Abdominal distension after colonic lactulose fermentation recorded by a new extensometer

Colonic lactulose fermentation induces bloating, but whether it also causes abdominal distension is not known. The aim of this study was to assess the effect of colonic lactulose fermentation on abdominal girth using a new extensometer. We recorded abdominal girth in 24 healthy subjects by means of an extensometer that measures the phase shift of an ultrasound wave propagating in a tube encircling the abdomen. The recordings were continuously made for 3 h after the ingestion of 100 mL of tap water with (16 subjects) or without (eight subjects) 10 g of lactulose. Every 10 min, H2 in the breath was analysed and the intensity of bloating was recorded. Bloating was never reported after water ingestion, whereas it was reported by 10 subjects after lactulose ingestion (P = 0.002). The mean +/- SD changes in abdominal girth in comparison with resting conditions were statistically significant after lactulose ingestion (3 +/- 2.9 mm; P = 0.002) but not after water ingestion (-0.2 +/- 2.7 mm; P = 0.82). The area under the curve of the changes in abdominal girth after lactulose were significantly greater than after water ingestion (P = 0.03). In conclusion, colonic lactulose fermentation induces bloating and abdominal distension. The new extensometer is useful for continuously recording changes in abdominal girth.     

古拉定在肝硬化亚临床肝性脑病治疗中的临床意义

目的　探讨古拉定 (GLT)在肝硬化亚临床性肝性脑病 (SHE)治疗中的临床意义。方法　以古拉定联合乳果糖治疗 4 7例SHE ,在 1mon治疗结束后随访 6mon ,并以单用乳果糖治疗的 5 0例SHE作对照 ,观察智力测验好转情况及肝功能改变情况。结果　数字连接试验 (NCT)及数字符合试验 (DST)在治疗结束及随访 6mon时的好转率分别为 69 0 %、5 2 6%和 4 7 6%、5 0 % ,而对照则分别为 4 0 8%、4 5 0 %和 17 4 % ,除DST治疗 1mon时两组差异无显著性外 ,两组其余各项比较差异均有显著性 (P <0 0 5或P <0 0 1) ;治疗组肝功能Child Pugh计分在治疗前为 8 92± 1 16,治疗 1mon时降为 7 73± 1 3 1(P <0 0 1) ,随访 6mon时为 8 0 2± 1 17(P <0 0 5 ) ,而对照组在治疗前为 8 65± 2 4 1,1mon时为 7 86± 1 4 6(P <0 0 5 ) ,至 6mon时为 8 4 4± 1 87,与治疗前差异无显著性。结论　古拉定能提高乳果糖对肝硬化SHE治疗的近期疗效及远期疗效 ,机制可能是通过改善肝功能状态而起作用     

Mechanistic insight,diagnosis, and treatment of ammonia‐induced hepatic encephalopathy

Hepatic encephalopathy is a neuropsychological syndrome due to biochemical disturbance of brain function in advanced liver disease patients. Diagnosis and treatment of the condition is very demanding and has negative toll on finances with increased healthcare utilization. The pathophysiology is not completely understood; however, there is evidence that ammonia plays an important role in the etiology. Conventional methods of solely relying on blood ammonia level to diagnose hepatic encephalopathy did not help much; likewise, the use of lactulose alone in treating hepatic encephalopathy has also been discouraged. This paper analyzed the current knowledge regarding the mechanism of how ammonia disrupts the normal brain function as well as the use of latest diagnosing tools including those under development to evaluate the neuropsychiatric state of patients and their quality of life. The efficacies of lactulose and rifaximin combination for short‐term and long‐term treatment in addition to nutritional interventions and other drugs undergoing clinical trials were also reviewed.     

