The relation between plasma tyrosine concentration and fatigue in primary biliary cirrhosis and primary sclerosing cholangitis

Background  

In primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) fatigue is a major clinical problem. Abnormal amino acid (AA) patterns have been implicated in the development of fatigue in several non-hepatological conditions but for PBC and PSC no data are available. This study aimed to identify abnormalities in AA patterns and to define their relation with fatigue.     

Depression in patients with primary biliary cirrhosis and primary sclerosing cholangitis

BACKGROUND/AIMS: Former studies reported a high prevalence of depression in patients with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). These studies hypothesized that the presence of depression could explain the fatigue experienced by these patients. METHODS: Our aim was to study the prevalence of depression in a Dutch population with PBC and PSC. In addition, to investigating the effects of using an additional diagnostic structured psychiatric interview, after screening with the Beck Depression Inventory (BDI), a self-report severity scale instrument used in former studies. Patients with PBC and PSC (n=92) completed the BDI. Patients with scores of 10 or higher (n=39) were interviewed using a structured psychiatric interview. Patients with scores lower than 10 were at random (30/53, 57%) also interviewed using a structured psychiatric interview. RESULTS: Of the 92 patients that were included 42% had depressive symptoms according to the BDI. However, of these patients only 3.7% had a depressive syndrome according to the DSM-IV criteria as assessed with the structured psychiatric interview. CONCLUSIONS: The prevalence of a depressive disorder in patients with PBC and PSC is not higher than in the general population. Fatigue in patients with PBC and PSC cannot be explained by depression.     

Waitlist mortality and post-transplant survival in patients with cholestatic liver disease – Impact of changes in allocation policy

Background

This study investigated the impact of Model of end-stage liver disease (MELD)-score introduction (MELDi) on waitlist mortality and post-liver transplant (LT) survival in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC).

Fatigue in primary biliary cirrhosis

Background—Fatigue is a frequent and debilitatingsymptom in patients with primary biliary cirrhosis (PBC).
Aims—To study fatigue in relation to sleep,depression, and liver disease severity.
Methods—Patients with PBC completedvalidated self report questionnaires measuring fatigue, sleep quality,depression, and functional capacity. Verbally reported fatigue andobserver rated measure of depression and ursodeoxycholic acid (UDCA)use were recorded. Liver biochemistry and tests to rule out metaboliccauses of fatigue were performed.
Results—Mean age of the 88 patientsenrolled was 57 years; 86% were female and mean duration of diseasewas 6.6 years. Median bilirubin was 13 µmol/l (mean 18.6). Verballyreported fatigue (for more than six months) was present in 60 patients(68%). The self rated Fatigue Severity Score (FSS) correlated wellwith verbally reported fatigue (p=0.0001). The FSS did not correlatewith age, duration of disease, serum bilirubin, Mayo Risk Score, orUDCA use, but correlation was seen with sleep quality. Fatiguedpatients had more sleep problems and higher depression scores thannon-fatigued patients. Self rated depression was present in 28%(17/60) of fatigued compared with 4% (1/28) of non-fatigued patients.
Conclusions—Long term fatigue affected 68% ofthe patients with PBC but it was not related to the severity of theirliver disease. Poor sleep quality and depression were commonlyassociated with fatigue.

Keywords:primary biliary cirrhosis; fatigue; depression; sleep

     

Medical treatment of primary biliary cirrhosis and primary sclerosing cholangitis.

Treatment of primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) with ursodeoxycholic acid (UDCA) has been in common use since 1985. In PBC, treatment with UDCA improves laboratory data, liver histology, enables a longer transplantation-free interval and prolongs disease survival. Because UDCA is unable to cure the disease newer drugs or combination therapies are still needed. Studies with UDCA and immunosuppressants such as prednisone, budesonide and azathioprine have shown that in selected patients combination therapy may be superior to UDCA monotherapy. PSC is treated successfully with UDCA and endoscopic dilatation of the bile duct strictures. Treatment of extrahepatic manifestations of cholestatic liver disease such as pruritus, fatigue, osteoporosis and steatorrhea can be problematic and time-consuming.     

