Hypozincemia is associated with human hepatocarcinogenesis in hepatitis C virus-related liver cirrhosis.

AIM: Hypozincemia is associated with the progression of chronic liver diseases, but it is unknown whether hypozincemia promotes human hepatocarcinogenesis. Our aim is to evaluate the serum zinc levels in liver cirrhosis (LC) patients and clarify the relationship between the serum zinc levels and the development of hepatocellular carcinoma (HCC). METHODS: Cirrhotic patients without HCC (n = 299) were enrolled from 14 medical institutes in Japan as a multicenter prospective study (No. 2028). Of the 299 patients, 157 were included in the present study based on reliable and consistent serum zinc levels and no history of oral zinc supplementation. Clinical parameters associated with the development of HCC were determined. Furthermore, the cumulative incidence of HCC was analyzed using Kaplan-Meier methods and was calculated using the log-rank test. A Cox regression analysis was utilized for the multivariate analysis to evaluate the predictors of hepatocarcinogenesis. RESULTS: Thirty of 157 patients (19.1%) developed HCC during an observation period of 3 years. Serum zinc levels were significantly decreased in hepatitis C virus-related LC (C-LC) patients with HCC (0.0180). The risk factors for incidence of HCC were hypozincemia (0.0014), high α-fetoprotein (0.0080), low branched chain amino acids-to-tyrosine ratio (0.0128), or female sex (0.0228). Hypozincemia (hazard ratio 1.61, 0.0324) was the only significant predictor of hepatocarcinogenesis by multivariate Cox regression analysis. CONCLUSIONS: Hypozincemia is associated with hepatocarcinogenesis in C-LC patients.

The Prevalence and Implication of Zinc Deficiency in Patients With Chronic Liver Disease.

BACKGROUND: Patients with liver cirrhosis often exhibit zinc deficiency. Although zinc is involved in many bioactivities, many aspects of clinical implications of zinc deficiency in liver cirrhosis remain unclear. We aimed to reveal the prevalence and implications of zinc deficiency in liver cirrhosis by assessing associations with parameters such as clinical symptoms and laboratory data. METHODS: In 235 cirrhosis patients enrolled at multiple medical institutions in 2009, we assessed how blood zinc levels were associated with their clinical symptoms, patients characteristics, and liver function test results. RESULTS: Blood zinc levels were most strongly correlated with blood albumin levels among the study parameters (r = 0.587, P < 0.0001). When blood albumin levels were ≤ 3.5 g/dL, blood zinc levels were < 70 µg/dL in 88% of patients. Additionally, significant correlations were observed with age (r = -0.253, P = 0.0014), aspartate aminotransferase levels (r = -0.254, P = 0.0020), total bilirubin levels (r = -0.222, P = 0.0053), prothrombin time (r = -0.255, P = 0.0029), branched-chain amino acid to tyrosine ratio (r = 0.357, P < 0.0001), Child-Pugh score (r = 0.469, P < 0.0001), ammonia levels (r = -0.246, P = 0.0028), and total cholesterol levels (r = 0.314, P < 0.0001). Blood zinc levels were significantly lower in patients with edema/ascites (P < 0.0001), those with hepatic encephalopathy (P = 0.0215), those receiving oral diuretics (P = 0.0045), and those receiving oral branched-chain amino acids (P < 0.0001) than in those without these conditions. CONCLUSIONS: Zinc deficiency is prevalent in cirrhosis patients, whereas nitrogen metabolic disorders, particularly hypoalbuminemia, can be an indicator of zinc deficiency. Thus, cirrhosis patients exhibiting a nitrogen metabolic disorder should be examined for the presence of zinc deficiency.

Study of pruritus in chronic hepatitis C patients.

