Is the increase in serum cystathionine levels in patients with liver cirrhosis a consequence of impaired homocysteine transsulfuration at the level of gamma-cystathionase?

BACKGROUND: It has been suggested that the major metabolic block in the methionine catabolic pathway in cirrhotics exists at the level of the enzyme S-adenosylmethionine synthetase because in previous studies using conventional amino-acid analyzers, no intermediates of transmethylation/transsulfuration were found to accumulate in plasma downstream of S-adenosylmethionine synthesis. We therefore measured serum concentration intermediates of methionine transmethylation/transsulfuration using an improved gas chromatography/mass spectrometry technique. METHODS: Serum concentrations of methionine, homocysteine, cystathionine, N,N-dimethylglycine, N-methylglycine, methylmalonic acid, 2-methylcitric acid and alpha-aminobutyric acid were determined by gas chromatography/mass spectrometry in 108 consecutive patients with liver cirrhosis at Child stages A (mild cirrhosis, n = 27) and B/C (severe cirrhosis, n = 81), 18 outpatients with non-cirrhotic liver disease, and 55 healthy individuals. RESULTS: Serum levels of methionine, N,N-dimethylglycine, N-methylglycine, cystathionine, and homocysteine were significantly higher in patients at Child stages B/C compared with those of healthy controls (P < 0.01), and they were also significantly higher than in patients with non-cirrhotic liver disease (P < 0.01 and P < 0.05 for homocysteine, respectively). They also correlated with the Child-Pugh score (P < 0.01). Homocysteine, cystathionine, N,N-dimethylglycine, N-methylglycine, methylmalonic acid, and 2-methylcitric acid correlated with serum creatinine. The mean cystathionine concentration was significantly higher in patients with creatinine > or = 1.4 mg/dl than in patients with normal creatinine values (P < 0.01). However, the differences between cirrhotics and healthy controls were still significant after correcting for creatinine. CONCLUSIONS: Our data provides indirect evidence for two hitherto unrecognized alterations of methionine metabolism in cirrhotics, i.e. impairment of the transsulfuration of homocysteine at the level of cystathionine degradation and a shift in remethylation of homocysteine towards the betaine-homocysteine-methyltransferase reaction.     

Can serum fibrosis markers predict medium/large oesophageal varices in patients with liver cirrhosis?

Background and study aimsNon-invasive predictors of medium/large oesophageal varices (LOVs) could reduce the number of screening endoscopies. As portal hypertension is a consequence of liver fibrosis, serum fibrosis markers were evaluated together with other variables as possible non-invasive predictors of medium OV/LOV.Patients and methodsA total of 154 cirrhotic patients with splenomegaly and 30 healthy control subjects were recruited in a prospective study in two gastroenterology centres in Upper Egypt. Clinical parameters assessed included Child–Pugh class, liver size and ascites. Laboratory parameters included complete blood count, liver function tests, and aspartate aminotransferase (AST)/platelet ratio. Transforming growth factor-β₁ (TGF-β₁), alpha₂ macroglobulin (A₂M) and hyaluronic acid (HA) were assayed. Ultrasonographic examination was done for assessment of liver span, portal vein diameter and detection of minimal ascites. Oesophageal varices were diagnosed and graded by oesophagogastroduodenoscopy.ResultsFifty-four patients (35%) had no or small varices and 100 (65%) patients had medium OV/LOV by endoscopy. On multivariate analysis, the independent predictors of medium OV/LOV were the presence of ascites (β = 0.258, p = 0.047) and serum HA (β = 0.449, p = 0.009). The receiver operating characteristic curve for HA showed the area under the curve to be 0.916. The sensitivity, specificity, positive and negative predictive values and diagnostic accuracy of HA at a cut-off value of 207 μg l^?1 were 94%, 77.8%, 88.7%, 87.5% and 88.3%, respectively.ConclusionsThe presence of ascites and serum HA level higher than 207 μg l^?1 can predict the presence of medium OV/LOV in cirrhotic patients. This would help physicians to identify patients who would most likely benefit from screening endoscopy and thus, reduce costs and discomfort from unnecessary endoscopic procedures.     

Can non-invasive measurements aid clinical assessment of volume in patients with cirrhosis?

