Edoardo G. Giannini

Liver enzyme alteration: a guide for clinicians

ISOLATED ALTERATIONS OF BIOCHEMICAL MARKERS OF LIVER DAMAGE in a seemingly healthy patient can present a challenge for the clinician. In this review we provide a guide to interpreting alterations to liver enzyme levels. The functional anatomy of the liver and pathophysiology of liver enzyme alteration are briefly reviewed. Using a schematic approach that classifies enzyme alterations as predominantly hepatocellular or predominantly cholestatic, we review abnormal enzymatic activity within the 2 subgroups, the most common causes of enzyme alteration and suggested initial investigations.

Platelet count/spleen diameter ratio: proposal and validation of a non-invasive parameter to predict the presence of oesophageal varices in patients with liver cirrhosis

Background and aims: Cirrhotic patients frequently undergo screening endoscopy for the presence of oesophageal varices (OV). In the future, this social and medical burden will increase due to the greater number of patients with chronic liver disease and their improved survival. In this study, our aims were (1) to identify clinical, biochemical, and ultrasonographic parameters which might non-invasively predict the presence of OV in patients with liver cirrhosis; (2) to evaluate the reproducibility of the obtained results in a different, although related, further group of patients; and (3) to assess the predictiveness of the identified rules in patients with compensated cirrhosis. Methods: In the first part of the study we retrospectively evaluated the presence of OV in 145 cirrhotic patients, and in the second part we evaluated the reproducibility of the study results in a subsequent group of 121 patients. Finally, we evaluated these parameters in a subgroup of 145 patients with compensated disease. All 266 patients underwent a complete biochemical workup, upper digestive endoscopy, and ultrasonographic measurement of spleen bipolar diameter. Platelet count/spleen diameter ratio was calculated for all patients. Results: The prevalence rates of OV were 61% and 58% in the first and second groups of patients, respectively. In the first part of the study, we found that platelet count, spleen diameter, platelet count/spleen diameter ratio, and Child- Pugh class were significantly different among patients with or without OV, although the platelet count/spleen diameter ratio was the only parameter which was independently associated with the presence of OV in a multivariate analysis. A platelet count/spleen diameter ratio cut off value of 909 had 100% negative predictive value for a diagnosis of OV. This result was reproduced in the second group of patients as well as in patients with compensated disease. In a cost-benefit analysis, screening cirrhotic patients according to the “platelet count/spleen diameter ratio strategy” was far more cost effective compared with the “scope all strategy”. Conclusions: The platelet count/spleen diameter ratio is the only parameter which is independently associated with the presence of OV, and its negative predictive value is reproducible. Its use is of value even in the subgroup of patients with compensated disease, and it is also cost effective.

MELD scoring system is useful for predicting prognosis in patients with liver cirrhosis and is correlated with residual liver function: a European study

Background: Indices for predicting survival are essential for assessing prognosis and assigning priority for liver transplantation in patients with liver cirrhosis. The model for end stage liver disease (MELD) has been proposed as a tool to predict mortality risk in cirrhotic patients. However, this model has not been validated beyond its original setting. Aim: To evaluate the short and medium term survival prognosis of a European series of cirrhotic patients by means of MELD compared with the Child-Pugh score. We also assessed correlations between the MELD scoring system and the degree of impairment of liver function, as evaluated by the monoethylglycinexylidide (MEGX) test. Patients and methods: We retrospectively evaluated survival of a cohort of 129 cirrhotic patients with a follow up period of at least one year. The Child-Pugh score was calculated and the MELD score was computed according to the original formula for each patient. All patients had undergone a MEGX test. Multivariate analysis was performed on all variables to identify the parameters independently associated with one year and six month survival. MELD values were correlated with both Child-Pugh scores and MEGX test results. Results: Thirty one patients died within the first year of follow up. Child-Pugh and MELD scores, and MEGX serum levels were significantly different among patients who survived and those who died. Serum creatinine, international normalised ratio, and MEGX60 were independently associated with six month mortality while the same variables and the presence of ascites were associated with one year mortality. MELD scores showed significant correlations with both MEGX values and Child-Pugh scores. Conclusions: In a European series of cirrhotic patients the MELD score is an excellent predictor of both short and medium term survival, and performs at least as well as the Child-Pugh score. An increase in MELD score is associated with a decrease in residual liver function.