AIM: To investigate the occurrence and severity of pruritus in chronic hepatitis C patients treated with or without interferon (IFN) therapy. METHODS: A total of 89 patients with chronic hepatitis C and 55 control (non-hepatitis) patients were asked to rate their experience of diurnal and nocturnal pruritus in the preceding week using a visual analogue scale (VAS) and a five-point scale, respectively. Blood samples were taken and serum thymus and activation-regulated chemokine (TARC) levels were measured by enzyme-linked immunosorbent assay. RESULTS: A significantly greater proportion of chronic hepatitis C patients experienced nocturnal pruritus compared with control (58.4% vs 5.5%, P < 0.0001). Chronic hepatitis C patients also had more severe pruritus compared with control patients, indicated by the higher mean VAS scores in both the IFN-treated and non-IFN-treated groups. In particular, patients who received combined peginterferon alfa-2b and ribavirin had significantly higher mean VAS scores than those receiving peginterferon alfa-2a or no IFN treatment. Serum TARC levels did not correlate with pruritus scores, and no significant differences in TARC levels were observed between the IFN-treated and non-IFN-treated groups. CONCLUSION: Patients with chronic hepatitis C experience pruritus more than those without. Serum TARC levels do not correlate with pruritus severity in chronic hepatitis C patients.

Effect of zinc on liver cirrhosis with hyperammonemia: a preliminary randomized, placebo-controlled double-blind trial.

OBJECTIVE: To our knowledge, no randomized study has shown whether zinc replacement therapy is effective for hyperammonemia in liver cirrhosis; therefore, we performed a double-blind, placebo-controlled trial to examine efficacy and safety of the zinc replacement therapy. METHODS: Patients with liver cirrhosis and hyperammonemia (at or above the institutional reference value) and hypozincemia (≤65 µg/dL) were enrolled in the outpatient units of the participating institutions and were randomly divided to receive placebo (P group) or zinc acetate preparation at a dose of 3 capsules/d for a total zinc content of 150 mg/d (Z group) by the envelope method. Of the 18 enrolled patients, 6 dropped out; thus, the analyses included 12 patients (5 in the P group and 7 in the Z group). Variations in blood concentrations of zinc and ammonia as well as liver function test results were compared. RESULTS: Blood zinc levels significantly increased in the Z group (P = 0.0037; Friedman test) but not the P group. Blood ammonia levels significantly decreased in the Z group (P = 0.0114; Friedman test) but not the P group. The percent change in blood ammonia level also revealed significant reduction at the eighth week in the Z group (P = 0.0188: Mann-Whitney test). No serious adverse events attributable to the zinc preparation were noted. CONCLUSION: Although this study is preliminary and includes a small sample, it is, to our knowledge, the first randomized controlled trial to show that zinc supplementation for 3 mo seems effective and safe for treating hyperammonemia in liver cirrhosis. Studies with a larger sample size are needed to confirm our findings.

Branched-chain amino acids prevent hepatocarcinogenesis and prolong survival of patients with cirrhosis.

BACKGROUND & AIMS: Although a low plasma level of branched-chain amino acids (BCAAs) is a marker of cirrhosis, it is not clear whether BCAA supplements affect disease progression. We performed a multicenter study to evaluate the effects of BCAA supplementation on hepatocarcinogenesis and survival in patients with cirrhosis. METHODS: We enrolled 299 patients from 14 medical institutions in Japan in a prospective, multicenter study in 2009; 267 patients were followed through 2011. Patients were given BCAA supplements (5.5-12.0 g/day) for more than 2 years (n = 85) or no BCAAs (controls, n = 182). The primary end points were onset of hepatocellular carcinoma (HCC) and death. Factors associated with these events were analyzed by competing risk analysis. RESULTS: During the study period, 41 of 182 controls and 11 of 85 patients given BCAAs developed HCC. On the basis of the Cox and the Fine and Gray models of regression analyses, level of α-fetoprotein, ratio of BCAA:tyrosine, and BCAA supplementation were associated with development of HCC (relative risk for BCAAs, 0.45; 95% confidence interval, 0.24-0.88; P = .019). Sixteen controls and 2 patients given BCAAs died. Factors significantly associated with death were Child-Pugh score, blood level of urea nitrogen, platelet count, male sex, and BCAA supplementation (relative risk of death for BCAAs, 0.009; 95% confidence interval, 0.0002-0.365; P = .015) in both regression models. CONCLUSIONS: On the basis of a prospective study, amino acid imbalance is a significant risk factor for the onset of HCC in patients with cirrhosis. BCAA supplementation reduces the risk for HCC and prolongs survival of patients with cirrhosis.

