High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: a double-blind, randomized, placebo-controlled trial.

UNLABELLED: In uncontrolled clinical studies, ursodeoxycholic acid (UDCA) had a beneficial effect on nonalcoholic steatohepatitis (NASH). However, a large controlled trial using UDCA (13-15 mg/kg/day) was unable to confirm these results. Accordingly, a randomized, placebo-controlled study was initiated with a high dose of UDCA (23-28 mg/kg/day). The allocation of patients and the evaluation of liver histology were performed according to a modified Brunt score and the nonalcoholic fatty liver disease activity score (NAS). With the modified Brunt score, 185 patients with histologically proven NASH were randomized [intention to treat (ITT)], and 147 were treated per protocol (PP). With the NAS, 137 patients were confirmed to have NASH, 48 had borderline NASH, and 1 did not have NASH. The treatment time was 18 months. At entry, the treatment groups were comparable. A second biopsy sample was obtained from 139 of 185 patients (NAS: 107/137). The primary criterion for evaluation was a change in the liver histology; the secondary criteria were single histological variables and liver biochemistry. Significant differences in the overall histology could not be detected between the two treatment groups with the modified Brunt score (P = 0.881) or NAS (P = 0.355). Only lobular inflammation improved significantly (P for the modified Brunt score = 0.011, P for NAS = 0.005). In subgroup analyses, significant improvements in lobular inflammation were also observed in males, younger patients up to 50 years of age, slightly overweight patients, and patients with hypertension and an increased histology score. The fibrosis score did not change (P for ITT = 0.133, P for PP = 0.140). With the exception of gamma-glutamyl transferase, UDCA did not improve laboratory data. CONCLUSION: High-dose UDCA failed to improve the overall histology in patients with NASH in comparison with placebo.

Primary biliary cirrhosis in Lithuania: diagnosis and clinical picture.

BACKGROUND: The rising detection and considerable geographical variation of primary biliary cirrhosis (PBC) in some regions demand increased awareness of the disease. The aim was to analyze the clinical, biochemical, immunological, and histological criteria of PBC patients in Lithuania and evaluate the patterns of disease presentation and histological features. MATERIAL/METHODS: One hundred thirty-one PBC patients were examined and followed in the Center of Hepatology, Gastroenterology, and Dietetics, Vilnius University Hospital. Their case records were evaluated in this retrospective record-review study. RESULTS: Most of the patients were women (94.6%) older than 50 years with late stages of PBC. Men were significantly older and had a threefold shorter duration from disease presentation to diagnosis (4.0+/-0.4 vs. 1.4+/-0.4 years). 29.8% of patients had asymptomatic disease at presentation and at diagnosis, were older than the symptomatic ones, and presented with significantly lower prevalence of jaundice, skin signs, and lower alkaline phosphatase (ALP) activity, but higher frequency of sicca syndrome. Antimitochondrial antibody (AMA) positivity was found in 91.7%, bile duct lesions in all patients, while the frequency of histological signs of cholestasis (except copper accumulation) was lower. No significant differences in these parameters in asymptomatic and symptomatic patients were found. CONCLUSIONS: Most PBC patients in Lithuania were at late histological stages, with a predominance of females older than 50 years and long duration from disease presentation to diagnosis. One third of these PBC patients initially had asymptomatic course, with some differences in clinical signs and their prevalence compared with initially symptomatic patients.

13C-methacetin and 13C-galactose breath tests can assess restricted liver function even in early stages of primary biliary cirrhosis.

OBJECTIVE: The 13C-methacetin breath test quantitatively evaluates cytochrome P450-dependent liver function. The 13C-galactose breath test non-invasively measures the galactose oxidation capacity of the liver. The aim of this study was to find out whether these breath tests are sensitive parameters also in non-cirrhotic patients with primary biliary cirrhosis. MATERIAL AND METHODS: Nineteen patients with early-stage primary biliary cirrhosis (no cirrhotic alterations in the liver biopsy, Ludwig stage I-III) and 20 healthy controls underwent the 13C-methacetin and 13C-galactose breath tests. RESULTS: Patients with primary biliary cirrhosis metabolized less 13C-methacetin than controls (cumulative recovery within 30 min 7.5+/-2.4% versus 14.0+/-2.6%; p < 0.001). When a cut-off > 9.8% was used for the cumulative recovery after 30 min, the methacetin breath test reached 84.2% sensitivity and 95.0 specificity. In the 13C-galactose breath test, the percentage recovery at 60 min in patients was 3.1+/-1.3%/h, and 6.3+/-1.1%/h in controls (p < 0.001). Using a cut-off > 4.7%/h, the galactose breath test reached 89.5% sensitivity and 95.0 specificity. CONCLUSIONS: In non-cirrhotic, early-stage, primary biliary cirrhosis the 13C-methacetin breath test and the 13C-galactose breath test reliably indicate decreased liver function. The 13C-galactose breath test can also predict the histological score.

Toxicity of ethanol and acetaldehyde in hepatocytes treated with ursodeoxycholic or tauroursodeoxycholic acid.