Platelet Count/Spleen Diameter Ratio for the Noninvasive Diagnosis of Esophageal Varices: Results of a Multicenter, Prospective, Validation Study

BACKGROUND AND AIMS:Noninvasive assessment of esophageal varices (EV) may improve the management of patients with cirrhosis and decrease both the medical and financial burden related to screening. In this multicenter, international study, our aim was to prospectively validate the use of the platelet count/spleen diameter ratio for the noninvasive diagnosis of EV.METHODS:A total of 218 cirrhotic patients underwent screening endoscopy for EV. Platelet count/spleen diameter ratio ((N/mm3)/mm) was assessed in all patients and its diagnostic accuracy was calculated. On the basis of previous results, a platelet count/spleen diameter ratio cutoff of 909 was applied to this population. The diagnostic accuracy of the platelet count/spleen diameter ratio was further evaluated for both severity and etiology of disease subgroups.RESULTS:Prevalence of EV was 54.1%. The platelet count/spleen diameter ratio had 86.0% (95% CI, 80.7–90.4%) diagnostic accuracy for EV, which was significantly greater as compared with either accuracy of platelet count alone (83.6%, 95% CI 78.0–88.3%, P = 0.038) or spleen diameter alone (80.2%, 95% CI 74.3–85.3%, P = 0.018). The 909 cutoff had 91.5% sensitivity (95% CI 85.0–95.9%), 67.0% specificity (95% CI 56.9–76.1%), 76.6% positive predictive value, 87.0% negative predictive value, 2.77 positive likelihood ratio, and 0.13 negative likelihood ratio for the diagnosis of EV. Accuracy of the platelet count/spleen diameter ratio was maintained for both severity and etiology of disease subgroups.CONCLUSIONS:The platelet count/spleen diameter ratio may be proposed as a safe and reproducible means to improve the management of cirrhotic patients who should undergo screening endoscopy for EV.

Semiannual surveillance is superior to annual surveillance for the detection of early hepatocellular carcinoma and patient survival

BACKGROUND & AIMS The current guidelines recommend the surveillance of cirrhotic patients for early diagnosis of hepatocellular carcinoma (HCC), based on liver ultrasonography repetition at either 6 or 12 month intervals, since there is no compelling evidence of superiority of the more stringent program. This study aimed at comparing cancer stage, treatment applicability, and survival between patients on semiannual or annual surveillance. METHODS We analyzed the clinical records of 649 HCC patients in Child-Pugh class A or B, observed in ITA.LI.CA centers. HCC was detected in 510 patients submitted to semiannual surveillance (Group 1) and in 139 submitted to annual surveillance (Group 2). In Group 1 the survival was presented as observed and corrected for the lead time. RESULTS The cancer stage was less severe in Group 1 than in Group 2 (p<0.001), with more single tiny (2 cm) and less advanced tumors. Treatment applicability was improved by the semiannual program (p=0.020). The median observed survival was 45 months (95% CI 40.0-50.0) in Group 1 and 30 months (95% CI 24.0-36.0) in Group 2 (p=0.001). The median corrected survival of Group 1 was 40.3 months (95% CI 34.9-45.7) (p=0.028 with respect to the observed survival of Group 2). Age, platelet count, alpha-fetoprotein, Child-Pugh class, cancer stage, and hepatocellular carcinoma treatment were independent prognostic factors. CONCLUSIONS Semiannual surveillance increases the detection rate of very early hepatocellular carcinomas and reduces the number of advanced tumors as compared to the annual program. This translates into a greater applicability of effective treatments and into a better prognosis.

Eltrombopag before Procedures in Patients with Cirrhosis and Thrombocytopenia

BACKGROUND Eltrombopag is an oral thrombopoietin-receptor agonist. This study evaluated the efficacy of eltrombopag for increasing platelet counts and reducing the need for platelet transfusions in patients with thrombocytopenia and chronic liver disease who are undergoing an elective invasive procedure. METHODS We randomly assigned 292 patients with chronic liver disease of diverse causes and platelet counts of less than 50,000 per cubic millimeter to receive eltrombopag, at a dose of 75 mg daily, or placebo for 14 days before a planned elective invasive procedure that was performed within 5 days after the last dose. The primary end point was the avoidance of a platelet transfusion before, during, and up to 7 days after the procedure. A key secondary end point was the occurrence of bleeding (World Health Organization [WHO] grade 2 or higher) during this period. RESULTS A platelet transfusion was avoided in 104 of 145 patients who received eltrombopag (72%) and in 28 of 147 who received placebo (19%) (P<0.001). No significant difference between the eltrombopag and placebo groups was observed in bleeding episodes of WHO grade 2 or higher, which were reported in 17% and 23% of patients, respectively. Thrombotic events of the portal venous system were observed in 6 patients who received eltrombopag, as compared with 1 who received placebo, resulting in the early termination of the study. The incidence and severity of other adverse events were similar in the eltrombopag and placebo groups. CONCLUSIONS Eltrombopag reduced the need for platelet transfusions in patients with chronic liver disease who were undergoing elective invasive procedures, but it was associated with an increased incidence of portal-vein thrombosis, as compared with placebo. (Funded by GlaxoSmithKline; ELEVATE ClinicalTrials.gov number, NCT00678587.).

