[Budd-Chiari syndrome and splanchnic vein thrombosis: masked myeloproliferative neoplasms and JAK2V617F]. / Sindrome di Budd-Chiari e trombosi delle vene splancniche: neoplasie mieloproliferative mascherate e mutazione di JAK2V617F.

The Budd-Chiari Syndrome (BCS) and the splanchnic vein thrombosis are characterized by hepatic venous outflow obstruction, generally due to venous thrombosis. These rare diseases are usually caused by multiple concurrent factors, including acquired and inherited thrombophilias. Since the diagnosis of myeloproliferative neoplasms (MPNs) is often difficult in patients with BCS and splanchnic vein thrombosis because of spleen enlargement, secondary pancytopenia and bleeding disorders, recent observations have included in the diagnostic work-up the analysis of the JAK2 mutation. The revision of several recent reports clarify the importance of the JAK2V617F detection in the diagnostic work-up of the BCS and splanchnic vein thrombosis, allowing the demonstration of masked MPNs among these cases that may benefit, in the near future, of target molecular therapies directed toward the JAK2 mutation.

The treatment of hepatic encephalopathy.

Current recommendations for the treatment of hepatic encephalopathy are based, to a large extent, on open or uncontrolled trials, undertaken in very small numbers of patients. In consequence, there is ongoing discussion as to whether the classical approach to the treatment of this condition, which aims at reducing ammonia production and absorption using either non-absorbable disaccharides and/or antibiotics, should be revisited, modified or even abandoned. Pros and cons of present therapeutic strategies and possible future developments were discussed at the fourth International Hannover Conference on Hepatic Encephalopathy held in Dresden in June 2006. The content of this discussion is summarized.

ESPEN Guidelines on Enteral Nutrition: Liver disease.

Enteral nutrition (EN) by means of oral nutritional supplements (ONS) and tube feeding (TF) offers the possibility to increase or to insure nutrient intake in case of insufficient oral food intake. The present guideline is intended to give evidence-based recommendations for the use of ONS and TF in patients with liver disease (LD). It was developed by an interdisciplinary expert group in accordance with officially accepted standards and is based on all relevant publications since 1985. The guideline was discussed and accepted in a consensus conference. EN by means of ONS is recommended for patients with chronic LD in whom undernutrition is very common. ONS improve nutritional status and survival in severely malnourished patients with alcoholic hepatitis. In patients with cirrhosis, TF improves nutritional status and liver function, reduces the rate of complications and prolongs survival. TF commenced early after liver transplantation can reduce complication rate and cost and is preferable to parenteral nutrition. In acute liver failure TF is feasible and used in the majority of patients.

Predictive factors of outcome after liver transplantation in patients with cirrhosis and hepatocellular carcinoma.

Studies to define the optimal upper limits of tumor size and number as predictors of outcome after orthotopic liver transplantation (OLT) have yielded conflicting results. We analyzed 72 patients with cirrhosis and hepatocellular carcinoma (HCC) who underwent OLT over a 12-year period in a single center. Predictive factors for survival and tumor recurrence, according to the Milan criteria, were also examined. Our cohort included 60 men and 12 women of mean age 54 +/- 8 years and mean follow-up of 40 +/- 39 months. Origin of cirrhosis was postviral in 70% and Child class B or C in two thirds of patients. HCC was multifocal in 61%; about one fifth of patients had micro- or macrovascular involvement or positive nodes upon histologic examination. The cumulative size of the lesions was <3 cm in 17 patients; >3 to < or =5 cm in 28 patients; >5 to < or =8 cm in 14 patients; and >8 cm in 13 patients. According to the number and size of tumor nodules, 49 patients met the Milan criteria. During follow-up 25 patients died, 13 due to tumor recurrence. The 1- and 2-year survivals were 90% and 85% for patients who met the Milan criteria versus 57% and 51% for patients exceeding those limits (P = .006). A cumulative tumor size >8 cm was predictive of survival and tumor recurrence upon multivariate analysis. The adoption of Milan criteria for selection of cirrhotic patients has improved survival and reduced the rate of tumor recurrence. The evaluation of cumulative tumor size might further improve patient selection.

