Complication Of Primary Biliary Cirrhosis Research Articles

Trehalose reduces bone loss in experimental biliary cirrhosis rats via ERK phosphorylation regulation by enhancing autophagosome formation.

Bone loss is a severe complication of primary biliary cirrhosis (PBC). Trehalose was intermittently administered in bile duct-ligated (BDL) male rats, a PBC-related osteoporosis model, for 4weeks to reduce osteoporosis. Femoral bones were assessed ex vivo by micro computed tomography (CT) and histomorphometry. The potential mechanisms related to the reduction of osteoporosis were explored by evaluating the effect of trehalose on osteoblast autophagy, osteogenesis, osteoclastogenesis, and ERK phosphorylation. The results demonstrated that trehalose reduced osteoporosis of BDL rats and decreased osteoblast-mediated osteoclast differentiation by enhancing osteoblast autophagy to regulate osteoprotegerin (OPG) secretion. Hydroxychloroquine (HCQ) increased the expression of OPG and OPG/receptor activator genes for nuclear factor-κB ligand (RANKL) ratio, and reduced osteoblast-mediated osteoclastogenesis by inhibiting autophagy flux and inducing autophagosome formation. Furthermore, trehalose increased the phosphorylation of ERK1/2 in MC3T3-E1 cells, and the ERK inhibitor PD98059 reversed the upregulation of OPG gene and reduction of trehalose-induced osteoclastogeneis. The treatment with HCQ markedly increased the ERK phosphorylation. The correlation between autophagosome formation and ERK phosphorylation was confirmed in autophagy proteins (ATG) 4B or ATG5-deficient cells. Thus, trehalose could decrease osteoblast-mediated osteoclastogenesis and reduce PBC-related bone loss by regulating ERK phosphorylation via autophagosome formation.

Strengthening the bones in primary biliary cirrhosis

Strengthening the bones in primary biliary cirrhosis

PWE-277 Fracture prevalence and vitamin D status in primary biliary cirrhosis: the Leicestershire experience

IntroductionMetabolic bone disease is a recognised complication in Primary Biliary Cirrhosis (PBC) and increases the risk of developing fractures. Although osteoporosis is the major contributor, Vitamin D (25- hydroxy- vitamin-...

P09 Hepatocellular carcinoma in primary biliary cirrhosis: defining risk in an era of ursodeoxycholic acid use

IntroductionHepatocellular carcinoma (HCC) is a rare complication in primary biliary cirrhosis (PBC). Current clinical guidance from the British Society of Gastroenterology advises that only male patients with histologically advanced PBC...

Tubulointerstitial nephritis and renal tubular acidosis of different types are rare but important complications of primary biliary cirrhosis

A very few cases of biopsy-proven tubulointerstitial nephritis (TIN) in patients with primary biliary cirrhosis (PBC) have been reported. Although the clinical importance of this association has been suggested, information on its clinicopathological features and prognosis is limited. We reviewed 5955 renal biopsies processed at our department, and identified four patients with TIN associated with asymptomatic PBC. We evaluated clinicopathological features and outcomes in these patients, and reviewed the previously reported cases of TIN associated with PBC. Our four patients were female. The patients' age at the time of renal biopsy ranged from 36 to 77. Three patients had been treated with ursodeoxycholic acid. All patients had urinary abnormalities such as proteinuria and elevated levels of urinary β(2)-microglobulin, and three patients had renal insufficiency. All patients had distal renal tubular acidosis (RTA), and two patients also had Fanconi syndrome. Renal biopsy showed severe lymphocyte infiltration in the tubules and interstitium with mild-to-moderate tubular atrophy and fibrosis. All patients responded well to steroid therapy. On review of the previously reported five cases, all patients were female. The patients' age ranged from 42 to 68. Apparent symptoms linked to PBC were not described. All patients had renal insufficiency. Three patients suffering from bone pains or bone fractures also had Fanconi syndrome. Marked or transient improvements were observed after steroid therapy in three patients. TIN and RTA of different types are extremely rare but one of the important extrahepatic complications of PBC. Steroid therapy can be beneficial in treating PBC patients with these renal complications.