Reproducible lactulose hydrogen breath test as a measure of mouth-to-cecum transit time

Breath hydrogen monitoring after oral lactulose syrup is a conventional measure of mouth-to-cecum transit time (MCTT), but its reproducibility has been questioned. We compared the reproducibility of five measurements of MCTT after a conventional breakfast (380 kcal) taken with tea containing 20 g lactulose to five measurements of MCTT after 20 g lactulose in water in eight normal volunteers. Individual mean breakfast transit time was not significantly different from lactulose transit time in each of the seven subjects, but one had a breakfast transit time of 151±15 min and a lactulose transit time of 86±22 minutes (¯X ±sd, P<0.001). The coefficient of variation of breakfast transit time (11.6±5.3%, range: 6.9–24.2%) was less than that of lactulose transit time (30.7±7.8%, range: 22.1–50.0%, P<0.001). In a second set of experiments, the liquid phase marker ( ^99m Technetiumdiethylene triamine pentaacetic acid) emptied from the stomach more rapidly after the lactulose solution (T1/2 16.3±5.4) than after the breakfast (33.9±10.9 min, P<0.01) and MCTT was shorter after lactulose (77±32 vs 104±40 min, trespectively, P<0.05). There was no correlation between MCTT of lactulose and breakfast and between half-time gastric emptying and MCTT of either lactulose or breakfast. We conclude that the ingestion of inert lactulose induces an abnormally rapid MCTT and that breakfast MCTT is a much more reproducible investigation and should be employed in studies requiring serial measurements.     

Assessment of Intestinal Permeability and Absorption in Cirrhotic Patients with Ascites Using Combined Sugar Probes

Gastrointestinal dysfunction in patients with cirrhosis may contribute to complications such as malnutrition and spontaneous bacterial peritonitis. To determine whether cirrhotic patients with ascites have altered intestinal function, we compared intestinal permeability and absorption in patients with liver disease and normal subjects. Intestinal permeability and absorption were investigated in 66 cirrhotic patients (48 with ascites, 18 without ascites) and 74 healthy control subjects. Timed recovery of 3-O-methyl-D-glucose, D-xylose, L-rhamnose, and lactulose in urine following oral administration was measured in order to assess active and passive carrier-mediated, and nonmediated, absorptive capacity, as well as intestinal large-pore/small-pore (lactulose/rhamnose) permeability. Test sugars were measured by quantitative thin-layer chromatography and results are expressed as a percentage of test dose recovered in a 5-h urine collection. Sugar excretion ratios relating to small intestinal permeability (lactulose/rhamnose) and absorption (rhamnose/3-O-methyl-D-glucose) were calculated to avoid the effects of nonmucosal factors such as renal clearance, portal hypertension, and ascites on the recovery of sugar probes in urine. Compared with normal subjects, the mean lactulose/rhamnose permeability ratio in cirrhotic patients with ascites was significantly higher (0.058 vs. 0.037, P < 0.001) but not in cirrhotic patients without ascites (0.041 vs. 0.037). Cirrhotic patients with ascites had significantly lower mean recoveries of 3-O-methyl-D-glucose (23.0 vs. 49.1%; P < 0.001), D-xylose (18.8 vs. 34.5%; P < 0.001), L-rhamnose (4.0 vs. 9.1%; P < 0.001), and lactulose (0.202 vs. 0.337%; P < 0.001) than normal subjects. However, the mean rhamnose/3-O-methyl-D-glucose ratio was the same in cirrhotic patients with ascites as normal subjects (0.189 vs. 0.189), indicating that the reduction in probe recovery was due to nonmucosal factors. Compared with normal subjects, cirrhotic patients with ascites have abnormal intestinal permeability, measured by urinary lactulose/rhamnose excretion, and normal small intestinal absorption, assessed by the urinary rhamnose/3-O-methyl-D-glucose ratio. Low urine recovery of sugar probes found in cirrhotic patients appears to be the result of nonintestinal factors affecting clearance rather than reduced intestinal absorption.     