Guidelines on nutritional management in Japanese patients with liver cirrhosis from the perspective of preventing hepatocellular carcinoma.

AIM: The Japanese Nutritional Study Group for Liver Cirrhosis (JNUS) was assembled in 2008 with the support of a Health Labor Sciences Research Grant from the Ministry of Health, Labor and Welfare of Japan. The goal of the study group was to propose new nutritional guidelines for Japanese patients with liver cirrhosis (LC), with the aim of preventing hepatocellular carcinoma. METHODS: Between 2008 and 2010, the member investigators of JNUS conducted various clinical and experimental studies on nutrition on LC. These included anthropometric studies, a questionnaire study on daily nutrient intake, clinical trials, experimental studies using animal models, re-evaluation of previous publications and patient education. Over this 3-year period, the group members regularly discussed the nutritional issues related to LC, and a proposal was finally produced. RESULTS: Based on the results of JNUS projects and discussions among the members, general recommendations were made on how Japanese patients with LC should be managed nutritionally. These recommendations were proposed with a specific regard to the prevention of hepatocarcinogenesis. CONCLUSION: The new JNUS guidelines on nutritional management for Japanese patients with LC will be useful for the actual nutritional management of patients with LC. The JNUS members hope that these guidelines will form the basis for future discussions and provide some direction in nutritional studies in the field of hepatology.

[Effects of Calorie Mate Jelly eating before abdominal ultrasonography on the diagnosis--an evaluation in healthy adults].

In transabdominal ultrasonography, the production of gas in the gastro-intestinal tract and contraction of the gallbladder have to be prevented to obtain clear observation images of any lesions. Therefore, patients avoid food and drink for many hours from the night before the examination. However, long-term fasting exacerbates energy homeostasis in patients with cirrhosis. Thus, it is necessary to develop a method of transabdominal ultrasonography allowing the shortening of the fasting time. In this study, subjects ingested Calorie Mate Jelly three hours before transabdominal ultrasonography. Then, we studied the effect of the Jelly on ultrasonographic images. Three hours after its consumption, imaging diagnosis involving the liver, in liver, gallbladder, pancreas, spleen, and kidney could be successfully carried out in all healthy adults. Thus, our observations indicated that the abdominal organs can be effectively observed by transabdominal ultrasonography if Calorie Mate Jelly is consumed up to three hours before the examination. Calorie Mate Jelly may help to prevent worsening energy homeostasis in patients who are required to fast for a prolonged period.

Effects of late evening snack on diurnal plasma glucose profile in patients with chronic viral liver disease.

AIM: Glycemic control is important to improve the prognosis in cirrhotic patients with complications from diabetes. A late evening snack (LES) has been recommended for cirrhotic patients. We investigated the effects of LES on diurnal plasma glucose levels. METHODS: Subjects comprised 47 patients with chronic viral liver disease (chronic hepatitis, n = 11; cirrhosis, n = 36) treated in the Department of Gastroenterology & Hepatology, Dokkyo Medical University Koshigaya Hospital. Diurnal variations in plasma glucose were first investigated with three meals/day, in accordance with the European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines. Starting the next day, patients were given four meals including a LES, without changing meal content. Diurnal variations in plasma glucose were examined on day 7, and urine C-peptide immunoreactivity (CPR), and homeostasis model assessment insulin resistance (HOMA-IR) were investigated. RESULTS: With a LES, plasma glucose levels in patients with chronic hepatitis were significantly lower 2 hours before and 2 hours after dinner. In cirrhotic patients, significant decreases in plasma glucose levels were seen 2 hours after breakfast, before lunch, and before dinner. Significant decreases were noted in average plasma glucose levels and highest plasma glucose levels with four meals including a LES in patients with liver cirrhosis. This decrease was greater when maximum plasma glucose levels were higher on the three-meal regimen. CONCLUSIONS: Improvements in plasma glucose levels were seen with four meals per day, including a LES, in viral chronic liver disease, particularly cirrhosis.