Variceal bleeding in primary biliary cirrhosis patients: a subgroup with improved prognosis and a model to predict survival after first bleeding

Varices are a late complication in primary biliary cirrhosis (PBC). However, patients without clinical jaundice do bleed from varices; whether their prognosis differs is unknown. Evaluate PBC patients, particularly those with bilirubin <or=34 micromol/l at the time of bleeding. One hundred and two variceal bleeders were present (median, follow-up 20.5 months, range 0-180), who at diagnosis had: pruritus (51%), fatigue (32%) and 23 (22.5%) variceal bleeding. Histologically advanced disease was present in 96 of 100 patients (stage 3: 14 and stage 4: 82); 83 died, 24 within 6 weeks of first bleeding. At the time of bleeding, 26 patients had bilirubin <or=34 micromol/l. In this group, 24 patients were stage 4, in 13 bleeding was the first presentation of PBC and they were older (59.4 vs. 55.4 years, P=0.09), had lower alkaline phosphatase (491.5 vs. 510, P=0.03) but similar albumin values, surviving a median 61 versus 12 months, compared with the 76 patients with bilirubin >34 micromol/l (P=0.001, log rank test). Hazard ratios (95% confidence intervals) for independent predictors of mortality after bleeding were: age 1.02 (1-1.05), log10 bilirubin 4.64 (2.56-8.41), ascites 2.13 (1.29-3.51) and hepatic encephalopathy 2.72 (1.56-4.74). Variceal bleeding complicates histologically advanced PBC. A distinct subgroup with near normal bilirubin and lower alkaline phosphatase first presents with variceal bleeding in 50% of cases and has a better prognosis than jaundiced PBC variceal bleeders.

Pulmonary hypertension in primary biliary cirrhosis: A prospective study in 178 patients

Objective. To analyze the incidence, clinical features, and prognosis of patients with primary biliary cirrhosis (PBC) complicated by pulmonary hypertension (PH). Material and methods. A total of 178 consecutive PBC patients, who were admitted to Peking Union Medical College Hospital from January 2001 to March 2007, were included in this prospective study. A structured interview, systemic rheumatological examination, laboratory tests (including autoantibodies), and Doppler echocardiography were conducted for each patient and compared between patients with and without PH. Results. Twenty-one PBC patients (11.8%) had PH. Among them, four patients (19.0%) had moderate to severe PH, and one patient died of right heart failure instead of liver failure. The incidences of Raynaud's phenomenon, interstitial lung disease, Sjögren's syndrome, and portal hypertension, the proportion of patients with a positive anti-SSA, the level of serum IgA, as well as the Mayo risk score in the PH–PBC patients were significantly higher than in the non-PH-PBC group (p = 0.02, 0.001, 0.02, 0.03, 0.006, 0.04 and 0.02, respectively). Conclusions. PH, including moderate to severe PH, is not a rare complication of PBC. This complication is closely associated with portal hypertension and immunological dysregulation and indicates a poor prognosis.

Portal Hypertension and Primary Biliary Cirrhosis: Effect of Long-Term Ursodeoxycholic Acid Treatment