Pharmacological prophylaxis of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt: a randomized controlled study.

BACKGROUND/AIMS: Hepatic encephalopathy is a frequent event after transjugular-intrahepatic-portosystemic-shunt (TIPS), especially during the first months. Aim of this study was to compare two different treatments (lactitol 60 g/day, rifaximin 1200 mg/day) with no-treatment in the prevention of post-TIPS hepatic encephalopathy. METHODS: Seventy-five consecutive cirrhotics submitted to TIPS were randomized to receive either one of the above treatments or no-treatment. The main end-point was the occurrence of an episode of overt hepatic encephalopathy during the first month post-TIPS. Before the procedure and weekly thereafter the patients were evaluated by examining their mental status, asterixis, ammonia and trail-making-test Part-A (TMT-A). RESULTS: The three groups were comparable for age, sex, etiology, Child-Pugh-score, post-TIPS porto-systemic gradient, previous hepatic encephalopathy, basal values of ammonia and psychometric performance. Twenty-five patients developed hepatic encephalopathy (33%, CI 95%=22-45%). One-month incidence was similar in the three groups (P=0.97). Previous hepatic encephalopathy (Relative Hazard=3.79;1.27-11.31) and basal-TMT-A Z-score>1.5 (RH=3.55;1.24-10.2) were predictors of post-TIPS encephalopathy at multivariate analysis. A <5 mmHg porto-systemic gradient was also significantly related to the occurrence of encephalopathy. CONCLUSIONS: Our data show that treatment with lactitol or rifaximin is not effective in the prophylaxis of hepatic encephalopathy during the first month after a TIPS.

Malnutrition is not related to alterations in energy balance in patients with stable liver cirrhosis.

BACKGROUND AND AIMS: Little information are available on the relationship between energy balance and the alterations in nutritional status occurring in cirrhotic patients. The aim of the present study was to evaluate the daily energy balance in clinically stable cirrhotic patients with or without malnutrition. PATIENTS: Seventy-four consecutive cirrhotic patients and nine healthy controls were studied. METHODS: Basal energy expenditure was measured by indirect calorimetry and adjusted according to the patients' physical activity to estimate the daily energy expenditure. Food intake was evaluated based on a 3-day dietary diary. Nutritional status and body composition were assessed using skinfold anthropometry and dual energy X-ray absorptiometry, respectively. RESULTS: Thirty-two patients in the cirrhotic group were classified as severely malnourished according to anthropometric parameters. Two different patterns of soft-tissue loss were observed in the malnourished cirrhotic group: a significant reduction in fat mass and in fat-free mass was observed in males, whereas, females showed a significant reduction in fat mass only. Basal energy expenditure was similar in all groups, while the non-protein respiratory quotient was lower in cirrhotics notwithstanding their nutritional status. This suggests that lipids were the preferred oxidized fuel in the post-absorptive state in these patients. No difference in the estimated daily energy expenditure and energy intake was observed among groups. Lipid content of the diet was significantly lower in malnourished cirrhotics than in controls (33.1+/-1% vs 37.8+/-1%, P=0.02). CONCLUSIONS: Cirrhotic patients in stable clinical condition with malnutrition show a normal energy balance.

Is spontaneous bacterial peritonitis an inducer of vasopressin analogue side-effects? A case report.