Critical flicker frequency fails to disclose brain dysfunction in patients with primary biliary cirrhosis

Background

Recent studies suggest that stage-independent symptoms of primary biliary cirrhosis (PBC) such as chronic fatigue are a consequence of structural and functional abnormalities of the brain. Critical flicker frequency (CFF) is a psychophysiological modality analysing function of cerebral cortex.

Aim

To analyse the usefulness of CFF in detection of brain dysfunction in patients with PBC.

Methods

Fifty-one (37 non-cirrhotic/14 cirrhotic) patients with PBC were included. Control group consisted of 31 matched healthy individuals. Fatigue and health-related quality of life (HRQoL) were assessed using Fatigue Impact Scale (FIS) and questionnaire PBC-40. CFF was analysed with HEPAtonorm Analyzer^®.

Results

When compared to healthy controls all patients with PBC showed significantly impaired HRQoL in majority of PBC-40 domains and increased fatigue level in physical domain of FIS. No differences in HRQoL and PBC-40 domains were seen, when patients with and without cirrhosis where compared. CFF analysis showed no difference between healthy controls and patients with PBC. CFF did not correlate with PBC-40 and FIS domains.

Conclusion

CFF fails to determine brain dysfunction in non-encephalopatic patients with PBC, suggesting that functional efficiency of their cerebral cortex remains unaffected and other central mechanisms are responsible for chronic fatigue in these patients.     

Autoimmune liver diseases and diabetes: A propensity score matched analysis and a proportional meta-analysis

Background and Aims

Patients with some chronic liver diseases have increased risk of diabetes. Whether this is also the case for patients with autoimmune liver diseases is unknown. The study aimed to calculate risk and worldwide prevalence of diabetes in patients with autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC).

Methods

We performed a case–control study using data from the United Kingdom Biobank (UKB) and compared frequency of type 1 diabetes (T1D) and type 2 diabetes (T2D) in AIH and PBC with age-, sex-, BMI- and ethnicity-matched controls. Next, we performed a systematic review and proportional meta-analysis searching PubMed, Embase, Cochrane Library and Web of Science (inception to 1 May 2022 [AIH]; 20 August 2022 [PBC]; 11 November 2022 [PSC]). The pooled prevalence of diabetes was calculated using an inverse method random effects model.

Results

Three hundred twenty-eight AIH patients and 345 PBC patients were identified in UKB and risk of T1D and T2D significantly increased compared with matched controls. Our systematic search identified 6914 records including the UKB study. Of these, 77 studies were eligible for inclusion comprising 36 467, 39 924 and 4877 individuals with AIH, PBC and PSC, respectively. The pooled prevalence of T1D was 3.8% (2.6%–5.7%), 1.7% (0.9%–3.1%), 3.1% (1.9%–4.8%) and of T2D 14.8% (11.1%–19.5%), 18.1% (14.6%–22.2%), 6.3% (2.8%–13.3%) in patients with AIH, PBC and PSC, respectively.

Conclusions

Patients with autoimmune liver diseases have increased risk of diabetes. Increased awareness of diabetes risk in patients with autoimmune liver diseases is warranted.     

Treatment options for primary biliary cirrhosis and primary sclerosing cholangitis

Opinion statement Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are chronic cholestatic liver diseases that affect 0.5 to 40 per 100,000 and 1 to 6 per 100,000 Americans, respectively. Prompt recognition and management of the clinical manifestations of these diseases is essential for the patients’ well-being and ultimate outcome. Ursodeoxycholic acid (UDCA), 13 to 15 mg/kg per day, is the standard therapy for PBC and should be offered to every patient. It has been shown to slow progression of the disease and prevent the need for liver transplantation, which is the last recourse for patients with end-stage disease. However, there is no effective therapy for PSC yet. Patients are managed symptomatically, with surgical or endoscopic interventions as needed in cases of significant biliary obstruction. Complications of chronic cholestasis are seen in both PBC and PSC, with pruritus and fatigue being the most common complaints. The first choice for the treatment of pruritus is still cholestyramine, starting at 4 g/d. The pathogenesis of fatigue is poorly understood in this population; unrecognized hypothyroidism should be excluded. The use of antidepressants is currently under evaluation, but there is no specific therapy for fatigue as of yet. For prevention of severe osteoporosis, we recommend supplementation with 800 IU vitamin D and 1500 mg calcium/d. In patients with PBC and established osteoporosis, the use of alendronate and vitamin K appears to cause an increase in bone mineral density. Further studies are necessary before either of these drugs is routinely recommended. Finally, fat-soluble vitamin deficiencies are noted with more advanced disease. We recommend that serum levels be checked in high-risk patients, and that vitamins are replaced as appropriate with water-soluble supplements. However, other causes of malabsorption must be ruled out, including pancreatic insufficiency and celiac sprue.     