Efficacy of Lactulose in Cirrhotic Patients with Subclinical Hepatic Encephalopathy

To investigate the role of lactulose in the treatment of cirrhotic patients with subclinical hepatic encephalopathy (SHE), 40 cirrhotic patients, 33 males and 7 females, were included in the study. The diagnosis of SHE was made by quantitative psychometric tests including the number connection test (NCT), figure connection test (FCT) parts A and B, and two performance subtests of Wechsler adult intelligence scale, ie, picture completion (PC) and block design (BD) tests. SHE was diagnosed in 26 (65%) of 40 patients. Of these 26 patients, 14 patients were randomized to treatment group (lactulose 30–60 ml/day for three months, SHE-L) and 12 patients to no treatment group (no lactulose, SHE-NL). Psychometric tests were repeated in all patients in both groups and in six patients with no SHE (group NSHE, N = 14) after three months. The mean scores and number of the abnormal psychometric tests at entry were significantly higher in patients in groups SHE-L and SHE-NL than in patients in group NSHE; however, there was no significant difference between SHE-L and SHE-NL. The mean number of the abnormal psychometric tests decreased in patients in group SHE-L after three months of treatment with lactulose (2.9 ± 0.9 vs 0.8 ± 1.2; P = 0.004); however, there was no change in patients in group SHE-NL after three months (3.7 ± 1.5 vs 3.5 ± 1.3; P = NS). While SHE improved in 8 of 10 patients in group SHE-L, none of the patients in group SHE-NL improved after three months of follow-up (P < 0.001). Two patients in group SHE-NL also developed overt encephalopathy during the study period. We conclude that lactulose treatment in cirrhotic patients with SHE is effective.     

Lactitol in treatment of chronic hepatic encephalopathy

The efficacy and side effects of lactitol in the treatment of chronic hepatic encephalopathy was compared to that of other disaccharides in a meta-analysis of published randomized clinical trials (RCTs). The outcomes assessed were: (1) the rate of patients free from episodes of clinically detectable encephalopathy, and (2) the rate of patients free from one or more side effects in the different treatment groups. Four RCTs were eligible for analysis; in three lactitol was compared to lactulose, in one the alternative treatment was lactose in lactase-deficient patients. The methodological quality of these studies was high. Meta-analysis showed that lactitol was as effective as other disaccharides in the treatment of encephalopathy: pooled odds ratio was 0.83, 95% confidence interval was 0.38–1.82. Results were not sensitive to the use of alternative methods of counting and attributing events in these trials. Patients experienced fewer side effects during treatment with lactitol, but the pooled odds ratio was not statistically significant. In all studies lactitol was considered more palatable. Clinical effectiveness of lactitol, in long-term treatment of chronic encephalopathy, is similar to those of lactulose. It seems that lactitol has lower side effects than lactulose. Future RCTs with a double-blind design could be mainly aimed at evaluating the side-effect profile of the two disaccharides.This work was supported by grants from the Zyma S. A.     

Assessment of the pharmacokinetics,removal rate of hemodialysis,and safety of lactulose in hemodialysis patients

Lactulose is often used to treat hepatic encephalopathy or constipation, and also exhibits benefits to chronic renal insufficiency due to reduce nitrogen-related products in serum. The present study investigated the pharmacokinetics of lactulose, its removal rate through dialysis, and safety by administering lactulose 6.5 g (Lagnos Jelly Divided Pack 16.05 g) orally to six hemodialysis patients who resided in Taiwan. As a result, the means of maximum plasma concentrations (C_max) and Time to reach C_max (Tmax) were 3090 ± 970 ng/mL and 6.5 ± 2.3 hours, respectively. The mean plasma concentration was 2220 ± 986 ng/mL after administration for 24 hours. Sequentially, the mean plasma concentration reduced to 307 ± 117 ng/mL after the application of 4-hour dialysis. Area under the plasma concentration-time curve from zero to 24 h post-dose (AUC_0–24h) were 56,200 ± 21,300 ng h/mL and the AUC_0–28h was 61,200 ± 23,300 ng h/mL. The rate of lactulose removal by dialysis was 83.6 ± 8.9%. In addition, the multiple doses of lactulose using a simulated model suggested that no plasma accumulation would be expected while coordinating with dialysis. Good tolerability was confirmed, while the mild adverse effect of diarrhea was observed in one case during the study period. No death or serious adverse effect was reported. Based on the present study, we demonstrated the pharmacokinetic transition with respect to plasma levels of lactulose in patients with impaired renal excretion treated with hemodialysis.