In recent years, the use of vasopressin analogues in the treatment of hepatorenal syndrome has become an effective therapeutic strategy leading to improved survival and often allowing the completion of liver transplantation. Terlipressin, in particular, has proven to be safe and effective. Due to the limited number of patients treated so far, it is, however, difficult to draw any definite conclusions on the optimal dosage and on the occurrence of side-effects in these patients. The case is reported of an ascitic cirrhotic patient who developed spontaneous bacterial peritonitis followed by a type-I hepatorenal syndrome. Treatment with terlipressin boluses (0.5 mg/4 h) associated with albumin infusion was then started. The course of the disease was monitored by clinical and laboratory means. After 10 boluses of terlipressin, rectorrhagia and severe ischaemic complications involving the skin of the abdomen, lower limbs, scrotus, and penis, occurred. These ischaemic complications improved after terlipressin withdrawal, while renal failure evolved leading to the patient's death. This case report shows that, in patients with type-I hepatorenal syndrome, the use of terlipressin, even at low dosages, may induce life-threatening ischaemic complications and, moreover, suggests that the recent occurrence of spontaneous bacterial peritonitis, even if properly treated, may significantly increase the risk of major ischaemic complications.

Modification of cardiac function in cirrhotic patients with and without ascites.

OBJECTIVES: Abnormalities in cardiac function have been reported in liver cirrhosis, suggesting a latent cardiomyopathy in these patients. In this study we investigated cardiac function in cirrhotic patients and in controls. METHODS: A total of 20 cirrhotic patients without previous or ongoing ascites, 20 cirrhotic patients with moderate-to-severe ascites, and 10 healthy controls were studied by two-dimensional Doppler echocardiography. Cardiac dimensions and left and right ventricular function were evaluated. The left ventricular geometric pattern was calculated according to Ganau's criteria. Diastolic function was evaluated by the peak filling velocity of E wave and A wave, E/A ratio, and deceleration time of E wave. The pulmonary systolic arterial pressure was also estimated in patients with tricuspid insufficiency. RESULTS: Right and left atrium and right ventricle diameters were significantly enlarged in cirrhotic patients versus controls. E/A ratio was decreased (p < 0.05) in patients with ascites (0.9 +/- 0.2) versus those without ascites (1.3 +/- 0.4) and controls (1.3 +/- 1). The estimated pulmonary systolic arterial pressure was slightly elevated in patients with ascites (35 +/- 5 mm Hg, six patients) versus those with no ascites (28 +/- 5, 10 patients) and controls (27 +/- 8, 6 controls, analysis of variance, p < 0.05). The pattern of left ventricular geometry was normal in the majority of patients. Nitrite and nitrate levels were increased in cirrhotics irrespective of the presence of ascites. CONCLUSIONS: Liver cirrhosis is associated with enlarged right cardiac chambers. Diastolic dysfunction and mild pulmonary hypertension are evident in cirrhotic patients with ascites. These changes do not depend on variations in the left ventricular geometry.

Clinical nutrition practice in Italian Gastroenterology Units.

BACKGROUND: Nutritional status affects the course, ensuing complications and prognosis of virtually all diseases. AIMS: To define the role of nutrition in Gastroenterology Units by means of two investigations that analyse: a) availability of devices for assessing nutritional status; b) nutritional treatment in clinical practice: incidence and frequency of indications for its use, together with type of treatment adopted. PATIENTS AND METHODS: Two questionnaires were sent to Italian Academic and Hospital Gastroenterology Units, all with clinical wards. RESULTS: Results refer to 27 Units, 22 of which took part in both parts of the analysis, enrolling 547 patients during the two-week study The first analysis shows that scales and the altimeter are not available everywhere, while more specific tools, such as skinfold calipers are available in 54% of the Units, and caloric intake can be assessed in 22-41%. The second analysis reveals that nutritional treatment was necessary in 50% of patients in the series examined, and that this was taken into account and prescribed in almost all cases (91%). Of the patients treated, 69% received dietetic supplementation and 31% artificial nutrition [12% enteral, 88% parenteral), although supportive parenteral nutrition is often contraindicated in conditions where good bowel function provides the conditions for enteral nutrition. CONCLUSION: Data emerging from the investigation showed that i) artificial nutrition is commonly used in gastroenterology Units in Italy although 23% of them never consider either enteral or parenteral nutrition as medical treatment of gastrointestinal disease; ii) malnutrition is a very frequent complication (mean 27%; range 4-55%0) in Gastroenterology Unit patients albeit only 42% of malnourished patients received artificial nutrition; iii) indications for enteral and parenteral nutrition are not always respected, as there is an excessive use of parenteral nutrition and an unjustified resistance to the use of enteral nutrition; iv] nutritional treatment is often administered without adequate nutritional assessment and without a complete adherence to the standards recommended for preparation of parenteral bags, supported by suitable technology; v) only two Gastroenterology Units report admitting and following patients in a home parenteral nutrition programme; vi) this investigation probably reflects the response of those Gastroenterology Units most aware of the importance of nutritional problems. Better awareness of correct practices for nutritional support should be promoted, encouraging greater use of diagnostic and monitoring techniques and a more discerning choice of the most suitable type of artificial nutrition to be administered in gastroenterology