Biliary tract inflammatory disorders: Primary sclerosing cholangitis and primary biliary cirrhosis

Primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) are chronic progressive cholestatic diseases that frequently lead to biliary cirrhosis. The exact pathogenesis of these diseases remains elusive but is likely immunologically based. Complications range from fatigue and pruritus to end-stage liver disease. The risk of developing hepatocellular carcinoma is low for patients with PBC, whereas cholangiocarcinoma is common in PSC and carries an ominous prognosis. Although ursodeoxycholic acid is effective in slowing the progression of PBC, no effective medical therapy exists for PSC. Liver transplantation is the only option for patients with endstage liver disease and yields excellent long-term survival in both groups.     

Biliary tract inflammatory disorders: Primary sclerosing cholangitis and primary biliary cirrhosis

Primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) are chronic progressive cholestatic diseases that frequently lead to biliary cirrhosis. The exact pathogenesis of these diseases remains elusive but is likely immunologically based. Complications range from fatigue and pruritus to end-stage liver disease. The risk of developing hepatocellular carcinoma is low for patients with PBC, whereas cholangiocarcinoma is common in PSC and carries an ominous prognosis. Although ursodeoxycholic acid is effective in slowing the progression of PBC, no effective medical therapy exists for PSC. Liver transplantation is the only option for patients with end-stage liver disease and yields excellent long-term survival in both groups.     

Analysis of regulatory T cells and IgG4-positive plasma cells among patients of IgG4-related sclerosing cholangitis and autoimmune liver diseases

Objectives

Patients with autoimmune pancreatitis (AIP) characteristically show elevated serum levels of immunoglobulin G4 (IgG4) and abundant infiltration of IgG4-positive plasmacytes in the involved organs. The most common involved organ showing extrapancreatic lesions is the bile duct, which exhibits sclerosing cholangitis (SC). However, the role of IgG4 in the development of IgG4-related SC (IgG4-SC) remains unclear. To clarify the role of IgG4 in IgG4-SC, we have performed an immunohistochemical analysis of the bile duct.

Methods

Laboratory and immunohistochemical findings of liver biopsy specimens obtained from patients with IgG4-SC, primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH), and primary biliary cirrhosis (PBC) were compared. The biopsy specimens were first stained with anti-IgG1, anti-IgG4, and anti-Foxp3 (forkhead box P3) antibodies, and the ratio of IgG4-, IgG1-, and Foxp3-positive cells, respectively, to infiltrated mononuclear cells (IgG4/Mono, IgG1/Mono, Foxp3/Mono) was assessed.

Results

The ratio of IgG4/IgG1-positive plasma cells was significantly higher in specimens obtained from patients with IgG4-SC than in those from patients with PSC, AIH, and PBC. The Foxp3/Mono ratio in patients with PBC was significantly higher than that in patients with IgG4-SC and PSC. In patients with IgG4-SC, the number of Foxp3-positive cells was significantly correlated with the number of IgG4-positive cells; in the other patient groups, there was no correlation.

Conclusions

The IgG4/IgG1 ratio in the liver may be a useful marker for differential diagnosis of IgG4-SC and PSC. In IgG4-SC, abundant infiltration of regulatory T cells (Tregs) may affect the switching of B cells to IgG4-producing plasmacytes, and there is a possibility that the function of Tregs is different in IgG4-SC and other liver diseases (PSC, AIH, and PBC).     

