Carlo Sabbà

Observer variability in echo-Doppler measurements of portal flow in cirrhotic patients and normal volunteers

The intraobserver and interobserver variability in measuring the portal vein flow by the echo-Doppler technique was evaluated in a blind controlled study. A total of 22 cirrhotic patients and 14 normal volunteers were examined by two skilled operators using duplex Doppler within a period of 1-3 mo (6 cirrhotics and 7 normal volunteers by both observers). Area, mean velocity, and flow were measured (4 measurements: A, B on day 1; C, D on day 2). The intraclass correlation coefficient was used to assess both the statistical and clinical significance of intraobserver and interobserver agreement for the measurements of these three parameters. The level of intraobserver agreement for each parameter on normal subjects and cirrhotics was obtained from the two measurements on the same day and from the two measurements at the same time on consecutive days. Overall agreement between the four measurements was also calculated. Levels of interobserver agreement were obtained by calculating separately the intraclass correlation coefficient from each of the four pairs by measurements made on the same subject by the two observers over the same period of 2 days. The coefficient of variation was also used to compare the variability in these measurements. Overall, intraobserver agreement on normal subjects varied from good to excellent for observer 1, and from fair to good for observer 2. On cirrhotic patients, observer 1 was excellent at all times for all parameters. Observer 2 had lower intraclass correlation coefficient values, especially for velocity on consecutive days. For the best of the two observers on the portal flow, the coefficient of variation in cirrhotic patients ranged from 2%-30% with a mean +/- SEM of 12% +/- 4%. No acceptable interobserver agreement was found between the two observers in either of the two samples of subjects. These results support the use of this technique mainly for the determination of rapid and large changes in portal hemodynamics within a short period of time. The technique seems to have low precision in monitoring chronic changes in portal hemodynamics.

Liver involvement in hereditary hemorrhagic telangiectasia: consensus recommendations.

Abstract: Study Purpose: To formulate recommendations about clinical management of liver involvement in hereditary hemorrhagic telangiectasia (HHT), using a formal consensus development process.

Propionyl-l-carnitine in intermittent claudication: Double-blind, placebo-controlled, dose titration, multicenter study

OBJECTIVES The aim of this double-blind, placebo-controlled, dose titration, multicenter trial was to assess the efficacy and safety of propionyl-carnitine in intermittent claudication. BACKGROUND Human and animal studies indicate that propionyl-L-carnitine increases carnitine content and improves energy metabolism in the ischemic skeletal muscle. METHODS After a 2-week preliminary period to assess maximal walking distance, 245 patients were randomly assigned to receive propionyl-L-carnitine (n = 118) or placebo (n = 127). The initial oral dose of 500 mg twice daily was increased at 2-month intervals to 2 g/day and then to 3 g/day in patients showing improvement in treadmill performance < 30% over baseline. Efficacy analysis was conducted for the 214 patients who completed the 24 weeks of treatment by comparing the effect of placebo and propionyl-L-carnitine on day 180. RESULTS Analysis of variance showed a significant improvement of 73 +/- 9% (mean +/- SE) in maximal walking distance with propionyl-L-carnitine (n = 99) compared with 46 +/- 6% for placebo (n = 115, p = 0.03). For distance walked at onset of claudication, propionyl-L-carnitine showed about double the improvement of placebo; however, the difference was not statistically significant. There were no changes in electrocardiographic and routine biochemical and hematologic tests that would indicate an adverse effect of propionyl-L-carnitine. Adverse events requiring drug discontinuation (11 in the propionyl-L-carnitine group, 3 in the placebo group) were unrelated to study medication. The dose titration design of the study also provided information on the dose-response relation. Slightly less than 67% of patients were expected to improve their maximal walking distance by at least 30%, assuming 2 g/day of propionyl-L-carnitine (95% confidence interval 0.51 to 0.70). The response rate during the entire titration course was significantly in favor of propionyl-L-carnitine compared with placebo. CONCLUSIONS Although the precise mode of therapeutic action requires clarification, propionyl-L-carnitine, at a dose of 1 to 2 g/day, appears to be effective and well tolerated, with minimal adverse effects.

Liver Transplantation for Hereditary Hemorrhagic Telangiectasia: Report of the European Liver Transplant Registry