Effect of sodium benzoate on blood ammonia response to oral glutamine challenge in cirrhotic patients: a note of caution.

OBJECTIVE: The administration of sodium benzoate provides an alternative pathway for the disposal of waste nitrogen and this substance has been used to treat patients with urea cycle defects and more recently cirrhotics with hepatic encephalopathy. The aim of the study was to assess the ammonia-lowering effect of benzoate in cirrhotic patients without overt hepatic encephalopathy. METHODS: Glutamine challenge, a method to induce an increase of blood ammonia, was performed in six cirrhotics before and after 5 days of benzoate treatment (10 microg/day). Number Connection Test and Posner's Attention Test were also performed before and after benzoate treatment. RESULTS: Blood ammonia increased after the glutamine load both before (from 66 +/- 12 microg/dl to 123 +/- 34 microg/dl and 179 +/- 53 microg/dl after 30 and 60 min, respectively; ANOVA p = 0.0004) and after benzoate treatment (from 102 +/- 27 microg/dl to 185 +/- 49 microg/dl and 250 +/- 39 microg/dl after 30 and 60 min, respectively; ANOVA p = 0.00001). However, after benzoate treatment, the basal values (102 +/- 27 vs 66 +/- 12 microg/dl; p = 0.01) and peak increments of ammonia (166 +/- 56 microg/dl vs 102 +/- 40 microg/dl; p = 0.04) were significantly higher than before. The Number Connection test and the Posner's test were not altered by benzoate treatment. CONCLUSIONS: Benzoate increased both the basal and post-glutamine ammonia levels. These results confirm what has already been observed in experimental animals and suggest a note of caution in the use of sodium benzoate in cirrhotic patients.

Clinical practice guidelines for the management of cirrhotic patients with ascites. Committee on Ascites of the Italian Association for the Study of the Liver.

An ad hoc Committee appointed by the Italian Association for the Study of the Liver prepared these Clinical Practice Guidelines for the Management of Cirrhotic Patients with Ascites. The initial evaluation of a patient with ascites should include a history, physical evaluation, paracentesis with ascitic fluid analysis, abdominal ultrasonography and biochemistry to assess the severity of liver disease and renal functionality. To improve the efficiency of the choice between the different opportunities available in the treatment of ascites, patients can be classified into two subgroups: patients with uncomplicated ascites and patients with complicated ascites, including refractory ascites, bacterial peritonitis, hyponatraemia and renal failure. Based upon evidence emerging from controlled clinical trials or case-control studies, satisfactory treatment for uncomplicated ascites is represented by paracentesis, sodium-restricted diet and diuretics, whereas the treatment of patients with complicated ascites requires other specific approaches. As the prognosis for most patients with ascites is poor, the last part of the paper offers simple criteria in the selection of patients candidates for liver transplantation. The aim of these guidelines is to reduce inappropriate practice and to improve efficiency in the management of patients with ascites. The Committee holds that a periodic update will be necessary to conform to future scientific developments.

