No effective therapy currently exists for patients with nonalcoholic steatohepatitis (NASH). Betaine, a naturally occurring metabolite of choline, has been shown to raise S-adenosylmethionine (SAM) ...levels that may in turn play a role in decreasing hepatic steatosis. Our aim was to determine the safety and effects of betaine on liver biochemistries and histological markers of disease activity in patients with NASH.
Ten adult patients with NASH were enrolled. Patients received betaine anhydrous for oral solution (Cystadane) in two divided doses daily for 12 months. Seven out of 10 patients completed 1 yr of treatment with betaine.
A significant improvement in serum levels of aspartate aminotransferase (p = 0.02) and ALAT (p = 0.007) occurred during treatment. Aminotransferases normalized in three of seven patients, decreased by >50% in three of seven patients, and remained unchanged in one patient when compared to baseline values. A marked improvement in serum levels of aminotransferases (ALT -39%; AST -38%) also occurred during treatment in those patients who did not complete 1 yr of treatment. Similarly, a marked improvement in the degree of steatosis, necroinflammatory grade, and stage of fibrosis was noted at 1 yr of treatment with betaine. Transitory GI adverse events that did not require any dose reduction or discontinuation of betaine occurred in four patients.
Betaine is a safe and well tolerated drug that leads to a significant biochemical and histological improvement in patients with NASH. This novel agent deserves further evaluation in a randomized, placebo-controlled trial.
Data from animal models of fibrosis and fatty liver suggest that leptin may mediate the profibrogenic responses in the liver, but the association of leptin and liver fibrosis in human nonalcoholic ...fatty liver disease (NAFLD) remains undefined. We aimed at determining the relation between leptin and liver fibrosis in human NAFLD.
Human plasma leptin and several indicators of insulin resistance were measured in 88 NAFLD patients and matched controls.
Leptin levels were significantly greater in patients with more advanced fibrosis (
P=0.005). By multivariate analysis, the significant association between leptin and fibrosis was abolished (adjusted
P=0.3) when controlling for confounders including age, gender, BMI, diabetes and insulin resistance. Only age (adjusted
P=0.006) and insulin sensitivity (adjusted
P=0.04) correlated significantly with fibrosis stage. A second liver biopsy was performed in 39 out of the 88 patients at 27.9±16 months. Leptin levels were not significantly different between patients who had fibrosis progression (
n=10) and those who did not (
n=29).
In human NAFLD, no relationship between leptin levels and fibrosis stage was demonstrated. The correlation of leptin and fibrosis severity seems to be an indicator of the factors that determine leptin production.
Some patients with inflammatory bowel disease (IBD) have chronic cholestasis and hepatic histology compatible with primary sclerosing cholangitis (PSC) but normal findings on cholangiography. These ...patients with small-duct PSC have remained largely unstudied. Our aim was to determine the prevalence and long-term outcomes of patients with small-duct PSC. Eighteen patients with small-duct PSC (7 female and 11 male patients; mean age, 39.9 ± 15.3 years range, 13-68 years) seen over a 4-year period were matched blindly by age and sex to 36 patients with classic PSC and followed up for 32.5 years. Small-duct PSC represented 5.8% of patients (18 of 309) with sclerosing cholangitis. Subsequent endoscopic retrograde cholangiography (ERC) performed in 5 patients with small-duct PSC showed progression to typical PSC in 3 patients at 4, 5.5, and 21 years of follow-up. None of the patients with small-duct PSC but 4 of the patients with classic PSC developed hepatobiliary malignancy. There were 3 deaths (17%) or liver transplantations in patients with small-duct PSC (2 after progressing to classic PSC) and 15 (42%) in the classic PSC group. Survival free of liver transplantation was significantly greater in the small-duct than in the classic PSC group (
P = .04). Compared with the general U.S. population, survival in patients with small-duct PSC was similar (
P = .4) but significantly lower in patients with classic PSC (
P < .001). In conclusion, small-duct PSC may represent an earlier stage of PSC associated with a significantly better long-term prognosis. Some patients, however, progress to classic PSC and/or end-stage liver disease with the consequent necessity of liver transplantation. (H
EPATOLOGY 2002;35:1494-1500.)