Differential detection of nuclear envelope autoantibodies in primary biliary cirrhosis using routine and alternative methods

Background  

Detection of autoantibodies giving nuclear rim pattern by immunofluorescence (anti-nuclear envelope antibodies - ANEA) in sera from patients with primary biliary cirrhosis (PBC) is a useful tool for the diagnosis and prognosis of the disease. Differences in the prevalence of ANEA in PBC sera so far reported have been attributed to the methodology used for the detection as well as to ethnic/geographical variations. Therefore, we evaluated the prevalence of ANEA in sera of Greek patients with PBC by using methods widely used by clinical laboratories and a combination of techniques and materials.     

Hepatic copper content is normal in early primary biliary cirrhosis and primary sclerosing cholangitis

In previous studies, the majority of patients with the cholestatic liver diseases, primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), had increased hepatic copper (Cu) levels even in early stages of disease. We prospectively measured hepatic copper content by atomic absorption spectrophotometry in 55 patients with PBC, 6 patients with PSC, and 29 patients with other chronic noncholestatic liver diseases. Hepatic Cu content was normal in 22/61 (36%) of patients with PBC or PSC; 18 of the 22 did not have cirrhosis (82%). Hepatic Cu content increased with increasing stage of disease (r=0.61,P<0.001) and was positively correlated with serum total bilirubin (r=0.6,P<0.0001) and alkaline phosphatase (r=0.5,P<0.001). All patients with stage I and II disease had hepatic Cu<150 µg/g dry weight, and all patients with hepatic Cu>150 µg/g dry weight had stage III and IV disease. Hepatic Cu content is normal in early PBC and PSC. Copper accumulation in the liver in these cholestatic liver diseases is secondary to cholestasis rather than a primary phenomenon.Supported by General Research Center grant MOIRR0054 from the National Institutes of Health.     

The role of psychological factors in the fatigue of primary biliary cirrhosis.

Fatigue impairs the quality of life of primary biliary cirrhosis (PBC) patients. In this study, we explored the psychological factors and coping strategies in fatigued PBC patients. Patients participated in a semi-structured interview examining thoughts regarding the impact of fatigue and coping strategies. All completed the disease-specific quality-of-life tool, PBC-40, the Penn State Worry Questionnaire (PSWQ) (degree of habitual worry) and Hospital Anxiety and Depression Scale (HADS) (current anxiety and depression). PBC patients were allocated into high (>38, n=10) and low-fatigue (<38, n=14) groups. No differences were seen between high-fatigue and low-fatigue groups regarding age, marital status, employment status, PBC stage, years with diagnosis and years experiencing fatigue. High-fatigue participants were significantly more anxious (P=0.008), more depressed (P<0.001), and more likely to worry (<0.05). High-fatigue participants had more frequent thoughts about the impact of fatigue (P<0.005) and lower self-efficacy scores (P<0.001). In conclusion, PBC patients can experience profound distress associated with fatigue. PBC patients with high levels of fatigue seem to be more vulnerable to emotional distress, more likely to perceive that their quality of life has been negatively affected and are less confident to engage in everyday activities compared with those with low levels of fatigue.     

Bezafibrate for the treatment of primary sclerosing cholangitis

Background

It is known that bezafibrate decreases serum alkaline phosphatase (ALP) in patients with hyperlipidemia, and the efficacy of this drug for the treatment of primary biliary cirrhosis has been confirmed. However, there has been little evidence of its efficacy for the treatment of primary sclerosing cholangitis (PSC).

Methods

Bezafibrate (400 mg/day) was orally administered to 7 consecutive patients with PSC, and we analyzed their clinical features and the drug efficacy in terms of the effect on hepatobiliary enzymes, including ALP, gamma-glutamyl transpeptidase (γ-GTP), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) after 6 months. The latest hepatobiliary enzyme levels were also evaluated.

