Axel Josefsson

Factors related to fatigue in patients with cirrhosis before and after liver transplantation.

BACKGROUND & AIMS We performed a prospective study to evaluate fatigue and identify potential determinants among patients with cirrhosis. We also studied the effects of liver transplantation on fatigue in these patients. METHODS A total of 108 patients with cirrhosis being evaluated before liver transplantation completed the fatigue impact scale (FIS), the hospital anxiety and depression (HAD) scale, and the short-form 36 (SF-36). Results were compared with controls from the general population. Fasting serum levels of insulin and glucose were measured in all patients. Levels of serum thyrotropin, free T(3) and T(4), cortisol, free testosterone, dehydroepiandrosterone sulfate, estradiol, interleukin-6, and tumor necrosis factor-α were measured in a subgroup of 80 patients. Transplant recipients were followed for 1 year. RESULTS Compared with controls, patients with cirrhosis had more pronounced fatigue, on the basis of higher FIS domain and total scores (P < .05), which were related to all SF-36 domains (r = -0.44 to -0.77, P < .001). All FIS scores improved significantly after liver transplantation, although physical fatigue levels remained higher than in controls (P < .05). In multivariate analysis, pretransplant FIS scores were only related to depression, anxiety, cirrhosis severity, and low serum levels of cortisol (P < .05 for all). Impaired renal function and anemia were independent predictors of physical fatigue (P < .05). CONCLUSIONS Fatigue is common among patients with cirrhosis and associated with impaired quality of life. Psychological distress, severity of cirrhosis, and low levels of cortisol determine general fatigue, whereas anemia and impaired renal function also contribute to physical fatigue. Physical fatigue remains of concern for patients who have received liver transplants for cirrhosis.

Increased Risk for Malignant Neoplasms Among Patients With Cirrhosis

BACKGROUND & AIMS It is not clear how cirrhosis affects the risks for hepatocellular carcinoma (HCC) and non-HCC cancers, which are rare among these patients. We assessed the risk for malignant neoplasms in patients with cirrhosis. METHODS Patients diagnosed with cirrhosis in Gothenburg, Sweden, from 1994 to 2005 were identified and linked to the National Cancer and Death registers. We studied data from 1019 patients with cirrhosis: 68% men, 48% with alcoholic liver disease (ALD), 10% with hepatitis C virus (HCV), and 12% with HCV + ALD. Standardized incidence ratios for malignant neoplasms were calculated (corrected for sex, age, and calendar year according to data from the general Swedish population). The follow-up period was 3290 person-years. RESULTS Overall, 114 (11%) patients developed HCC; HCC occurred more frequently among patients with HCV than other diseases (P < .05). HCC risk did not differ among patients with HCV, with or without ALD (P > .05). Compared with the general population, cirrhotic patients had increased risk for HCC (26-fold); cholangiocarcinoma (13-fold); and esophageal (8-fold), pancreatic (5-fold), and colorectal and lung cancers (each 4-fold). The risk for cholangiocarcinoma increased mainly among patients with non-ALD cirrhosis, whereas the risk for extrahepatic malignancies increased mainly among patients with ALD and cirrhosis. CONCLUSIONS The overall risk for non-HCC malignancies is more than 2-fold greater for patients with cirrhosis (mostly in biliary and gastrointestinal malignancies) than of the general population. The risk for non-HCC cancers differs between patients with ALD and non-ALD cirrhosis. The increased risk for HCC among patients with cirrhosis is associated with HCV; it is the same among patients with HCV, with or without ALD.

Impact of peri-transplant heart failure & left-ventricular diastolic dysfunction on outcomes following liver transplantation

Assess the prevalence of peri‐transplant heart failure and its potential relation to post‐transplant morbidity and mortality.