Measurement of serum branched-chain amino acids to tyrosine ratio level is useful in a prediction of a change of serum albumin level in chronic liver disease.

AIM: In patients with hepatitis C virus (HCV)-associated chronic liver diseases, especially in those with liver cirrhosis, accurate evaluation of their protein nutrition status is very important to improve their quality of life. Whereas the serum albumin level is commonly used to evaluate patients' protein nutrition status, in the present study, the serum amino acid levels were measured, as they also provide valuable information. METHODS: Serum albumin levels and branched-chain amino acids (BCAA) to tyrosine ratio (BTR) were determined in 447 patients with HCV-associated chronic liver diseases (313 with chronic hepatitis and 134 with liver cirrhosis). RESULTS: Chronic hepatitis progressed to liver cirrhosis, serum albumin and serum BTR levels decreased significantlyas chronic hepatitis progressed to liver cirrhosis. Hypoalbuminemia was significantly more common in patients with liver cirrhosis than in those with chronic hepatitis; however, the incidence of an amino acid imbalance was significantly higher than that of hypoalbuminemia in patients with liver cirrhosis. The presence of an amino acid imbalance was associated with a reduction in the serum albumin level 1 year later. CONCLUSIONS: It is important to evaluate serum albumin levels and the BTR in patients with HCV-associated chronic liver diseases.

Effect of symptomatic gastroesophageal reflux disease on quality of life of patients with chronic liver disease.

AIM: Reflux esophagitis is becoming increasingly more prevalent in Japan. It has been noted that symptomatic gastroesophageal reflux disease (GERD) and chronic liver disease may adversely affect patients' quality of life. METHODS: In the present study, 238 chronic liver disease patients (151 patients with chronic hepatitis and 87 patients with liver cirrhosis) were enrolled. The diagnosis of GERD was made based on the Quality-of-Life and Utility Evaluation Survey Technology questionnaire. Health-related quality of life was evaluated using the Short Forum 36 questionnaire. RESULTS: Symptomatic GERD was present in 31.8% (48/151) of patients with chronic hepatitis and 36.8% (32/87) of patients with liver cirrhosis. Among the chronic hepatitis group, compared to the GERD-negative group, the GERD-positive group had significantly lower scores in six domains, including "rolelimitation due to physical problem", "bodily pain", "general health perception", "vitality", "role limitation due to emotional problem", and "mental health". Among the cirrhotic group, compared to the GERD-negative group, the GERD-positive group had significantly lower scores in the "role limitation due to emotional problem" domain. Significant improvement in the "physical functioning", "bodily pain", and "general health perception" domain scores was noted in chronic hepatitis patients treated with rabeprazole. CONCLUSION: The QOL of chronic liver disease patients with symptomatic GERD was impaired.

[Controversies in the determination of serum albumin concentration in chronic liver diseases].

OBJECTIVE: It is known that there is quantitative alteration in serum albumin in the patients with chronic liver diseases. To clarity the quantitative alteration of serum albumin, serum albumin levels were measured by the Bromcresol green (BCG) method, the modified Bromcresol purple (BCP) method and immunoassay. METHODS: We enrolled 313 patients with chronic hepatitis, 74 cirrhotic patients and 36 healthy subjects. Serum albumin levels were measured by immunoassay, the BCG method and the modified BCP methods. RESULTS: The measurement of immunoassay showed a significant correlation in the measurement of the modified BCP method in the patients with chronic liver diseases. With the progress of chronic liver diseases, the serum albumin levels by the BCG method and electrophoresis were higher than the levels by the modified BCP method. In other hands, it was 0.07 g/dl higher level in chronic hepatitis and 0.18 g/dl higher in liver cirrhosis. And the serum albumin levels by the BCG method and electrophoresis were higher than the levels by the new BCP method in the patients with leg edema and ascites. In the malnourished patients Subjective global assessment (SGA-B), the serum albumin levels by the BCG method and electrophoresis were higher than the levels by the modified BCP method. CONCLUSIONS: Serum albumin levels were different by the method for measurements. The clinical implications of quantitative changes in albumin should be investigated in consideration of the microheterogeneity of albumin. The modified BCP method is superior method to evaluate the serum albumin levels.