Results

In 3 patients (effective group), the levels of all hepatobiliary enzymes had decreased after 6 months. Mean ALP had decreased to approximately 40% of the baseline in this group. The efficacy of bezafibrate was observed for a long period (range, 8–27 months) in these 3 patients. There seemed to be no definite association between the efficacy of bezafibrate and the clinical features in the short term.

Conclusions

This study showed that bezafibrate could lower the levels of hepatobiliary enzymes in about half of a cohort of patients with PSC.     

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. Methods: We compared the prevalence and incidence of thyroid dysfunction (TD) in a series of patients with PBC (n=67) with patients with primary sclerosing cholangitis (PSC) (n=79) and non‐alcoholic fatty liver disease (NAFLD) (n=97) seen in a tertiary referral centre who had previously participated in clinical trials. Results: At initial evaluation, prevalence of TD in PBC was 13% compared with 11% in PSC (P=0.71) and 25% in NAFLD (P=0.08). Incidence of TD was 2.9 patients per 100 person‐years in PBC compared with 2.1 patients per 100 person‐years in PSC (P=0.57) and 1.8 patients per 100 person‐years in non‐alcoholic liver disease (P=0.45). Older age, female gender, biochemical abnormalities and concurrent autoimmune disorders were not predictive of the development of TD. Conclusions: TD was unexpectedly as common in patients with PBC as in patients with PSC and NAFLD, yet significantly more common than expected in the general population. Further investigation of thyroid disease in PSC and NAFLD is warranted.     

High prevalence of lower limb atherosclerosis is linked with the gut–liver axis in patients with primary biliary cholangitis

Background and Aims

Hypercholesterolemia is frequent in people with primary biliary cholangitis (PBC); however, it does not seem to confer an increased risk of cardiovascular disease. We aimed to evaluate the prevalence of peripheral arterial disease in PBC women and its association with the gut–liver axis and systemic inflammation.

Methods

Thirty patients affected by PBC and hypercholesterolemia were enrolled, with equal-sized groups of women with non-alcoholic fatty liver disease (NAFLD) and healthy controls (CTRL). All patients underwent Doppler ultrasound examination of peripheral arteries, assessment of flow-mediated dilation, quantification of circulating cytokines and vasoactive mediators and characterization of the gut microbiota.

Results

PBC patients had a higher prevalence of lower extremity arterial disease (LEAD) defined as atherosclerotic plaques in any of femoral, popliteal and/or tibial arteries compared with both NAFLD and CTRL women (83.3% vs. 53.3% and 50%, respectively; p = .01). Factors associated with LEAD at univariate analysis were VCAM-1 (p = .002), ICAM-1 (p = .003), and TNF-alpha (p = .04) serum levels, but only VCAM-1 (OR 1.1, 95% CI 1.0–1.1; p = .04) and TNF-alpha (OR 1.12, 95% CI 0.99–1.26; p = .04) were confirmed as independent predictors in the multivariate model. Gut microbiota analysis revealed that Acidaminococcus (FDR = 0.0008), Bifidobacterium (FDR = 0.001) and Oscillospira (FDR = 0.03) were differentially expressed among groups. Acidaminococcus, which was increased in PBC, was positively correlated with TNF-alpha serum levels. Down-regulation of metabolic pathways linked to fatty acid and butyrate metabolism, glyoxylate metabolism and branched-chain amino acids degradation was found in the functional gut metagenome of PBC women.

Conclusions

LEAD is common in patients affected by PBC and is associated with inflammatory markers and alterations in the gut–liver axis.     

The Impact of Fragility Fractures on Health-Related Quality of Life in Patients With Primary Sclerosing Cholangitis

Background:

Osteoporosis occurs frequently in patients with chronic cholestatic liver diseases, yet data are scarce regarding the prevalence of osteoporosis and fragility fractures and their impact on Health-Related Quality of Life (HRQoL) in Primary Sclerosing Cholangitis (PSC).

Objectives:

We aimed to assess Bone Mineral Density (BMD), physical activity and incidence of fragility fractures in patients with PSC. We also sought associations between prior fractures and HRQoL.

