative PBC are believed to have a similar clinical course, response to treatment, and prognosis as their AMA-positive counterparts. As more sensitive and specific serologic tests are developed to detect serum AMA, it is possible we may find that these patients initially believed to be AMA-negative are indeed AMA-positive, suggesting a single disease process.