Effect of lactitol on blood ammonia response to oral glutamine challenge in cirrhotic patients: evidence for an effect of nonabsorbable disaccharides on small intestine ammonia generation.

OBJECTIVE: Nonabsorbable disaccharides are widely used to decrease blood ammonia concentration. Their principal mode of action is the modification of pH and bacterial flora in the colon. The aim of the present study was to test the hypothesis that these drugs may also reduce small intestine ammonia generation. METHODS: Eight male cirrhotics without overt hepatic encephalopathy received 20 g of glutamine in 100 ml of water. Venous samples for whole blood ammonia were taken before, 30 and 60 min after the load. Immediately after the last blood sample the patients were submitted to the following psychometric tests: number connection test, Posner's attention test, and Sternberg paradigm. After the first glutamine load, patients were started on lactitol (initial dose 20 g, three times a day). Once two bowel movements/day were obtained and maintained for at least 5 days, oral glutamine challenge and psychometric tests were repeated. RESULTS: Ammonia increased significantly after the glutamine load (from 83 +/- 13 to 164 +/- 30 microg/dl at 30 min and 210 +/- 29 microg/dl at 60 min; mean +/- SE; p = 0.006 analysis of variance) but not after glutamine load after lactitol treatment (from 77 +/- 17 to 111 +/- 21 microg/dl and 142 +/- 24 microg/dl; p = not significant). The peak increment (127 +/- 24 vs 65 +/- 18 microg/dl; p = 0.008) of ammonia elevation was significantly smaller during lactitol administration. The patients' psychometric performance after the glutamine load did not differ significantly after lactitol treatment. CONCLUSIONS: Lactitol reduces the elevation in blood ammonia that follows oral glutamine challenge. Because enterally administered glutamine is efficiently absorbed in the jejunum and, in part, metabolized to ammonia we suggest that lactitol affects small intestine ammonia generation probably by shortening the residence time of intestinal contents.

Glucose intolerance and insulin resistance in cirrhosis are normalized after liver transplantation.

Cirrhosis is often associated with insulin resistance and glucose intolerance. We evaluated if these alterations are restored by liver transplantation (LT). Glucose tolerance (oral glucose tolerance test [OGTT]), peripheral insulin sensitivity (euglycemic insulin clamp technique), glucose oxidation (indirect calorimetry), nonoxidative glucose disposal, and insulin secretion (hyperglycemic clamp technique) were measured in 6 patients (Group 1) before and 6 months after LT, in 12 patients (Group 2) who underwent LT 6 to 30 months previously, and in 6 healthy individuals (controls). In Group 1, glucose tolerance and insulin sensitivity (3.24 +/- 0.37 mg/kg/min) were normalized after LT (8.6 +/- 0.77 mg/kg/min; P <.0001; P = not significant vs. controls). The improved insulin-mediated glucose uptake was the result of a normalization of nonoxidative glucose disposal. Fasting insulin and C-peptide decreased from 24.6 +/- 3.3 microU/mL and 4.37 +/- 0.46 ng/dL, respectively, to 12.7 +/- 1.9 microU/mL and 2.46 +/- 0.5 ng/dL (controls: 10.0 +/- 3 microU/mL and 1.45 +/- 0.34 ng/dL). The glucose-induced increase of insulin concentration, which was higher before LT, showed a significant reduction, although the first phase of beta-cell secretion remained significantly higher compared with that of controls. All these findings were also confirmed in Group 2. The present data indicate that LT normalizes glucose tolerance and insulin sensitivity in cirrhotic patients through an improvement of both hepatic glucose clearance and the peripheral glucose disposal. The latter effect may be the result of the correction of chronic hyperinsulinemia. An increased first-phase beta-cell insulin secretion in response to high glucose levels persists, suggesting that a memory of previous insulin resistance is maintained.

Clotting activation after transjugular intrahepatic portosystemic stent shunt.