Background:Hereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber disease is a rare disease characterized by the presence of arteriovenous malformations. Hepatic involvement can lead to life-threatening conditions. Material and Methods:Forty patients, reported to the European Liver Transplant Registry, were analyzed to define the role of liver transplantation in the treatment of the hepatic disease form. Indications for transplantation were classified according to Garcia-Tsao: cardiac failure (14 patients), biliary necrosis causing hepatic failure (12 patients), severe portal hypertension (5 patients), cardiac failure and biliary necrosis (6 patients), cardiac failure and portal hypertension (2 patients), and cardiac failure associated with biliary necrosis and portal hypertension (1 patient). Eighteen (81%) of 22 patients had pulmonary artery hypertension. Twelve (30%) patients had pretransplant hepatic interventions. Follow-up was complete for all patients with a mean of 69 months (range, 0–230 months). Results:One-, 5- and 10-year actuarial patient and graft survival rates are 82.5%. Six of the 7 pretransplant procedures performed on the hepatic artery were severely complicated. Cardiovascular function documented in 24 patients improved in 18 patients and remained stable in 5 patients; 1 patient died perioperatively of acute heart failure. Twenty-four (60%) patients had post-transplant complications, all but one occurring within the first 4 posttransplant months. Seven (17.5%) patients died perioperatively, 6 of them due to bleeding and 1 due to cardiac failure; 1 (2.5%) patient died late due to chronic rejection. There were 2 possible recurrences. Quality of life markedly improved in all 32 surviving patients. Conclusion:The results of the largest reported transplant series in the treatment of hepatic-based HHT are excellent. Elimination of hepatobiliary sepsis and reversal of cardiopulmonary changes dramatically improve quality of life of the recipients. LT should be proposed earlier in the course of symptomatic hepatic HHT presenting with life-threatening conditions. Palliative interventions, especially on the hepatic artery, should be avoided in view of their high (infectious) complication rate.

Hereditary hemorrhagic telangiectasia: clinical features in ENG and ALK1 mutation carriers

Summary.  Background: Hereditary hemorrhagic telangiectasia (HHT) is a genetic disorder characterized by epistaxis, mucocutaneous telangiectases and visceral arteriovenous malformations (AVMs), particularly in the brain (CAVMs), lungs (PAVMs), liver (HAVMs) and gastrointestinal tract (GI). The identification of a mutated ENG (HHT1) or ALK‐1 (HHT2) gene now enables a genotype–phenotype correlation. Objective: To determine the incidence of visceral localizations and evaluate phenotypic differences between ENG and ALK1 mutation carriers. Methods: A total of 135 consecutive adult patients were subjected to mutational screening in ENG and ALK1 genes and instrumental tests to detect AVMs, such as chest–abdomen multislice computed tomography (MDCT), brain magnetic resonance imaging and magnetic resonance angiography (MRI/MRA), upper endoscopy, were offered to all patients, independent of presence of clinical symptoms. The 122 patients with identified mutations were enrolled in the study and genotype–phenotype correlations were established. Results: PAVMs and CAVMs were significantly more frequent in HHT1 (75% vs. 44%, P < 0.0005; 20% vs. 0%, P < 0.002, respectively) and HAVMs in HHT2 (60% vs. 84%, P < 0.01). No age difference was found for PAVMs whereas HAVMs were significantly higher in older patients in both HHT1 and HHT2. Neurological manifestations secondary to CAVMs/PAVMs were found only in HHT1 patients, whereas severe liver involvement was detected only in HHT2. Respiratory symptoms were mainly detected in HHT1. Conclusions: Our study evidences a higher visceral involvement in HHT1 and HHT2 compared with previous reports. HHT1 is more frequently associated with congenital AVM malformations, such as CAVMs and PAVMs whereas HHT2 predominantly involves the liver. The ENG gene should be first targeted for mutational screening in the presence of large PAVM in patients < 45 years.

Interobserver and interequipment variability of hepatic, splenic, and renal arterial Doppler resistance indices in normal subjects and patients with cirrhosis

BACKGROUND/AIMS Doppler arterial resistance indices are used to evaluate alterations in arterial hemodynamics in the liver, spleen, and kidney. The purpose of this study was to determine the interobserver and interequipment variability of hepatic, splenic, and renal arterial Doppler resistance indices, and the influence of a cooperative training program of the operators on the reproducibility of the results. METHODS In the first part of the study, hepatic (PI-L, RI-L), splenic (PI-S, RI-S), and renal (PI-K, RI-K) pulsatility and resistive indices were measured by echo-color-Doppler in eight control subjects and ten patients with cirrhosis by three operators using three different machines. In the second part of the study, measurements were taken by the three operators in nine controls and nine patients with cirrhosis, after cooperative training, with a single machine. RESULTS Significant interobserver variability was present for all parameters except RI-L. Significant interequipment variability was present for all parameters except PI-S and RI-S. Only 0-3% of variance was equipment- or operator-related, while 58-72% was patient-related. Hepatic and renal coefficients of variation were similar in patients with cirrhosis and controls, while splenic coefficients of variation were higher in patients with cirrhosis than in controls. After training, differences among operators disappeared for all variables except RI-K, and the operator-related component of variance nearly disappeared for all parameters. CONCLUSIONS Hepatic, splenic, and renal arterial resistance indices show small but significant interobserver and interequipment variability. Interobserver variability can be decreased to non-significant levels by a common training program. Thus, these indices can be widely applied to the study of arterial circulation in these organs.

Quality of life in patients with intermittent claudication: relationship with laboratory exercise performance.

