Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fatigue is a common symptom in primary biliary cirrhosis (PBC). In animal models of cholestasis, abnormalities in serotonin neurotransmission are observed with fatigue. The role of selective serotonin reuptake inhibitors in fatigue-related PBC, however, is unknown. A double-blind, placebo-controlled study design was conducted to determine the safety and efficacy of fluoxetine for the treatment of fatigue in PBC. Patients were randomized to fluoxetine, 20 mg daily, or matched placebo for 8 weeks' duration. Fatigue was assessed by the Fisk Fatigue Impact Scale (FFIS). The primary study endpoint was a > or =50% reduction in overall FFIS score at the end of treatment. Health-related quality of life (HRQL) was assessed as a secondary endpoint. Among 220 consecutively screened patients, only 18 (9%) eligible individuals were randomized to fluoxetine (n=10) or placebo (n=8) for 8 weeks. Baseline variables including median FFIS scores (52 vs 42; P=0.21) were similar between treatment arms (P > 0.05). After 8 weeks of therapy, no statistically significant change in median FFIS score was observed in the fluoxetine group. Median FFIS score in the placebo group was reduced (42 to 28), but not statistically significant. No difference in HRQL was observed between treatment arms after 8 weeks. Fourteen (78%) patients completed therapy, while four (22%) individuals withdrew from the trial. Three of the four patients had drug-related adverse events with fluoxetine. In this study, fluoxetine did not improve fatigue in PBC and was associated with adverse events.
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PMID:Fluoxetine for the treatment of fatigue in primary biliary cirrhosis: a randomized, double-blind controlled trial. 1705 55

A 75 year old patient was admitted to hospital due to painless jaundice and fatigue. Patient's history was not remarkable for chronic viral hepatitis, autoimmune hepatitis, hereditary metabolic disorders or a hepatotoxic damage. Laboratory tests revealed significant elevation of the parameters of cholestasis and aminotransferase activity, a significantly elevated titer of both antinuclear (ANA) and antimitochondrial (AMA) antibodies. Abdominal ultrasound and computertomography showed no mechanic cholestasis nor tumorous process but a situs inversus abdominalis of the abdominal parenchymatous organs. Portal and periportal inflammation, consistent with autoimmune hepatitis, was diagnosed histologically after performing laparoscopic liver biopsy. Regarding the significantly elevated cholestatic parameters and the positive AMA-autoantibodies AIH-PBC overlap syndrome was highly probable so medical treatment including both ursodeoxycholic acid and immunosuppressive therapy with corticosteroids and azathioprine was started resulting in a continous downward tendency of liver enzymes and an improvement of the patient's clinical condition. Finding the correct diagnosis and therapy of autoimmune liver disease is not always easy and unproblematic. Regarding its sometimes fatal progression and good response towards medical treatment prompt diagnosis and institution of autoimmune hepatitis--alone or combined as PBC/AIH overlap syndrome--should not be deferred. Laparoscopic liver biopsy should be the method of choice in patients's with situs inversus abdominalis regading the variable anatomy.
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PMID:[Cholestatic hepatitis in situs inversus abdominalis]. 1763 66

The serotonin neurotransmitter system, including the 5-HT(3) receptor, has been implicated in the genesis of fatigue in patients with liver disease. Therefore, we examined the possible role of 5-HT(3) receptors in cholestasis-associated fatigue. Rats were either bile duct resected (BDR) or sham resected and studied 10 days postsurgery. A significant decrease in hypothalamic 5-HT(3) receptor expression was detected by immunohistochemistry and Western blot in BDR vs sham rats, coupled with increased hypothalamic serotonin turnover identified by an elevated 5-hydroxyindoleacetic acid (5-HIAA) to 5-HT ratio in BDR vs sham rats. To examine fatigue-like behaviour, an activity meter was used. BDR rats exhibited significantly lower locomotor activity than did sham animals. Subcutaneous injection of the 5-HT(3) receptor antagonist tropisetron (0.1 mg kg(-1)) resulted in significantly increased locomotor activity in BDR rats compared to the activity in saline-treated controls, but was without effect in sham rats. However, a 10-fold higher dose of tropisetron significantly increased locomotor activity in both BDR and sham rats compared to saline-injected controls. These findings indicate that cholestasis in the rat is associated with increased hypothalamic serotonin turnover, decreased hypothalamic 5-HT(3) receptor expression, and enhanced sensitivity to locomotor activation induced by 5-HT(3) receptor antagonism, thereby implicating the 5-HT(3) receptor system in cholestasis associated fatigue.
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PMID:Downregulated hypothalamic 5-HT3 receptor expression and enhanced 5-HT3 receptor antagonist-mediated improvement in fatigue-like behaviour in cholestatic rats. 1791 12