Portal hypertension can complicate primary biliary cirrhosis, but studies evaluating the direct measurement of the portohepatic gradient (PHG) are rare. The aim of the study was to determine the prevalence and prognostic value of portal hypertension in patients treated with ursodeoxycholic acid. A total of 132 patients from a local "PBC clinic" were enrolled in this cohort study. The PHG and biochemical values were measured at inclusion and every 2 years. Factors associated with survival were analyzed. Mean PHG at inclusion was 7.2 +/- 5.8 mm Hg. It was higher than normal (6 mm Hg) in 46 patients (34.9%) and higher than 12 mm Hg (variceal bleeding risk limit) in 26 patients (19.7%). There was a difference between the 3 subgroups in the probability of survival free of liver transplantation (P < .0003). After 2 years of treatment, a decreased or stable PHG (hazard ratio, 4.64; 95% confidence interval, 2.01-10.72) and normalization of aspartate aminotransferase (AST) level (hazard ratio, 2.89; 95% confidence interval, 1.03-8.05) were predictive of better survival on multivariate analysis. "Responders" (stable or improved PHG and normalized AST level at 2 years) have a 15-year survival similar to that of a control Quebec female population. Significant portal hypertension is a common complication of primary biliary cirrhosis. Changes in the PHG and normalized AST level after 2 years of ursodeoxycholic acid treatment can be used to identify a subgroup of responders with survival comparable to that of a control population.

Health‐related quality of life in Chinese patients with primary biliary cirrhosis

Symptoms and complications of primary biliary cirrhosis (PBC) have been shown to impair patients' health-related quality of life (HRQOL) in the West. We aimed to measure the HRQOL and to determine the factors associated with worse HRQOL among the Chinese PBC patients in Hong Kong. Chinese patients with biopsy-proven PBC were compared with an age- and gender-matched control group of patients suffering from uncomplicated hypertension (HT) and chronic hepatitis B (CHB). Their HRQOL was assessed by a Chinese (Hong Kong) version of the 36-item short-form health survey (SF-36). The psychological aspect of patients was assessed by the Hospital Anxiety and Depression Scale (HADS). Forty-four PBC patients aged 60 +/- 11 years were identified. PBC patients had more profound impairment in their HRQOL, as evidenced by their significantly lower Physical Component Summary (PCS) scores (39 +/- 11 vs 45 +/- 9 and 45 +/- 11, P = 0.009 and 0.01) and slightly lower Mental Component Summary (MCS) score (47 +/- 12 vs 51 +/- 10 and 48 +/- 11, P = 0.051 and 0.80) as compared with the HT and CHB control groups, respectively. High HADS-depression score was independently associated with lower PCS scores. More severe fatigue and higher HADS-anxiety and HADS-depression scores were independently associated with lower MCS scores. Chinese PBC patients have significant impairment of the HRQOL. The anxiety and depression status of patients had important contribution to the HRQOL.

Human Parathyroid Hormone 1–34 Prevents Bone Loss in Experimental Biliary Cirrhosis in Rats

Reduced bone mass and increased fracture rate are complications of primary biliary cirrhosis (PBC). The effect of intermittent administration of human parathyroid hormone (hPTH) 1-34 on bone mass and architecture in bile duct-ligated (BDL) rats was studied. Six-month-old male rats were subjected to BDL or sham operation (SO) and were treated from the second postoperative week intermittently with either hPTH 1-34 40 microg/kg per day, 80 microg/kg per day, or a vehicle for 4 weeks. Femoral and tibial bones were evaluated ex vivo by dual x-ray absorptiometry, microcomputed tomography, and histomorphometry. Serum osteocalcin and urinary deoxypyridinoline cross-links (DPD) were determined. BDL rats had decreased bone mass compared with SO rats as indicated by a 6% decrease in femoral and tibial bone mineral density (BMD), 18% reduction in femoral trabecular bone volume (bone volume/total volume [BV/TV]), 17% decrease in trabecular thickness, and 10% decrease in tibial cortical thickness. The administration of hPTH 1-34 at 40 microg/kg per day increased femoral and tibial BMD (9% and 9%), femoral trabecular BV/TV (50%), trabecular thickness (50%), tibial cortical thickness (17%), and serum osteocalcin (82%). On the other hand, hPTH 1-34 80 microg/kg per day had no effect on BMD and tibial cortical thickness, was associated with a smaller increase in trabecular BV/TV (24%), and had a higher osteoclast number and DPD compared with untreated BDL rats and the lower hPTH 1-34 dose treatment group. BDL rats exhibit loss of bone mass and structure, which can be prevented by the intermittent administration of hPTH 1-34, a potential therapy for osteoporosis in PBC.