AIM:To evaluate the non-invasive assessments of volume status in patients with cirrhosis.METHODS:Echocardiography and multifrequency bioimpedance analysis measurements and short synacthen tests were made in 20 stable and 25 acutely decompensated patients with cirrhosis.RESULTS:Both groups had similar clinical assessments,cortisol response and total body water(TBW),however the ratio of extracellular water(ECW)/TBW was significantly greater in the trunk(0.420±0.004 vs0.404±0.005),and limbs(R leg 0.41±0.003 vs 0.398±0.003,P<0.05,and L leg 0.412±0.003 vs 0.399±0.003)with decompensated cirrhosis compared to stable cirrhotics,P<0.05).Echocardiogram derived right atrial and ventricular filling and end diastolic pressures and presence of increased left ventricular end diastolic volume and diastolic dysfunction were similar in both groups.The decompensated group had lower systemic blood pressure,mean systolic 101.8±4.3 vs122.4±5.3 and diastolic 58.4±4.1 mmHg vs 68.8±3.1 mmHg respectively,P<0.01,and serum albumin30(27-33)vs 32(31-40.5)g/L,P<0.01.CONCLUSION:Decompensated cirrhotics had greater leg and truncal ECW expansion with lower serum albumin levels consistent with intravascular volume depletion and increased vascular permeability.     

Is computed tomography volumetric assessment of the liver reliable in patients with cirrhosis?

Objectives: The estimation of liver volume (LV) has been widely studied in normal liver, the density of which is considered to be equivalent to 1 kg/l. In cirrhosis, volumetric evaluation and its correlation to liver mass remain unclear. The aim of this study was to evaluate the accuracy of computed tomography (CT) scanning to assess LV in patients with cirrhosis.Methods: Liver volume was evaluated by CT (CTLV) and correlated to the explanted liver weight (LW) in 49 patients. Liver density (LD) and its association with clinical features were analysed. Commonly used formulae for estimating LV were also evaluated. The real density of cirrhotic liver was prospectively measured in explant specimens.Results: Wide variations between CTLV (in ml) and LW (in g) were found (range: 3–748). Cirrhotic livers in patients with hepatitis B virus infection presented significantly increased LD (P = 0.001) with lower CTLV (P = 0.005). Liver volume as measured by CT was also decreased in patients with Model for End-stage Liver Disease scores of >15 (P = 0.023). Formulae estimating LV correlated poorly with CTLV and LW. The density of cirrhotic liver measured prospectively in 15 patients was 1.1 kg/l.Conclusions: In cirrhotic liver, LV assessed by CT did not correspond to real LW. Liver density changed according to the aetiology and severity of liver disease. Commonly used formulae did not accurately assess LV.     

Can the MEGX test and serum bile acids improve the prognostic ability of Child-Pugh's score in liver cirrhosis?

BACKGROUND: Liver transplantation is nowadays the therapeutic option for end-stage liver disease. Correct disease staging is the main step towards improving the timing of listing for liver transplantation so as to avoid premature or late entry. The need for correct prognostic evaluation is due to the limited number of donors and to the increasing number of patients awaiting transplantation. Our aim was to verify whether Child-Pugh's score might be improved by adding the monoethylglycinexylidide (MEGX) formation test and/or serum bile acid determination. METHODS: We evaluated 182 cirrhotic patients (44 Child-Pugh class A, 97 class B, and 41 class C) of mixed aetiology referring to a tertiary care centre for functional staging of liver disease. These patients were prospectively followed-up for 12-72 months. During this period, 45 patients died, 46 received a transplant, and 91 survived without transplantation. The end-point of analysis was either survival or liver disease-related death at the 6th, 12th, 18th and 24th months of follow-up. The 46 transplanted patients were excluded from the study upon transplantation. RESULTS: In our study, a cut-off for Child-Pugh's score < 8 confirmed its usefulness, especially in short-term prognostic prediction, while mid- and long-term prediction improved by almost 10% by using the combination of a Child- Pugh's score > 8 and an MEGX value < 15 mg/l. Cox's multi-variate regression analysis indicated that MEGX values either with Child-Pugh's score or with prothrombin activity and ascites were independent prognostic variables. CONCLUSIONS: Besides confirming that Child-Pugh's score as the basis of prognostic evaluation of cirrhotic patients, these results suggest that the MEGX test might be a complement to the original score when a patient is being evaluated for a liver transplantation programme.     