Erectile dysfunction in patients with chronic viral liver disease: its relevance to protein malnutrition.

BACKGROUND: In patients with chronic liver disease (CLD), quality of life is generally accepted as poor, especially for physical function. However, sufficient data regarding erectile function has not been shown in patients with CLD. The international index of erectile function (IIEF) is widely used to assess erectile function, and a short form of the IIEF was recently developed (IIEF-5). Using this questionnaire, we evaluated erectile dysfunction (ED) in patients with CLD. METHODS: A total of 117 Japanese patients (64 with chronic hepatitis [CH] and 53 with liver cirrhosis [LC]) were analyzed. The etiologies were hepatitis B virus (HBV) in 21, HCV in 94, and non-B non-C in 2. The IIEF-5 and Medical Outcomes Study Short Form 36 (SF-36) were administered to the patients, and biochemical analyses for items serum albumin, prothrombin time, bilirubin, and ammonia were also performed. RESULTS: The incidence of ED was 85% in the total cohort with CLD, 78% in those with CH, and 92% in those with LC (P < 0.05 between CH and LC). ED was found in 50% of CLD patients under age 50 years, in 79% aged 50-59, and in 100% aged over 60 (P, overall <0.001). The scores for ED severity correlated with increasing grades of a modified Child-Pugh classification (P < 0.05). Simple regression analysis showed age (P < 0.01), physical function (P < 0.001), role physical (P < 0.001), and social functioning (P < 0.05) on the SF-36, and serum albumin (P < 0.001) as significant determinants of ED. Multiple regression analysis identified age (P < 0.001) and serum albumin (P < 0.001) as independent significant factors that determined ED. CONCLUSIONS: These data clearly demonstrate that liver disease is the cause of ED in patients with CLD, and serum protein status could be relevant to this condition in these patients.

Clinical significance of KL-6, a marker of interstitial pneumonia, in cases of HCV-associated chronic liver disease.

OBJECTIVE: Various antiviral therapies, including interferon therapy, are being conducted to treat chronic hepatitis C and suppress the onset of hepatocellular carcinoma. However, interstitial pneumonia is beginning to be recognized as one of the adverse reactions of this therapy, and is one of the complications associated with chronic hepatitis. Therefore, we measured the level of KL-6, an interstitial pneumonia marker, in patients with HCV-associated chronic disease, and then determined the possibility of utilizing serum KL-6 as a predictive factor for interstitial pneumonia and the clinical significance of KL-6 in HCV-associated chronic disease. SUBJECTS AND METHODS: The subjects were 308 patients who were diagnosed with chronic liver disease through biochemical blood tests and abdominal diagnostic imaging. All patients tested positive for either the HCV antibody or HCV-RNA, and those who were suspected of having autoimmune hepatitis were excluded. One hundred eighty-five patients had chronic hepatitis (average age: 56 +/- 14 years), while 123 patients had liver cirrhosis (average age: 64 +/- 9 years). The purpose of the present study was explained to every subject, and informed consent was obtained. RESULTS: The mean KL-6 level for chronic hepatitis patients without interstitial pneumonia was 283.5 +/- 131.4 U/ml, while that for cirrhotic patients without interstitial pneumonia was significantly higher, at 377.6 +/- 212.1 U/ml (p<0.0001). In addition, with a cut-off value of 500 U/ml, the ratio of high KL-6 for the chronic hepatitis patients was 5.41% (10/185), while that for the cirrhotic patients was significantly higher, at 20.33% (25/123) (p<0.0001). Furthermore, the mean KL-6 level for patients with a serum hyaluronic acid level of less than 100 ng/ml was 258.4 +/- 124.6 U/ml, while that for patients with a serum hyaluronic acid level of 100 ng/ml or above was significantly higher, at 381.0 +/- 197.3 U/ml (p<0.0001). CONCLUSION: Although KL-6 is a marker of interstitial pneumonia, the results of the present study suggest that, in HCV-associated chronic disease, this marker reflects hepatic fibrosis better than pulmonary fibrosis.