Hepatic encephalopathy is related to anemia and fat-free mass depletion in liver transplant candidates with cirrhosis

Abstract Background. Although muscle wasting may lead to decreased ammonia detoxification in cirrhosis, the potential role of lean mass depletion in hepatic encephalopathy (HE) has not been explored. Anemia, hormonal abnormalities, and psychological distress may contribute to cognitive dysfunction, but data on their potential relation to HE are limited. Methods. Data on 108 cirrhotic liver transplant candidates enrolled in a prospective study on fatigue were retrospectively analyzed. HE was assessed clinically and with the number connection tests (NCT) A and B. Psychosocial distress was assessed with a validated questionnaire. Fasting serum glucose, insulin, ammonia, and the glomerular filtration rate (GFR) were measured. Fat and fat-free mass was evaluated with dual-energy X-ray absorptiometry. Serum cortisol, testosterone, dehydroepiandrosterone, thyroid function tests, interleukin-6, and tumor necrosis factor-α (TNF-α) were measured in a subgroup of 80 patients. Results. A total of 28% of patients had (overt or minimal) HE. Anemia was present in 59%, diabetes in 29%, renal impairment in 16%, and fat-free mass depletion in 14%. In multivariate analysis, fat-free mass depletion was an independent predictor of HE and NCT-A; renal impairment of NCT-A and -B; and anemia of NCT-B (p < 0.05 for all). HE was also independently related to international normalized ratio and TNF-α (p < 0.05 for both), but not to other hormonal abnormalities or psychological distress. Plasma ammonia was independently associated to anemia (beta = 15.24, p = 0.049), fasting insulin (beta = 0.26, p < 0.05), and GFR (beta = -0.43, p = 0.003). Conclusions. Anemia and fat-free mass depletion are predictors of HE in cirrhotic liver transplant candidates along with liver failure, renal impairment, and systemic inflammation.

Pre-Transplant Renal Impairment Predicts Posttransplant Cardiac Events in Patients With Liver Cirrhosis.

Background Cardiovascular disease and renal impairment are common in cirrhotic transplant candidates. We aimed to investigate potential association between pretransplant renal function impairment and cardiac events after liver transplantation. Methods Adult cirrhotic patients undergoing first-time liver transplantation between 1999 and 2007 in a single institution with available glomerular filtration rate (GFR), assessed by 51Cr-EDTA clearance at pre-transplant evaluation, were retrospectively enrolled (n=202). Impaired renal function was defined as GFR less than 60 mL/min/1.73 sqm. Pretransplant QT-time corrected by heart rate (QTc) and left-ventricular dysfunction was also registered. Mortality and cardiac events were analyzed, until death or last follow-up (end 2009). Results Renal impairment was present in 24% (48/202). Cardiac events occurred in 28% (56/202) after transplantation, mean follow-up time of 3.8 years (2.2). Events were more common in patients with renal impairment compared with those without (48% versus 21%, P<0.001). In Cox regression analysis, pretransplant renal impairment was found to be an independent predictor of posttransplant cardiac events (HR 2.19, 95% CI 1.25–3.85) and reduced cardiac event-free survival (HR 2.27, 95% CI 1.31–3.94). Prolonged QTc interval was an independent predictor of posttransplant cardiac events in the subgroup with pretransplant electrocardiogram and echocardiogram (n=166 and n=112, HR 4.75, 95% CI 2.07–10.9); however, left-ventricular diastolic dysfunction was not (P>0.05). A pretransplant score comprising renal impairment, prolonged QTc interval, and age older than 52 was developed for prediction of 3- and 12-month cardiac events (c-statistic 0.73 and 0.75, respectively). Conclusions Pretransplant renal impairment is a predictor of cardiac event after liver transplantation together with prolonged QTc interval.

Gastrointestinal symptoms in patients with cirrhosis: a longitudinal study before and after liver transplantation.

Abstract Objective. Gastrointestinal (GI) symptoms are common in cirrhosis and have an impact on quality of life. Their pathophysiology and their relation to energy intake have not been fully elucidated and the effect of liver transplantation on GI symptoms has not been studied. We aimed to prospectively evaluate GI symptoms and their determinants before and after transplantation and their potential relation with energy intake in cirrhosis. Methods. A total of 108 cirrhotic liver transplant candidates completed the Gastrointestinal Symptom Rating Scale (GSRS) and the hospital anxiety and depression scale. Fasting serum glucose and insulin were measured in all patients. Serum thyrotropin, free T3/T4, cortisol, free testosterone, estradiol, dehydroepiandrosterone sulfate, interleukin-6 and tumor necrosis factor-α were measured in a subgroup of 80 patients. Transplant recipients were followed for 1 year. A separate cohort of 40 cirrhotic patients underwent a high-caloric satiation drinking test (SDT). Results. GI symptoms were more severe in cirrhotics compared to controls from the general population. In regression analysis, the total GSRS score was independently related to lactulose, anxiety and low free testosterone (p < 0.05 for all). Four out of six GSRS domain scores improved significantly 1 year post-transplant (p < 0.05) but the total GSRS score remained higher compared to controls. GI symptoms predicted ingestion of fewer calories at SDT compared to other patients and controls (p < 0.05). Conclusions. Psychological distress, lactulose treatment and low testosterone are predictors of GI symptoms which are common among cirrhotic transplant candidates. They are also associated with decreased energy intake as measured by a SDT. GI symptoms remain of concern post-transplant.