Biliary stasis can occur in many different diseases. Pruritus, metabolic bone disease, deficiencies of fat-soluble vitamins, steatorrhea, hyperlipidemia and fatigue represent the major extra-hepatic manifestations of cholestatic liver disease that considerably affect the patient's quality of life. The present article reviews pathogenetic and clinical aspects of and current therapeutic approaches to extra-hepatic manifestations of cholestatic liver disease.
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PMID:[Under-evaluated extrahepatic manifestations of cholestasis]. 1929 75

Fatigue is a common debilitating symptom in patients with primary biliary cirrhosis (PBC). The mechanism of fatigue is still poorly understood. However, it has been reported that levels of the steroid dehydroepiandrosterone sulphate (DHEAS) are reduced in plasma of patients with PBC, and substitutive therapy has been suggested to improve fatigue symptoms experienced during the course of this disease. In this study, we tested the effect of DHEAS on whole body fatigue in rats following bile duct ligation (BDL). Fatigue was estimated by the time spent on an electrified grid as a result of falling off a treadmill and by performance of rats on an infrared beam monitor which allows the assessment of travelled distance and stereotypic movement activities. On day 5 after BDL surgery, cholestatic rats exhibited increased whole body fatigue as reflected by significantly increased time spent on the electrified grid, reduced travelled distance and reduced stereotypic movements. Administration of 5 mg kg(-1) of DHEAS to BDL rats for three consecutive days significantly normalized their behaviour. Fatigue scores were also found to be reduced in cirrhotic rats 4 weeks after BDL surgery, and DHEAS treatment for 3 days reduced fatigue scores at this stage. Dehydroepiandrosterone sulphate treatment was sufficient to increase brain levels of DHEAS in the BDL rats in a manner that is significantly and highly correlated with those of plasma DHEAS and brain dehydroepiandrosterone (DHEA). Substitutive therapies with DHEAS or DHEA could represent novel approaches in the management of fatigue due to cholestasis-induced liver failure.
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PMID:Dehydroepiandrosterone sulphate improves cholestasis-associated fatigue in bile duct ligated rats. 1959 90

Primary biliary cirrhosis (PBC) is an immune-mediated chronic cholestatic liver disease with a slowly progressive course. Without treatment, most patients eventually develop fibrosis and cirrhosis of the liver and may need liver transplantation in the late stage of disease. PBC primarily affects women (female preponderance 9-10:1) with a prevalence of up to 1 in 1,000 women over 40 years of age. Common symptoms of the disease are fatigue and pruritus, but most patients are asymptomatic at first presentation. The diagnosis is based on sustained elevation of serum markers of cholestasis, i.e., alkaline phosphatase and gamma-glutamyl transferase, and the presence of serum antimitochondrial antibodies directed against the E2 subunit of the pyruvate dehydrogenase complex. Histologically, PBC is characterized by florid bile duct lesions with damage to biliary epithelial cells, an often dense portal inflammatory infiltrate and progressive loss of small intrahepatic bile ducts. Although the insight into pathogenetic aspects of PBC has grown enormously during the recent decade and numerous genetic, environmental, and infectious factors have been disclosed which may contribute to the development of PBC, the precise pathogenesis remains enigmatic. Ursodeoxycholic acid (UDCA) is currently the only FDA-approved medical treatment for PBC. When administered at adequate doses of 13-15 mg/kg/day, up to two out of three patients with PBC may have a normal life expectancy without additional therapeutic measures. The mode of action of UDCA is still under discussion, but stimulation of impaired hepatocellular and cholangiocellular secretion, detoxification of bile, and antiapoptotic effects may represent key mechanisms. One out of three patients does not adequately respond to UDCA therapy and may need additional medical therapy and/or liver transplantation. This review summarizes current knowledge on the clinical, diagnostic, pathogenetic, and therapeutic aspects of PBC.
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PMID:Primary biliary cirrhosis. 1960 70

Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are the two most common causes of chronic cholestatic liver disease in adults. In PBC, therapy with ursodeoxycholic acid (UDCA) is safe and has been associated with tangible biochemical, histologic, and survival benefits. However, a need for different or adjuvant therapies remains for specific subsets of PBC patients, including those who do not respond to UDCA and those who have advanced histologic disease at presentation. Similarly, beneficial therapies for disease-related symptoms that do not typically respond to UDCA (eg, fatigue and pruritus) are still needed. In contrast to PBC, no medical therapy of proven benefit has been identified for patients with PSC. In PBC and PSC, adequate management of complications of chronic cholestasis is important. For both diseases, liver transplantation is the only curative option.
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PMID:Latest and emerging therapies for primary biliary cirrhosis and primary sclerosing cholangitis. 2042 80

Primary biliary cirrhosis is a chronic liver disease characterised by intrahepatic bile-duct destruction, cholestasis, and, in some cases, cirrhosis. Evidence supporting the autoimmune nature of this disorder includes the appearance of highly specific antimitochondrial antibodies (AMAs) and autoreactive T cells. Concordance rates in monozygotic twins, familial prevalence, and genetic associations underscore the importance of genetic factors, whereas findings of epidemiological studies and murine models suggest a possible role for exogenous chemicals and infectious agents through molecular mimicry. The incidence of primary biliary cirrhosis has increased over recent decades, possibly attributable to augmented testing of liver biochemistry rather than a rise in disease incidence. AMAs remain the hallmark of diagnosis in most cases and allow detection of asymptomatic patients. Symptomatic individuals usually present with either pruritus or fatigue and, more rarely, with either jaundice or complications of cirrhosis. The prognosis of primary biliary cirrhosis has improved because of early diagnosis and use of ursodeoxycholic acid, the only established medical treatment for this disorder. Although not a cure, treatment can slow disease progression and delay the need for liver transplantation. However, some patients do not respond adequately to ursodeoxycholic acid and might need alternative therapeutic approaches.
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PMID:Primary biliary cirrhosis. 2152 26

Primary biliary cirrhosis is a chronic autoimmune inflammatory disease of the liver with a striking female preponderance. It has an insidious onset and typically affects middle-aged women. The disease manifests gradually with symptoms of fatigue, pruritis, and increased alkaline phosphatase levels on laboratory evaluation. The hallmark of the disease is the circulating antimitochondrial antibody. Histology is characterized by inflammation of the bile ducts, destruction of cholangiocytes, and subsequent cholestasis, progressing to biliary cirrhosis. The standard treatment for primary biliary cirrhosis is ursodeoxycholic acid, which improves survival, but the disease can still lead to cirrhosis and liver failure over decades.
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PMID:Primary biliary cirrhosis. 2160 85

Several hepatobiliary abnormalities have been described in association with inflammatory bowel disease (IBD), including primary sclerosing cholangitis (PSC), small duct PSC, chronic hepatitis, cryptogenic cirrhosis, cholangiocarcinoma, and cholelithiasis. PSC is the most common biliary condition in patients with IBD, with an incidence ranging from 2.5% to 7.5%. PSC usually progresses insidiously and eventually leads to cirrhosis independent of inflammatory bowel disease activity. There is a very high incidence of cholangiocarcinoma and an elevated risk for developing colon cancer in patients with PSC. Medical therapy has not proven successful in slowing disease progression or prolonging survival. Treatment of symptoms due to cholestasis, such as pruritis and steatorrhea, is an important aspect of the medical care of patients with PSC. Our preferred treatment of pruritis due to cholestasis is with bile acid binding exchange resins, such as cholestyramine or colestipol. Endoscopic manipulation is recommended for treating complications of recurrent cholangitis or worsening jaundice in the setting of a dominant stricture, but endoscopic approaches have not been conclusively demonstrated to improve survival or decrease the need for liver transplantation. Liver transplantation remains the only effective treatment of advanced PSC, and should be considered in patients with complications of cirrhosis or intractable pruritis or fatigue.
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PMID:Hepatobiliary complications of inflammatory bowel disease. 2177 6


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