Could albumin level explain the higher mortality in hemodialysis patients with pulmonary hypertension?

ABSTRACT: BACKGROUND: the pathogenesis of pulmonary hypertension (PH) in hemodialysis is still unclear. The aim of this study was to identify the risk factors associated with the presence of PH in chronic hemodialysis patients and to verify whether these factors might explain the highest mortality among them. Methods: we conducted a retrospective study of hemodialysis patients who started treatment from August 2001 to October 2007 and were followed up until April 2011 in a Brazilian referral medical school. According to the results of echocardiography examination, patients were allocated in two groups: those with PH and those without PH. Clinical parameters, site and type of vascular access, bioimpedance, and laboratorial findings were compared between the groups and a logistic regression model was elaborated. Actuarial survival curves were constructed and hazard risk to death was evaluated by Cox regression analysis. Results: PH>35 mmHg was found in 23 (30.6%) of the 75 patients studied. The groups differed in extracellular water, ventricular thickness, left atrium diameter, and ventricular filling. In a univariate analysis, extracellular water was associated with PH (relative risk = 1.194; 95% CI of 1.006 - 1.416; p=0,042); nevertheless, in a multiple model, only left atrium enlargement was independently associated with PH (relative risk =1.172; 95% CI of 1.010 - 1.359; p=0,036). PH (hazard risk = 3.008; 95% CI of 1.285 - 7.043; p=0,011) and age (hazard risk = 1.034 per year of age; 95% CI of 1.000 - 7.068; p=0,047) were significantly associated with mortality in a multiple Cox regression analysis. However, when albumin was taken in account the only statistically significant association was between albumin level and mortality (hazard risk = 0.342 per mg/dL; 95% CI of 0.119 - 0.984; p=0,047) while the presence of PH lost its statistical significance (p=0.184). Mortality was higher in patients with PH (47.8% vs 25%) who also had a statistically worse survival after the sixth year of follow up. CONCLUSIONS: PH in hemodialysis patients is associated with parameters of volume overload that sheds light on its pathophysiology. Mortality is higher in hemodialysis patients with PH and the low albumin level can explain this association.     

Do genetic variants in the SPINK1 gene affect the level of serum PSTI?

Background

The serine protease inhibitor Kazal type 1 (SPINK1), also known as pancreatic secretory trypsin inhibitor (PSTI), is a peptide secreted by pancreatic acinar cells. Genetic studies have shown an association between SPINK1 gene variants and chronic pancreatitis or recurrent acute pancreatitis. The aim of this study was to clarify whether the SPINK1 variants affect the level of serum PSTI.

Methods

One hundred sixty-three patients with chronic pancreatitis or recurrent acute pancreatitis and 73 healthy controls were recruited. Serum PSTI concentrations were determined with a commercial radioimmunoassay kit.

Results

Ten patients with the p.N34S variant, 7 with the IVS3+2T>C variant, two with both the p.N34S and the IVS3+2T>C variants, and one with the novel missense p.P45S variant in the SPINK1 gene were identified. The serum PSTI level in patients with no SPINK1 variants was 14.3?±?9.6?ng/ml (mean?±?SD), and that in healthy controls was 10.7?±?2.2?ng/ml. The PSTI level in patients carrying the IVS3+2T>C variant (5.1?±?3.4?ng/ml), but not in those with the p.N34S variant (8.9?±?3.5?ng/ml), was significantly lower than that in the patients without the SPINK1 variants and the healthy controls. The serum PSTI level in the patient with the p.P45S variant was 4.9?ng/ml. Low levels of serum PSTI (<6.0?ng/ml) showed sensitivity of 80?%, specificity of 97?%, and accuracy of 96?% in the differentiation of IVS3+2T>C and p.P45S carriers from non-carriers.

Conclusion

Serum PSTI levels were decreased in patients with the IVS3+2T>C and p.P45S variants of the SPINK1 gene.     

Does hepatic metabolism of melatonin affect the endogenous serum melatonin level in man?