Reduced plasma dehydroepiandrosterone sulfate levels are significantly correlated with fatigue severity in patients with primary biliary cirrhosis

Fatigue is a common debilitating complication of primary biliary cirrhosis (PBC), the pathophysiologic mechanism of which is poorly understood. Recently, the neuroactive steroid dehydroepinadrosterone sulfate (DHEAS) was reported to be implicated in Chronic Fatigue Syndrome in the absence of liver disease. The present study was undertaken to analyse fatigue scores and their relationship with disease severity and circulating levels of DHEAS as well as its precursors DHEA and pregnenolone in PBC patients with ( n = 15) or without fatigue ( n = 10) compared to control subjects ( n = 11). Fatigue was assessed using the fatigue impact scale (FIS) including cognitive, physical and psychosocial subclasses. Steroids were measured by radioimmunoassay or gas chromatography/mass spectrometry. Plasma concentrations of DHEAS were significantly reduced in PBC patients with fatigue as compared to controls, while those of its precursors DHEA and pregnenolone remained within the control range. Plasma levels of DHEAS in PBC patients were significantly correlated with fatigue severity as reflected by total FIS scores including total (rp = −0.42; p = 0.018), as well as the cognitive (rp = −0.37; p = 0.03), physical (rp = −0.48; p = 0.006) and psychosocial (rp = −0.35; p = 0.04) subclasses of fatigue scores. No correlation of fatigue scores was observed with indices of liver function. These findings suggest that reduced levels of the neurosteroid DHEAS may contribute to fatigue in patients with PBC; substitutive therapy using DHEAS or its precursor DHEA could be beneficial in the management of fatigue in patients with low levels of DHEAS.

Prevalence and Predictors of Esophageal Varices in Patients With Primary Biliary Cirrhosis

Esophageal varices and bleeding are among the most feared complications of primary biliary cirrhosis (PBC). We aimed to determine the prevalence of esophageal varices in patients with PBC, to evaluate noninvasive markers of esophageal varices in this population, and to validate the results in an independent set of patients. Data were collected on all patients with PBC seen for the first time at the University of Florida (study group) and at Case Western Reserve University hospitals (cross-validation group) during 7 consecutive years. Logistic regression analysis was used to identify independent predictors of esophageal varices. The best cut-off values were calculated based on receiver operating characteristic curves. The diagnostic accuracy of the independent predictors of esophageal varices identified in the study group were retested in the cross-validation group. Of 210 patients with PBC seen at the University of Florida, 113 had an endoscopy and 49.6% (56 of 113) were found to have esophageal varices. After excluding 22 patients with a history of variceal bleeding, data on 91 patients were analyzed. Thirty-four patients had esophageal varices (37%). Multivariate analysis revealed that a platelet count of less than 140,000 (odds ratio, 7.6; 95% confidence interval, 1.6-37) and a Mayo risk score of 4.5 or greater (odds ratio, 10.6; 95% confidence interval, 1.8-62) were independent predictors of esophageal varices. The diagnostic accuracy of these predictors was confirmed in an independent set of patients. Among patients with PBC, a platelet count of less than 140,000 and/or a Mayo risk score of 4.5 or greater appears to identify those patients more likely to benefit from a screening endoscopy.