Ursodeoxycholic acid (UDCA) has been proposed as beneficial therapy for patients with primary biliary cirrhosis (PBC). The effects of UDCA on metabolic bone disease, a major source of morbidity in ...patients with PBC, are essentially unknown. Preliminary information suggests that UDCA may improve biochemical indices of bone disease, although information about the effects of bone disease, although information about the effects of UDCA on bone density is lacking. In this study, we describe the effects of UDCA on lumbar spine bone mineral densities over a 3‐year period during which patients were enrolled in a randomized, double‐blind, therapeutic trial of UDCA for the treatment of PBC. Lumbar spine dual‐photon densitometry was measured at entry and annually. Eighty‐eight patients, 50 in the UDCA group and 38 in the placebo group, had serial measurements available for up to 3 years. There was no statistical difference between the two treatment groups at entry with respect to histologist stage, total bilirubin, age, use of calcium supplement, vitamin D levels, or estrogen. After 3 years of treatment, there was no significant difference in the lumbar spine bone desnitometry measurements between the UDCA‐treated and placebo groups. We conclude that, after 3 years of treatment, UDCA is not associated with statistically significant differences in the rate of bone loss from the lumbar spine in patients when compared with placebo despite beneficial effects of treatment on the underlying liver disease. Further efforts to define effective treatments for the bone disease need to be pursued. (HEPATOLOGY 1995;21:389–392.)
Primary sclerosing cholangitis (PSC) is increasingly diagnosed in children and adolescents, but its long-term prognosis remains uncertain. The aim of this longitudinal, cohort study was to determine ...the long-term outcome of children with PSC. Fifty-two children with cholangiography-proven PSC (34 boys and 18 girls; mean age 13.8 ± 4.2 years; range, 1.5-19.6 years) who were seen at our institution over a 20-year period were followed-up for up to 16.7 years. Two thirds presented with symptoms and/or signs of PSC and 81% had concomitant inflammatory bowel disease (IBD). Twenty-five percent had total alkaline phosphatase activity within the normal range for the age group, but all of them had elevated γ-glutamyl transpeptidase levels. Autoimmune hepatitis overlapping with PSC was present in 35% of children. A positive but transient clinical and/or biochemical response occurred under therapy with ursodeoxycholic acid, alone or in combination with immunosuppressive medications. During follow-up, 11 children underwent liver transplantation for end-stage PSC and 1 child died. The median (50%) survival free of liver transplantation was 12.7 years. Compared with an age- and gender-matched U.S. population, survival was significantly shorter in children with PSC (
P < .001). In a Cox regression model, lower platelet count, splenomegaly, and older age were associated with shorter survival. Presence of autoimmune hepatitis overlapping with PSC (
P = .2) or medical therapy (
P = .2) did not affect survival. In conclusion, PSC significantly decreases survival in this child population. Although pharmacologic therapy may improve symptoms and liver test results initially, it does not seem to impact the long-term outcome.(H
epatology 2003;38:210-217.)
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of young adults that is associated with significant morbidity and mortality. No effective medical therapy is available. ...Minocycline has been found to exert biological effects independent of its antimicrobial properties, including anti-inflammatory activities such as inhibition of inducible nitric oxide synthase, upregulation of interleukin 10, and direct suppressive effect on B- and T-cell function. Minocycline may also inhibit cell death pathways by reducing both proapoptotic and proinflammatory enzyme activation. We sought to investigate the safety and efficacy of minocycline among patients with PSC.
We evaluated the efficacy of minocycline in patients with PSC in a pilot study. Sixteen patients with PSC were enrolled. Minocycline, 100 mg orally twice daily, was given for 1 year.
A statistically significant improvement in serum alkaline phosphatase activity (330 U/l vs. 265 U/l, P=0.04) and Mayo risk score (0.55 vs. 0.02, P=0.05) occurred with treatment. Serum bilirubin and albumin remained essentially unchanged while on treatment.
The results of this pilot study indicate that minocycline is reasonably well tolerated and potentially effective in patients with PSC. These findings might be explained by the anti-inflammatory and antiapoptotic properties of minocycline. Though the data presented are too preliminary to support the clinical use of minocycline in the treatment of PSC at this time, its use should be further investigated.
Background/Aims: This study aimed at evaluating the effect of ursodeoxycholic acid (UDCA) treatment on histologic progression in primary biliary cirrhosis (PBC).
Methods: Using combined individual ...histologic findings from four clinical trials, we selected the patients in whom paired liver-biopsy specimens were available with a time interval of about 36 months between biopsies. A total of 367 patients were selected (UDCA: 200 vs. placebo: 167).