Review article: thrombocytopenia in chronic liver disease and pharmacologic treatment options

In patients with liver disease, thrombocytopenia is a clinical feature that may represent an obstacle to invasive diagnostic or therapeutic procedures, chemotherapy, and anti‐viral treatment. Stimulation of the bone marrow is the most promising therapeutic intervention for thrombocytopenia in patients with chronic liver disease.

Progressive Liver Functional Impairment Is Associated with an Increase in AST/ALT Ratio

The ratio of serum aspartate aminotransferase toalanine aminotransferase (AST/ALT ratio) has beenproposed as a noninvasive method of assessing liverfibrosis and cirrhosis. Our aims were to confirm the usefulness of the AST/ALT ratio in diagnosingcirrhosis noninvasively as well as to verify theexistence of a relationship between the ratio and liverfunctional impairment. In all, 348 patients (177 with chronic hepatitis, 171 with cirrhosis) wereretrospectively evaluated and the AST/ALT ratio wasrelated to monoethyl glycine xylidide (MEGX) formation.Moreover, in a subgroup of 54 patients we analyzed the relationships among the AST/ALT ratio andindocyanine green clearance and half-life. The AST/ALTratio was able to separate patients with mild fibrosisfrom those with severe fibrosis and cirrhosis. The AST/ALT ratio, MEGX, prothrombin activity,and platelet count were selected by multivariateanalysis as variables associated with cirrhosis. TheAST/ALT ratio showed significant correlations both with MEGX formation and with indocyanine greenclearance and half-life. The alterations of indocyaninegreen kinetics, which depend upon liver blood flow anduptake, were likely due to progressive fibrosis. These findings might partially explain theincrease in the AST/ALT ratio as diseaseprogresses.

Position paper of the Italian Association for the Study of the Liver (AISF): The multidisciplinary clinical approach to hepatocellular carcinoma

Patients with hepatocellular carcinoma should be managed with a multidisciplinary approach framed in a network where all the diagnostic techniques and therapeutic resources are available in order to provide the optimal level of care. Given this assumption, the Coordinating Committee of the Italian Association for the Study of the Liver nominated a panel of experts to elaborate practical recommendations for the multidisciplinary management of hepatocellular carcinoma aiming to provide: (1) homogeneous and efficacious diagnostic and staging work-up, and (2) the best treatment choice tailored to patient status and tumour stage at diagnosis. The 2010 updated American Association for the Study of Liver Disease Guidelines for hepatocellular carcinoma were selected as the reference document. For each management issue, the American Association for the Study of Liver Disease recommendations were briefly summarised and discussed, according to both the scientific evidence published after their release and the clinical expertise of the Italian centres taking care of these patients. The Italian Association for the Study of the Liver expert panel recommendations are finally reported.

Serum leptin levels in patients with viral chronic hepatitis or liver cirrhosis

BACKGROUND/AIM Serum levels of leptin, the adipocyte-derived hormone regulating food intake and energy expenditure in mammals, have been found to be increased in cirrhotic patients. The aim of the present study was to investigate leptin serum level in relation to anthropometric features and liver function in patients with viral chronic hepatitis or liver cirrhosis. METHODS Serum leptin levels were determined by radioimmunoassay in 30 male and 10 female patients with chronic hepatitis, in 42 male and 10 female patients with liver cirrhosis, and in four respective control groups. Liver function was evaluated by the monoethylglycinexylidide formation test. Body mass index and body fat mass were estimated by weight, height and skinfold thickness measurements. RESULTS Compared with controls, absolute serum leptin levels were significantly (p<0.01) lower in chronic hepatitis patients and similar in cirrhotic patients. Leptin serum levels were significantly (p<0.05) higher in cirrhotic than in chronic hepatitis patients. When expressed in relation to body fat mass, the above differences persisted; however, cirrhotic females showed significantly (p<0.05) higher serum leptin values than controls. Serum leptin values correlated negatively (p<0.01) with monoethylglycinexylidide serum values in all groups of patients. CONCLUSIONS In patients with chronic viral liver disease, serum leptin levels tend to increase as liver function worsens. This may reflect a decline in the ability to downregulate energy expenditure as an adaptation to anorexia and/or to defective substrate utilisation due to liver disease and may negatively influence body weight homeostasis in these patients.