Adenocarcinoma of the ampulla of Vater: does the histopathologic type matter?

Kimura et al. [1] were the first to demonstrate that there are two histpathologic types of adenocarcinoma of the ampulla of Vater, intestinal and pancreatobiliary, which has been confirmed by other authors in recent years [2–4]. There is evidence to suggest that these two types of ampullary cancer have different biological behaviors, as several investigators have shown that patients with intestinal-type ampullary cancer have better prognosis than those with pancreaticobiliary type [2,5]. However, the standard treatment for ampullary carcinoma has not been established and it is not known whether patients with different histological types of ampullary cancer should be treated differently. We report the case of a 63-year-old man who presented with obstructive jaundice due to an ampullary mass lesion. Abdominal computed tomography (CT) showed dilated biliary tree and several liver lesions with features compatible with liver metastases but did not demonstrate any cause of biliary obstruction. An endoscopic retrograde cholangiopancreatography (ERCP) was undertaken. An ampullary mass was detected and biopsied, and the biliary tree was successfully decompressed by means of a biliary stent. Histopathologic examination of endoscopic biopsies revealed a moderately differentiated adenocarcinoma which on immunohistochemistry was cytokeratin (CK)-20-positive, carcinoembryonic antigen (CEA)-positive, caudal homeobox gene transcription factor-2 (CDX-2)-positive and CK-7positive/negative, that is, it showed features consistent with an intestinal-type tumor (Figure 1A–D) [3,4]. The patient was not considered to be a candidate for surgery due to metastatic disease and was offered palliative chemotherapy. Treatment with FLOX (5-flourouracil (5-FU) 500 mg/m i.v., folinic acid 100 mg/m i.v., oxaliplatin 85 mg/m day 1 and 5-FU 500 mg/m i.v., folinic acid 100 mg/m i.v. day 2, new cycle on day 15), which is a standard chemotherapy regimen for colon cancer, was commenced, leading to partial regression of liver metastases. After a total of eight cycles of FLOX, the treatment was discontinued because of peripheral neuropathy. Chemotherapy was continued in the form of 5-FU 500 mg/m i.v., folinic acid 100 mg/m i.v. on days 1 and 2, repeated every 2 weeks for 6 months but because of the appearance of new liver metastases, the treatment was shifted to gemcitabine (1000 mg/m i.v. on days 1, 8, 15, new cycle every 28 days) which is a standard chemotherapy regimen for pancreatic cancer. After three cycles, gemcitabine chemotherapy was interrupted as progression of liver metastases was noted on a CT scan. In view of the fact that the patient had an intestinaltype adenocarcinoma of the ampulla of Vater and