Results: Overall, there was no significant difference in the progression of the histologic stage between the two groups. By contrast, in the subgroup of patients with initial stages I–II (
n=177) there was a significant decrease in the histologic stage progression in the UDCA group relative to the placebo group (
P<0.03). Overall, there was a significant delay in the progression of periportal necroinflammatory lesions (
P=0.03), and an improvement in the degree of ductular proliferation (
P=0.02) in the UDCA group compared with the placebo group. There was no significant difference in the progression of other specific lesions.
Conclusions: A 2-year UDCA treatment reduces periportal necroinflammation and improves ductular proliferation, and when initiated at the earlier stages I–II of the disease also delays the progression of histologic stage. These data support the early initiation of the drug to prevent these histologic features of PBC.
The natural history of secondary sclerosing cholangitis (SSC) is ill-defined. In order to better determine the natural history of this condition, we retrospectively reviewed data from the Mayo Clinic ...in Rochester, Minnesota. We also compared the natural history of patients diagnosed with SSC to a cohort with a diagnosis of primary sclerosing cholangitis (PSC).
We used a computer-assisted search to identify patients with a diagnosis of SSC seen from 1992 to 2002. The diagnosis was confirmed by chart review and information about age, gender, etiology, therapy, and clinical course was sought. We excluded those presumed SSC patients who had a history of inflammatory bowel disease, those with malignancy at the time of diagnosis, and those who had undergone liver transplantation prior to the diagnosis of SSC. Patients with PSC matched for age, gender, and serum bilirubin level served as disease controls.
We identified 31 patients, average age 57, (range 28-79). The causes of SSC included surgical trauma from cholecystectomy (13 patients), intraductal stones (12 patients), recurrent pancreatitis (4 patients), and abdominal injury (2 patients). Nine patients with SSC ultimately required liver transplantation and 4 patients have died. When compared to matched patients with PSC, the survival free of transplant was significantly shortened (p<0.03).
When the long-term outcome of SSC patients was compared to matched PSC controls, the SSC patients had a poorer outcome. The natural history of SSC is characterized by a shortened life expectancy.
Liver biopsies are performed in patients with primary sclerosing cholangitis (PSC) to stage disease and to rule out coexisting liver disease. The purpose of this study was to examine how often ...routine liver biopsies provide important information in patients with PSC.
We reviewed the charts of 138 patients with a cholangiographic diagnosis of PSC to determine whether information from liver biopsy had an impact on clinical management.
A total of 30 patients did not have a liver biopsy, whereas 29 patients had a biopsy before cholangiography. In 79 patients the liver biopsy was performed after the diagnosis of PSC was established by cholangiography (median time from cholangiography to liver biopsy, 21 days). In 78 of 79 patients (98.7%) the liver biopsy revealed no atypical findings and did not affect clinical management. In one patient the liver biopsy revealed findings of an overlap syndrome with autoimmune hepatitis, and the patient was treated with corticosteroids and azathioprine. This patient had biochemical features consistent with autoimmune hepatitis. One patient developed a bile leak after liver biopsy, requiring hospitalization (complication rate 0.9%).
Liver biopsies rarely contribute new information that affects the management of patients with PSC. Given the risks of the procedure, liver biopsies for patients with a diagnosis of PSC established by cholangiography may not routinely be necessary.
Bone loss is a well-recognized complication of primary biliary cirrhosis (PBC). Although it has been suggested that alendronate might improve bone mineral density (BMD) in PBC, no randomized ...placebo-controlled trial has been conducted. The primary aim of this study was to compare the effects of alendronate versus placebo on BMD and biochemical measurements of bone turnover in patients with PBC-associated bone loss. We conducted a double-blinded, randomized, placebo-controlled trial. Patients with a PBC and BMD t score of less than -1.5 were randomized to receive 70 mg per week of alendronate or placebo over 1 year. BMD of the lumbar spine and proximal femur were measured at entry and at 1 year. Changes from baseline in BMD and biochemical measurements of bone turnover were assessed. Thirty-four patients were enrolled. Seventeen patients were randomized to each arm. After 1 year, a significantly larger improvement (P = .005) in spine BMD was observed in the alendronate group (0.09 +/- 0.03 g/cm2 SD from baseline) compared with the placebo group (-0.003 +/- 0.02 g/cm2 SD from baseline). A larger improvement (P = .046) was also observed in the femoral BMD of alendronate patients versus placebo. BMD changes were independent of concomitant estrogen therapy. The rate of adverse effects was similar in both groups. In conclusion, in patients with PBC-related bone loss, alendronate significantly improves BMD compared with placebo. Although in this study oral alendronate appears to be well tolerated in patients with PBC, larger studies are needed to formally evaluate safety.
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