Patients and Methods:

The study was performed on 33 patients (11 females, 22 males) aged 35.3 ± 13 years. HRQoL was assessed by Short Form (SF)-36, Primary Biliary Cirrhosis (PBC)-40 and PBC-27 questionnaires. BMD was measured by densitometry in the lumbar spine and hip. Physical activity was assessed by questionnaire.

Results:

In 32% of patients, BMD measured in the hip or spine was below 1.0 Standard Deviation. A history of fragility fractures (distal forearm and ribs) was reported in six patients (18%). In SF-36 assessment, patients with fractures had lower scores in the role functioning, general health and vitality domains and Physical Component Summary (PCS) than those without fractures. Prior fractures adjusted for gender and PSC duration were associated with lower PCS and Mental Component Summary (MCS) scores. Symptoms and fatigue (assessed by PBC) and prior fractures were inversely associated with MCS (P = 0.007).

Conclusions:

In middle-aged subjects with PSC, we found a high rate of non-vertebral fractures and a moderately decreased BMD in lumbar spine and hip. Fragility fractures had an impact on physical and mental aspects of HRQoL.     

Fatigue in primary Sjögren's syndrome

OBJECTIVE—To assess fatigue in relation to depression, blood pressure, and plasma catecholamines in patients with primary Sjögren's syndrome (SS), in comparison with healthy controls and patients with rheumatoid arthritis.
METHODS—For the assessment of fatigue the Multidimensional Fatigue Inventory (MFI) was used, a 20 item questionnaire, covering the following dimensions: general fatigue, physical fatigue, mental fatigue, reduced motivation, and reduced activity. Furthermore, the Zung depression scale was used to quantify aspects of depression. Forty nine female primary SS patients, 44 female patients with rheumatoid arthritis (RA), and 32 healthy women filled in both questionnaires. In addition, supine values of blood pressure and plasma catecholamines were measured in the patients with primary SS.
RESULTS—Primary SS patients were more fatigued compared with the healthy controls on all the five dimensions of the MFI. When the analyses were repeated using depression as a covariate, group differences disappeared for the dimensions of reduced motivation and mental fatigue. In the primary SS patients, significant positive correlations between depression and the dimensions of reduced motivation and mental fatigue were found. Comparing patients with primary SS with those with RA, using depression as covariate, no statistically significant differences were found between these groups. No relation between fatigue and blood pressure was found, but a negative correlation was observed between the general fatigue subscale of the MFI and plasma noradrenaline.
CONCLUSION—Patients with primary SS report more fatigue than healthy controls on all the dimensions of the MFI and when controlling for depression significant differences remain on the dimensions of general fatigue, physical fatigue, and reduced activity. The negative correlations between levels of noradrenaline and general fatigue in patients with primary SS may imply the involvement of the autonomic nervous system in chronic fatigue.

Keywords: Sjögren's syndrome; fatigue     

Fatigue in patients with primary sclerosing cholangitis

Background: The occurrence of fatigue in primary sclerosing cholangitis (PSC), its impact on quality of life and the role of concomitant inflammatory bowel disease (IBD) and coexisting irritable bowel syndrome (IBS) is unexplored. Methods: Ninety‐three patients with PSC, associated with IBD in 80% of cases and 77 patients with IBD alone, were enrolled in the study. The patients completed the following questionnaires: the Fatigue Impact Scale (FIS), the Psychological General Well‐Being Index (PGWB), the Gastrointestinal Symptom Rating Scale (GSRS), the Beck Depression Inventory (BDI) and diagnostic criteria for IBS. Questionnaire data were related to liver tests and the latest liver biopsy in the PSC patients. Two sex‐ and age matched controls from the general population (GP) were assigned to each PSC patient and these controls completed the FIS and the BDI. Results: Total fatigue score did not differ significantly between patients with PSC and IBD alone. Median total fatigue score among GP subjects was 39 (13–72), which was higher than in PSC (19 (6–52) (P?=?0.02)) and in IBD patients (19 (5–35) (P?Conclusions: Fatigue in patients with PSC is related to depression but not to the severity of the liver disease. Both the PSC and IBD patients had lower total fatigue scores than subjects from the general population. This argues against fatigue as a specific symptom of PSC and IBD patients.