In hepatocytes ethanol (EtOH) is metabolized to acetaldehyde and to acetate. Ursodeoxycholic acid (UDCA) and tauroursodeoxycholic acid (TUDCA) are said to protect the liver against alcohol. We investigated the influence of ethanol and acetaldehyde on alcohol dehydrogenase (ADH)-containing human hepatoma cells (SK-Hep-1) and the protective effects of UDCA and TUDCA (0.01 and 0.1 mM). Cells were incubated with 100 and 200 mM ethanol, concentrations in a heavy drinker, or acetaldehyde. Treatment with acetaldehyde or ethanol resulted in a decrease of metabolic activity and viability of hepatocytes and an increase of cell membrane permeability. During simultaneous incubation with bile acids, the metabolic activity was better preserved by UDCA than by TUDCA. Due to its more polar character, acetaldehyde mostly damaged the superficial, more polar domain of the membrane. TUDCA reduced this effect, UDCA was less effective. Damage caused by ethanol was smaller and predominantly at the more apolar site of the cell membrane. In contrast, preincubation with TUDCA or UDCA strongly decreased metabolic activity and cell viability and led to an appreciable increase of membrane permeability. TUDCA and UDCA only in rather high concentrations reduce ethanol and acetaldehyde-induced toxicity in a different way, when incubated simultaneously with hepatocytes. In contrast, preincubation with bile acids intensified cell damage. Therefore, the protective effect of UDCA or TUDCA in alcohol- or acetaldehyde-treated SK-Hep-1 cells remains dubious.

Primary biliary cirrhosis--presentation and diagnosis.

Primary biliary cirrhosis is predominantly seen in middle-aged women. Typical symptoms are fatigue, pruritus, and abdominal pain. Jaundice develops in the endstage disease. At presentation, about 40% of the patients are asymptomatic, but 30% to 50% already have hepatomegaly, and 15% present with splenomegaly. Even patients with fully developed liver cirrhosis may be free of symptoms. Abnormal physical signs and advanced histological stage are more frequent in symptomatic than in asymptomatic patients. Fatigue, pruritus, and Sjögren's syndrome are more common in women than men, but other signs and symptoms do not differ in the two sexes. PBC is associated with a large variety of other diseases, like arthropathy, CREST syndrome, autoimmune thyroiditis, and so on, which in addition will or will not produce symptoms. Hepatocellular carcinoma is a rare complication in women, but more frequent in men. Diagnosis can be established by the triad antimitochondrial antibodies (AMA), cholestatic indices, and liver histology, diagnostic or compatible with PBC. When AMA are not detected, then antinuclear antibodies (autoantibodies against gp.210 and others) can be detected in 50% of AMA-negative patients. AMA titers do not correlate with the course of the disease nor histological progression. After liver transplantation, AMA recur in nearly 100%. The liver enzyme pattern in PBC patients is cholestatic: alkaline phosphatase and gammaglutamyltransferase increase to 10 or more times the upper limit of normal. The amount of enzymes does not correlate with disease progression or stage of the disease. The only prognostic factor in PBC is serum bilirubin. AMA-negative patients account for about 10% to 15%. Routine biochemical tests are not different from AMA-positive patients, but usually higher ANA, SMA, and IgG concentrations are detected. Histologically, it is PBC. The overlap-syndrome, autoimmune hepatitis-PBC presents with the histological features of autoimmune hepatitis and PBC, with AMA, ANA, or SMA. Imaging procedures are not helpful for the diagnosis of PBC, except for liver histology. Histologically, four different stages can be assessed, ranging from florid bile duct lesions, ductular proliferation, and fibrosis to liver cirrhosis. Liver histology is of interest for the assessment of the diagnosis and for staging of the disease.

The influence of sulindac on patients with primary biliary cirrhosis that responds incompletely to ursodeoxycholic acid: a pilot study.

OBJECTIVES: In 30% of patients with primary biliary cirrhosis (PBC) ursodeoxycholic acid (UDCA) causes full biochemical normalization, while 70% are incomplete responders. The only differences between the two groups are the significantly higher cholestasis indices in the incomplete responders. In these patients we investigated whether the strongly choleretic sulindac together with UDCA is superior to UDCA monotherapy. DESIGN AND METHODS: Twenty-three patients with PBC incompletely responding to UDCA monotherapy were entered in the open label study for 12 months. Eleven patients (stage II, seven; III, two; and IV, two) received UDCA (10-15 mg/kg/day) plus sulindac (100-300 mg/day) (Group I). Twelve patients (stage I, six; II, four; III, one; and IV, one) were treated with UDCA alone (Group II). Liver biochemistry, analysis of antimitochondrial, antinuclear, smooth muscle, and liver-kidney-microsomal antibodies, ultrasonography and gastroscopy were done in regular intervals. RESULTS: In Group I all liver indices, IgG, IgM and IgA significantly improved although pretreatment data and stages of the disease tended to be higher than in Group II. In five patients of Group I liver histology improved slightly. Sulindac was well tolerated. The biochemical indices did not further improve on UDCA monotherapy. CONCLUSIONS: Sulindac in combination with UDCA further improves liver biochemistries in patients with PBC who responded incompletely to UDCA alone.