In patients with peripheral arterial disease, limitation of exercise capacity will reduce the level of everyday physical activity and affect the quality of life. This study was designed (1) to examine the health-related quality of life of patients with intermittent claudication, and (2) to verify whether treadmill performance is related to the patients perceived ability to function in the community. In 251 patients with intermittent claudication and 89 matched normal subjects, quality of life was assessed by a general health index questionnaire, the McMaster Health Index Questionnaire (MHIQ), which covers three dimensions of life (physical, social and emotional function). The maximal walking capacity of intermittent claudication patients was measured by the treadmill test. When controls were compared to intermittent claudication patients using the MHIQ, it was found that intermittent claudication patients showed a significant (p<0.01) impairment of ‘general health’ and lower scores for physical (0.90±0.17 vs 0.65±0.17; p<0.01), social (0.71±0.11 vs 0.63±0.12; p<0.01) and emotional (0.75±0.17 vs 0.65±0.15; p<0.01) function. Age, gender and work status had a significant impact upon health scores in several areas. Treadmill performance did not correlate with social or emotional function, whereas there was a small but significant relationship between maximal walking capacity and physical function scores (r=0.197; p<0.01). This study suggests that impairment in quality of life experience by patients with intermittent claudication poorly correlates with the reduced exercised capacity assessed by the treadmill test. Therefore, the evaluation of medical and surgical treatment of intermittent claudication should include the administration of a questionnaire for quality of life assessment.

Oxidation of circulating proteins in alcoholics: role of acetaldehyde and xanthine oxidase

BACKGROUND/AIMS This study aimed to evaluate the protein and lipid redox status in plasma erythrocytes and erythrocyte ghosts of alcoholics and of patients with non-alcoholic liver disease; we also investigated the relation to glutathione levels and the role of acetaldehyde and xanthine oxidase activity in plasma. METHODS Carbonyl and sulfhydryl proteins, glutathione and malondialdehyde levels and the activity of the circulating xanthine oxidase were determined in: active and abstinent alcoholics, patients with chronic viral hepatitis and healthy controls. RESULTS Active alcoholics showed a decrease of sulfhydryl protein and glutathione concentrations in plasma, erythrocytes and ghosts compared to the other groups. Also, an increase of the carbonyl protein and malondialdehyde levels and of the activity of circulating xanthine oxidase (9.2 +/- 1.8 nmol.min.ml, p < 0.001) were observed. Significant correlations between carbonyl protein and malondialdehyde concentrations in plasma (r = 0.775, p < 0.001), as well as between daily alcohol intake and carbonyl protein content in plasma (r = 0.879, p < 0.001) and erythrocytes (r = 0.605, p < 0.01) were observed. However, carbonyl protein levels did not correlate with the degree of liver injury. Incubation of plasma with acetaldehyde, but not with ethanol, significantly increased the carbonyl protein formation. Administration of N-Ethylmaleimide, a thiol depletor, or glutathione significantly increased or delayed, respectively, the carbonyl protein formation. CONCLUSIONS Proteins are oxidatively modified in plasma and erythrocytes of active alcoholics, whereas no such alterations are detectable in patients with non-alcoholic liver disease. Protein oxidation in alcoholics does not seem to result directly from ethanol; circulating xanthine oxidase, delivered from injured cells, may play a contributory role and glutathione appears to be directly involved in the protection of plasma proteins against acetaldehyde toxicity.

Therapeutic potential of the endocrine fibroblast growth factors FGF19, FGF21 and FGF23

The endocrine fibroblast growth factors (FGFs), FGF19, FGF21 and FGF23, are critical for maintaining whole-body homeostasis, with roles in bile acid, glucose and lipid metabolism, modulation of vitamin D and phosphate homeostasis and metabolic adaptation during fasting. Given these functions, the endocrine FGFs have therapeutic potential in a wide array of chronic human diseases, including obesity, type 2 diabetes, cancer, and kidney and cardiovascular disease. However, the safety and feasibility of chronic endocrine FGF administration has been challenged, and FGF analogues and mimetics are now being investigated. Here, we discuss current knowledge of the complex biology of the endocrine FGFs and assess how this may be harnessed therapeutically.

Hepatic involvement in hereditary hemorrhagic telangiectasia

Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber disease, is an autosomal-dominant vascular disease characterized by mucocutaneous or visceral angiodysplastic lesions (telangiectases and arteriovenous malformations) that may be widely distributed throughout the cardiovascular system. The recognition of mucocutaneous telangiectases, the occurrence of spontaneous and recurrent episodes of epistaxis, the presence of visceral involvement, and a family history of this disease are the clinical criteria that allow diagnosis. In comparison with skin, lungs, gastrointestinal tract, and brain involvement, hepatic involvement defined by clinical criteria alone has long been considered uncommon. Our experience with a large group of HHT patients, even those asymptomatic for liver involvement, demonstrates that it is more frequent than reported and is characterized by the presence of intrahepatic shunts, disseminated intraparenchymal telangiectases, and other vascular lesions. Congestive cardiac failure, portal hypertension, portosystemic encephalopathy, cholangitis, and atypical cirrhosis have been reported as possible serious complications related to this condition. Thus, a correct diagnosis is important, and diagnostic imaging has a fundamental role in detecting alterations involving the liver. The possibilities to perform a multiphasic study and to provide high-quality multiplanar and angiographic reconstructions, gives multidetector row helical computed tomography the ability to detect and characterize the complex anatomopathologic alterations typical of this disease.