BACKGROUND AND AIM: Aim of the study was to investigate the behaviour of clotting system in peripheral circulation of cirrhotic patients undergoing transjugular intrahepatic portosystemic stent shunt (TIPS). METHODS: Clotting variables and endotoxemia were measured 48 h and 30 days after TIPS in patients randomised to receive heparin or not. RESULTS: Forty-eight hours after TIPS, a significant increase of prothrombin fragment F1+2 was observed; such increase was less evident in patients given heparin. Similar findings were observed for endotoxemia, which, however, was not affected by heparin treatment. Thirty days after TIPS procedure prothrombin fragment F1+2 and endotoxemia returned to baseline values independently of the treatment given. CONCLUSION: This study shows that TIPS is associated with an increase of clotting activation which might contribute to acute thrombosis observed after this procedure.

Cost analysis for the prevention of variceal rebleeding: a comparison between transjugular intrahepatic portosystemic shunt and endoscopic sclerotherapy in a selected group of Italian cirrhotic patients.

The aim of the present study was to compare the cumulative cost of the first 18-month period in a selected group of Italian cirrhotic patients treated with transjugular intrahepatic portosystemic shunt (TIPS) versus endoscopic sclerotherapy (ES) to prevent variceal rebleeding. Thirty-eight patients enrolled in a controlled trial were considered (18 TIPS and 20 sclerotherapy). The number of days spent in the hospital for the initial treatment and during the follow-up period were defined as the costs of hospitalization. ES sessions, TIPS procedures, angioplasty or addition of a second stent to maintain the shunt patency, were defined as the costs of therapeutic procedures. The two groups were comparable for age, sex, and Child-Pugh score. During the observation period 4 patients died in the TIPS group, and 2 died and 1 was transplanted in the sclerotherapy group. The rebleeding rate was significantly higher in the sclerotherapy group. Despite this, the number of days spent in the hospital was similar in the two groups. This was because of a higher number of hospital admissions for the treatment of hepatic encephalopathy and shunt insufficiency in the TIPS group. The therapeutic procedures were more expensive for TIPS. Consequently, the cumulative cost was higher for patients treated with TIPS than for those treated with sclerotherapy. The extra cost was because of the initial higher cost of the procedure and the difference was still maintained at the end of the 18-month follow-up. When the cumulative costs were expressed per month free of rebleeding, the disadvantage of TIPS disappeared. In conclusion, a program of prevention of variceal rebleeding with TIPS, despite the longer interval free of rebleeding, is not a cost-saving strategy in comparison with sclerotherapy.

A comparison of skinfold anthropometry and dual-energy X-ray absorptiometry for the evaluation of body fat in cirrhotic patients.

BACKGROUND AND AIMS: Skinfold anthropometry has been used to evaluate the nutritional status in cirrhosis. Such estimates are based on the calculations which derive from healthy subjects and may not apply to cirrhotic patients. We aimed to calculate the limits of agreement between Skinfold anthropometry (SA) and dual-energy X-ray absorptiometry (DXA) in estimating body fat in cirrhotics. METHODS: Forty cirrhotic patients were studied by both methods. The limits of agreement were estimated by the Bland and Altman method. RESULTS: Percentage body fat was similar when measured by DXA and SA (29.6 +/- 9.2 vs 28.9 +/- 7.5 %). Body fat mass was also similar (20.3 +/- 8.4 vs 20.3 +/- 7.7 kg). The limits of agreement between DXA and SA measurements were -7.04 (95%CI: -9.55 to -5.2) +8.56 (95%CI: +10.7 to +6.4.) in the assessment of percentage body fat and -5.32 (95%CI: -6.77 to -3.87) +5.24 (95%CI: +3.79 to +6.69) in the assessment of fat mass. CONCLUSION: Percentage body fat can be evaluated by SA or DXA with a difference of less then 5% in the majority of cirrhotic patients without overt fluid retention. This result is important when considering the large applicability of SA.