Melatonin (MT) is metabolized in the liver by cytochrome P450 (CYP) 1A2 but its importance for the metabolic process has not been fully elucidated. Therefore, the objective of this investigation was to study whether patients with different CYP1A2 activity would have different nocturnal serum MT levels. For that purpose serum MT concentrations were determined every second hour during the night in 12 healthy subjects and their MT areas under the curve (MT-AUCs) were calculated. Caffeine (CA) clearance was determined in advance. It is generally accepted that CA clearance reflects CYP1A2 activity. This made it possible to evaluate whether a relationship prevails between endogenous MT-AUCs and CYP1A2 activity. If CYP1A2 is of importance for the metabolism of MT one would expect to find an inverse correlation between the MT-AUCs and the CA clearance. However, such correlation did not exist in the current study (Rs=-0.021, NS). Since endogenous MT-AUC is dependent not only on MT elimination by CYP1A2 but also on MT secretion, it is possible that an increased MT secretion counter-balances an increased hepatic MT metabolism. If so, this could explain why the MT-AUCs and the CA clearance values were not inversely correlated in this study.     

Does enteral nutrition affect clinical outcome? A systematic review of the randomized trials

BACKGROUND: Both parenteral nutrition (PN) and enteral nutrition (EN) are widely advocated as adjunctive care in patients with various diseases. A systematic review of 82 randomized controlled trials (RCTs) of PN published in 2001 found little, if any, effect on mortality, morbidity, or duration of hospital stay; in some situations, PN increased infectious complication rates. OBJECTIVE: The objective was to assess the effect of EN or volitional nutrition support (VNS) in individual disease states from available RCTs. DESIGN: We conducted a systematic review. RCTs comparing EN or VNS with untreated controls, or comparing EN with PN, were identified and separated according to the underlying disease state. Meta-analysis was performed when at least three RCTs provided data. The evidence from the RCTs was summarized into one of five grades. A or B, respectively, indicated the presence of strong or weak (low-quality RCTs) evidence supporting the use of the intervention. C indicated a lack of adequate evidence to make any decision about efficacy. D indicated that limited data could not support the intervention. E indicated either that strong data found no effect, or that either strong or weak data suggested that the intervention caused harm. PATIENTS AND SETTINGS: RCTs could include either hospitalized or nonhospitalized patients. The EN or VNS had to be provided as part of a treatment plan for an underlying disease process. INTERVENTIONS: The RCT had to compare recipients of either EN or VNS with controls not receiving any type of artificial nutrition or had to compare recipients of EN with recipients of PN. OUTCOME MEASURES: These were mortality, morbidity (disease specific), duration of hospitalization, cost, or interventional complications. SUMMARY OF GRADING: A: No indication was identified. B: EN or VNS in the perioperative patient or in patients with chronic liver disease; EN in critically ill patients or low birth weight infants (trophic feeding); VNS in malnourished geriatric patients. (The low-quality trials found a significant difference in survival favoring the VNS recipients in the malnourished geriatric patient trials; two high-quality trials found nonsignificant differences that favored VNS as well.) C: EN or VNS in liver transplantation, cystic fibrosis, renal failure, pediatric conditions other than low birth weight infants, well-nourished geriatric patients, nonstroke neurologic conditions, AIDS; EN in acute pancreatitis, chronic obstructive pulmonary disease, nonmalnourished geriatric patients; VNS in inflammatory bowel disease, arthritis, cardiac disease, pregnancy, allergic patients, preoperative bowel preparation. D: EN or VNS in patients receiving nonsurgical cancer treatment or in patients with hip fractures; EN in patients with inflammatory bowel disease; VNS in patients with chronic obstructive pulmonary disease. E: EN in the first week in dysphagic, or VNS at any time in nondysphagic, stroke patients who are not malnourished; dysphagia persisting for weeks will presumably ultimately require EN. CONCLUSIONS: There is strong evidence for not using EN in the first week in dysphagic, and not using VNS at all in nondysphagic, stroke patients who are not malnourished. There is reasonable evidence for using VNS in malnourished geriatric patients. The recommendations to consider EN/VNS in perioperative/liver/critically ill/low birth weight patients are limited by the low quality of the RCTs. No evidence could be identified to justify the use of EN/VNS in other disease states.     

A multicenter, open-label, dose-ranging study to exploratively evaluate the efficacy, safety, and dose�Cresponse of tolvaptan in patients with decompensated liver cirrhosis

Objectives  

We examined the efficacy of tolvaptan, an orally effective nonpeptide vasopressin V₂ receptor antagonist, in a Japanese clinical study in patients with intractable ascites and/or lower limb edema associated with decompensated liver cirrhosis.