Tubulointerstitial Nephritis and Fanconi Syndrome in Primary Biliary Cirrhosis

Primary biliary cirrhosis is a chronic cholestatic liver disease of unknown cause that predominantly affects middle-aged women. Distal tubular acidosis is the main renal complication of primary biliary cirrhosis. Tubulointerstitial nephritis and Fanconi syndrome have been reported more rarely. We report on 2 patients with primary biliary cirrhosis who presented with tubulointerstitial nephritis and Fanconi syndrome and review similar cases published previously. Serum from 1 patient exerted an inhibitory effect on pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase, 2 mitochondrial enzymes that are the main targets of antimitochondrial antibodies in primary biliary cirrhosis. Antimitochondrial antibodies may have a role in the genesis of tubulointerstitial nephritis and Fanconi syndrome, 2 typical renal features of mitochondrial cytopathies. Tubulointerstitial nephritis and Fanconi syndrome have to be added to the spectrum of renal diseases associated with primary biliary cirrhosis.

Alendronate improves bone mineral density in primary biliary cirrhosis: A randomized placebo-controlled trial

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.

Earlier recurrence of esophageal varices, following therapy, in patients with primary biliary cirrhosis (PBC) compared with non-PBC patients

Variceal bleeding is a common, life-threatening complication of primary biliary cirrhosis (PBC). Recently, several reports have suggested that the existence of esophageal varices in patients with PBC is a significant factor in the assessment of disease prognosis. However, there have been no reports on the recurrence of esophageal varices following treatment in patients with PBC. In this study, we investigated the recurrence of esophageal varices in PBC patients and attempted to identify predictive factors for the recurrence of esophageal varices. Between April 1993 and August 2003, 138 patients with esophageal varices who had been treated by endoscopic variceal ligation (EVL; 96 men and 42 women; age, 33-83 years; mean, 62.6 +/- 10.1 years), were enrolled in the present study. The diagnosis of esophageal varices was made by upper gastrointestinal endoscopy, and the varices were graded according to the criteria of the Japanese Research Society for Portal Hypertension. The relationship between the recurrence of esophageal varices and factors such as biochemical and hematological parameters, as well as the etiology of the liver disease, was analyzed using the Kaplan-Meier method and the multivariate Weibull regression model. PBC patients had an earlier recurrence of esophageal varices compared to non-PBC patients, and two factors, prothrombin time and etiology (PBC/non-PBC), were indicative of significantly earlier recurrence of esophageal varices. We should be extra careful in the follow-up of patients with PBC after therapy for esophageal varices.

Osteoporosis: still a typical complication of primary biliary cirrhosis?

Osteoporosis is a recognized complication of primary biliary cirrhosis but it has been suggested that its prevalence may overlap that observed among postmenopausal women. To evaluate prevalence and risk factors of osteoporosis in primary biliary cirrhosis. A total of 133 female patients (age 53+/-10 years, menopausal status 70%, histological stage I-II 61%, portal hypertension 28%, Mayo Risk Score 4.11+/-0.59) were enrolled. Dual X-ray absorptiometry of the lumbar spine. Mean bone mineral density, T and Z score were 0.861+/-0.160 g/cm2, -1.87+/-1.45 and -0.78+/-2.63, respectively. At multivariate analysis, bone mineral density was inversely correlated with age (p<0.05). Osteoporosis was present in 39/92 (41%) postmenopausal and 8/41 (20%) premenopausal patients. In the premenopausal group, osteoporosis was significantly correlated with serum albumin (p<0.05) and Mayo Risk score (p<0.005). No significant correlation was present in the postmenopausal group. Despite the accepted wisdom that osteoporosis is a common complication of primary biliary cirrhosis, its frequency in post-menopausal patients overlaps that observed in the general population, but is much more frequent in premenopausal patients, where it appears to be related to severity of liver disease and cholestasis.

Ursodeoxycholic acid enhances fractional calcium absorption in primary biliary cirrhosis.