Validation of the Swedish version of the chronic liver disease questionnaire

Health-related quality of life (HRQL) is frequently impaired in chronic liver disease and thus its assessment is considered to be an important outcome measure in hepatology research [1–3]. Although generic HRQL instruments are commonly used, disease-specific HRQL instruments address specific aspects of a certain disease [1-3]. The chronic liver disease questionnaire (CLDQ) has been developed as a self-administered disease-specific HRQL instrument for patients with chronic liver disease of different etiology and severity [1]. It comprises 29 items graded on a seven-point Likert scale ranging from 1 (all of the time) to 7 (none of the time) and its results are presented as six domain scores (abdominal symptoms, fatigue, systemic symptoms, activity, emotional functioning, worry) and as a total CLDQ score [1]. There is an English (1), German (2), and Spanish (3) version of the CLDQ. However, there is no liverspecific HRQL instrument in Swedish. Thus, we aimed to test a Swedish version of the CLDQ for validity and reliability. A total of 80 clinically stable adult patients with chronic liver disease were enrolled (mean age 55 years, standard deviation (SD) 12 years; 55% female; 44% with cholestatic liver disease, 16% with alcoholic liver disease, 10% with hepatitis C; 72% with no cirrhosis, 13% with Child–Pugh class A, 15% Child–Pugh class B or C). Non-Swedish speakers, transplant recipients, and patients with encephalopathy grade >2 or other cognitive difficulties were excluded. A forward–backward translation of the original American English version of the CLDQ [1] was performed. During an outpatient clinic visit, patients were asked to complete theCLDQaswell as the short-form36 (SF-36) [4], the hospital anxiety and depression (HAD) scale [5], the gastrointestinal symptom rating scale (GSRS) [6], and the fatigue impact scale (FIS) [7]. Internal consistencywas assessedbymeans of theCronbach’sa coefficient and convergent validity by means of the Spearman’s coefficient between CLDQ scores and relevantSF-36,HAD,GSRS,andFISdomains scores. Discriminant validity was assessed by comparing the scores of patients with versus without cirrhosis. A subgroup of 60 patients were asked to complete the CLDQ again two weeks later for retest reliability assessment bymeans of the intraclass correlation coefficient [8]. All tests were two-tailed and conducted at a 5% significance level. In case ofmultiple comparisons, the significance level was set at 1‰. The Swedish version of CLDQ showed good convergent validity, as demonstrated by the correlations between its domains and the validation instruments used, and moderate-to-high internal consistency and reproducibility (Table I). As far as discriminant validity

Oesophageal symptoms are common and associated with other functional gastrointestinal disorders (FGIDs) in an English-speaking Western population

Background The prevalence and frequency of oesophageal symptoms suggestive of a functional oesophageal disorder according to the Rome IV criteria are unknown. Objective We aimed to describe the prevalence and risk factors for oesophageal symptoms compatible with functional oesophageal disorders in the general population. Methods Data were analysed from a population-based online survey of 6300 individuals aged ≥ 18 years in the USA, UK and Canada with equal demographic proportions across countries. Questions included the Rome IV diagnostic questionnaire, demographics, medication, somatization, quality of life, and organic gastrointestinal (GI) disease. Multivariate analysis was used to identify factors independently related to oesophageal symptoms. Results Data from 5177 participants (47.8% female; mean age 46.7 years) were available for analysis. Symptom prevalence was 8.1% for globus, 6.5% for heartburn, 4.5% for dysphagia and 5.2% for chest pain, and 17.0% reported at least one oesophageal symptom. Oesophageal symptoms were independently associated with younger age, female gender, previous abdominal surgery and the presence of other functional GI disorders. Reporting oesophageal symptoms was associated with reduced quality of life. Conclusion Oesophageal symptoms are common in the general population and important predictors include other functional GI disorders, age and gender. Oesophageal symptoms are associated with poorer quality of life.

Impact of cardiac dysfunction on health-related quality of life in cirrhotic liver transplant candidates.

Objective Cardiac dysfunction, in particular left ventricular diastolic dysfunction, is common in cirrhosis. We aimed to investigate the impact of cardiac dysfunction on health-related quality of life (QoL) in liver cirrhosis. Materials and methods A total of 88 cirrhotic liver transplant candidates with an available echocardiogram and ECG completed the Short form-36 (SF-36) and Fatigue Impact Scale. In a subgroup of 61 patients, levels of cardiac biomarkers, in particular serum N-terminal pro-brain natriuretic peptide, adiponectin, and high-sensitive troponin T, were also measured. Results Although left ventricular systolic diameter was related to a lower SF-36 physical component summary, neither left ventricular diastolic dysfunction nor any other echocardiographic feature was found to be associated with any other SF-36 or Fatigue Impact Scale domain (P>0.05 for all). On linear regression analysis after adjustment for confounders, a prolonged QTc interval was found to be related to a lower SF-36 mental component summary score (&bgr;=−9.7, P=0.009) and increased physical fatigue (&bgr;=10.5, P=0.004). Neither serum N-terminal pro-brain natriuretic peptide, high-sensitivity troponin T, nor adiponectin levels were found to be related to QoL (P>0.05 for all). Serum adiponectin levels did not differ among patients with versus those without echocardiographic cardiac alterations (P>0.05 for all). Conclusion A prolonged QTc interval, but not any echocardiographic abnormalities or cardiac biomarkers, seems to be predictive of QoL in cirrhosis.