Bone disease is a frequently reported complication in primary biliary cirrhosis (PBC), but its pathogenesis is poorly understood. Calcium malabsorption has been considered as an important contributing factor. Ursodeoxycholic acid (UDCA) is the treatment of choice in PBC, improving survival, but its effect on calcium absorption is unknown. In this study, we have measured fractional calcium absorption, using a single isotope method, in a group of female PBC patients (median age: 60 years, range: 46-78 years) and age-matched female controls (median age: 58 years, range: 36-74). Bone mineral density (BMD) in PBC patients was significantly lower than age-matched controls (g/cm(2) +/- SEM; lumbar spine: controls 1.139+/-0.028, PBC patients 1.004+/-0.026, p = 0.0028; femoral neck: controls 0.944+/-0.034, PBC patients 0.819+/-0.023, p = 0.0032). Twenty two PBC patients, who were not vitamin D-deficient, were off and on UDCA for approximately 1 month and approximately 8 weeks, respectively. Fractional calcium absorption in PBC patients prior to UDCA treatment (mean +/- SEM, 33.8+/-2.6%) was significantly lower than controls (52.0+/-2.4%, p<0.001). Following UDCA therapy, fractional calcium absorption increased significantly (Off UDCA: 33.1+/-2.6%, On UDCA: 36.6+/-2.5%, p<0.0058). Osteocalcin levels were significantly raised in the PBC group (mean +/- SEM, ng/ml, 41.4+/-2.02) compared to controls (31.1+/-2.64, p = 0.002). There were no differences in parathyroid hormone (PTH) or 25-hydroxyvitamin D levels between these two groups or following UDCA therapy. In conclusion, we found that PBC patients display low spinal and femoral neck BMD, reduced fractional calcium absorption, and elevated plasma osteocalcin. The calcium malabsorption is corrected partially by UDCA therapy. Long-term studies are required to determine whether this effect can be sustained, and whether a sustained increase in fractional calcium absorption can translate into a favorable change in bone strength in patients with PBC.

Osteoporosis is not a specific complication of primary biliary cirrhosis (PBC)

A case-control study of 196 histologically proved cases of renal cell carcinoma and 347 controls matched for age at interview, sex, hospital, and interviewer was conducted in France between 1987 and 1991. A complete occupational history was recorded for each patient and occupations were coded blindly according to the International Standard Classification of Occupations. In women, none of the risks were significant. Among men, after adjustment for the educational level, cigarette smoking, and Quetelet index before diagnosis, significantly increased matched odds ratios (ORs) were found for sales workers (OR = 2.1, 95% confidence interval (95% CI) 1.2-4.0), managers (OR = 3.3, 95% CI 1.2-8.9), and textile workers and tailors (OR = 6.2, 95% CI 1.1-33.7). For this last occupational group, an increase in risk was found with an increased duration of exposure.

Etidronate for osteoporosis in primary biliary cirrhosis: a randomized trial

Background/Aim: Osteoporosis is a common complication of primary biliary cirrhosis but there is no accepted therapy for the osteoporosis. In this randomized controlled trial, we compared the effects of etidronate to placebo on the treatment of osteoporosis associated with primary biliary cirrhosis. Methods: Sixty-seven patients with primary biliary cirrhosis and osteopenia, defined by bone mineral density criteria (T-score <−2.0) were enrolled. Measurements of the lumbar spine and proximal femur, as well as x-rays of the lumbar spine, were obtained. Patients received cyclical etidronate 400 mg/day for 14 days every 3 months for at least 1 year. Supplemental calcium was administered on the days patients did not receive etidronate. Results: Of the 67 patients entered, 60 completed at least 1 year of therapy. There was no significant difference in changes in bone density at either the lumbar spine or femur in patients receiving etidronate when compared to placebo. Fractures occurred in eight patients, four receiving etidronate. Etidronate therapy was associated with a significant reduction in markers of bone turnover compared to placebo. These changes did not correlate with changes in bone density. Conclusions: Cyclical etidronate administered with supplemental calcium did not significantly improve bone density in patients with primary biliary cirrhosis.

Osteoporosis is not a specific complication of primary biliary cirrhosis (PBC)

Osteoporosis is not a specific complication of primary biliary cirrhosis (PBC)