Updated thresholds for alanine aminotransferase do not exclude significant histological disease in chronic hepatitis C

Background and aim: Histological changes in hepatitis C virus (HCV)‐infected patients with persistently normal alanine aminotransferase (PNALT) have not been evaluated for updated upper limits of normal (ULN; ≤19/30U/L for females/males). We assessed significant fibrosis (≥F2, METAVIR) in patients with PNALT and persistently elevated alanine aminotransferase (PEALT). Patients and methods: Nine hundred and twenty consecutive, unselected HCV patients were stratified into four groups: Group I: (n=124) PNALT within the updated ULN [0.5 × ULN (corresponding to ≤19 U/L) for females; 0.75 × ULN (corresponding to ≤30 U/L) for males]; Group II (n=173): PNALT≤1 × ULN but greater than Group I; Group III (n=313): PEALT 1–2 × ULN; and Group IV (n=310): PEALT>2 × ULN. PNALT was defined as ≥3 determinations within the normal range over ≥6 months. Results: Advanced ≥F3 and ≥F2 fibrosis increased incrementally across Groups I; II; III; and IV: 24.2 and 45.2%; 25.4 and 56.1%; 36.1 and 64.2%; and 50 and 77.1% respectively (P<0.0001 for both). Multivariable logistic regression analysis identified age [odds ratio (OR), 1.05; 95% confidence intervals (CI): 1.02–1.08; P<0.0001], alanine aminotransferase (ALT) groups (OR 1.38; 95% CI: 1.03–1.83; P=0.030), presence of moderate–severe steatosis (OR 2.70; 95% CI: 1.19–6.15; P=0.018) and ≥A2 necroinflammation (OR 17.9; 95% CI: 8.88–36.20; P<0.0001) as independent predictors of ≥F2 fibrosis. Updated ULN for ALT were better at excluding ≥F2 fibrosis compared with traditional ULN (90.6 vs. 74.2%, P=0.0041) but less specific (20.8 vs. 44%, P=0.0007) with similar positive/negative predictive values. Conclusions: HCV patients with ‘updated’ normal ALT have the lowest prevalence of significant fibrosis, although utilizing these levels without resorting to biopsy would miss significant fibrosis in almost one‐half of such patients.     

Studies on human chorionic gonadotropin secretion: effects of EGTA, lanthanum, and the ionophore A23187.

Human malignant trophoblast cells that secrete human chorionic gonadotropin (hCG) in culture were employed to assess the calcium requirement for hormone production. Cellular and secreted hCG was measured by radioimmunoassay. Cells cultured for 7 h in Ca2+- and Mg2-free medium or in Ca2+-free medium, secreted less hCG than cells cultured in medium containing Ca2+. Addition of ethylene glycol bis (beta-aminoethyl ether)N,N'-tetraacetic acid (EGTA), ethylenediamine tetraacetic acid (EDTA), or La2+ inhibited hCG release from the cells, but did not affect the amount of hCG in the cells. Inhibition of hCG release was dependent on time of incubation and on concentration of agent added. Inhibition of hCG secretion by EGTA was reversed upon removal of the EGTA from the culture fluid or by addition of equimolar Ca2+ to the fluid. These results demonstrated that divalent cations, probably Ca2+, are required for release and further synthesis of hCG. Addition of the divalent cation ionophore A23187 (0.1 to 10 muM) failed to increase hCG secretion by the malignant trophoblast, in contrast to the stimulatory effect of this agent in other secretory systems. Incubation of the cells for 15 to 60 min with 10 muM A23187 reduced hCG secretion, and this inhibition was reversed upon removal of the ionophore from the culture fluid. The studies with the ionophore supported other evidence indicating basic differences between hormone secretory mechanisms in the trophoblast compared to other endocrine tissues.     

Clinical value of chromosome arms 19q and 11p losses in low-grade gliomas

Background

Diffuse low-grade gliomas (LGGs) form a heterogeneous subgroup of gliomas in adults. Chromosome (chr) arms 1p/19q codeletion and IDH mutation have been shown to be closely associated with oligodendroglial phenotype and better prognosis. We sought to identify relevant biomarkers in non 1p/19q codeleted LGGs.

Methods

We characterized a retrospective series of 126 LGGs using genomic arrays, microsatellite analysis, IDH sequencing, MGMT promoter methylation assay, and p53 expression analysis.

Results

Our study confirms that 1p/19q codeletion, mutually exclusive with p53 overexpression, was associated with: (i) better prognosis, (ii) oligodendroglial phenotype, (iii) MGMT promoter methylation, and (iv) IDH mutation. Interestingly, 1p/19q codeleted tumors occur in older patients at diagnosis. Our study shows that non 1p/19q codeleted LGGs can be divided in 5 main genomic subgroups: (i) 11p loss, (ii) 19q loss (iii) 7 gain, (iv) 19 gain, and (v) unclassified. In non 1p/19q codeleted LGGs, we demonstrated that (i) 11p loss is associated with astrocytoma phenotype and has an independent negative prognostic value, and (ii) 19q loss diminished the favorable prognostic value of IDH mutation. Our findings were validated in an independent cohort of 98 LGGs.

Conclusion

Novel genomic entities and biomarkers have been identified in non 1p/19q codeleted LGGs. Our findings may help to stratify non 1p/19q codeleted LGGs, facilitating future individualization of treatment. Further prospective studies are warranted to support our findings.     

Hepatic Fibrinogen Storage Disease Due to the Fibrinogen γ375 Arg → Trp Mutation “Fibrinogen Aguadilla” is present in Arabs

The mutation γ375Arg → Trp (fibrinogen Aguadilla) is one of four mutations (Brescia, Aguadilla, Angers, and AI duPont) capable of causing hepatic storage of fibrinogen. It has been observed in four children from the Caribbean, Europe, and Japan, suffering from cryptogenic liver disease. We report the first case of hepatic fibrinogen storage disease in Arabs due to a mutation in the fibrinogen γ-chain gene in a 3-year-old Syrian girl presenting with elevated liver enzymes. The finding of an impressive accumulation of fibrinogen in liver cells raised the suspicion of endoplasmic reticulum storage disease. Sequencing of the fibrinogen genes revealed a γ375Arg → Trp mutation (fibrinogen Aguadilla) in the child and in her father. In conclusion, when confronted with chronic hepatitis of unknown origin, one should check the plasma fibrinogen level and look carefully for the presence of hepatocellular intracytoplasmic globular inclusions to exclude hepatic fibrinogen storage disease.     

Choriocarcinoma: Blocking factor and monoclonal antibody iodine 131 imaging

Postoperative iodine 131 monoclonal antibody localization in metastatic choriocarcinoma was accomplished in this study. The monoclonal antibody was prepared to male choriocarcinoma which cross reacted with gestational choriocarcinoma. The antibody was raised against whole choriocarcinoma cells and human chorionic gonadotropin (hCG) cross reactivity was excluded. The purified antibody was iodinated with ¹³¹I and successfully imaged BeWo choriocarcinoma transplanted in nude mice; however, imaging of choriocarcinoma in a patient was verified only after resection. It is our belief that failure to sufficiently concentrate the antibody in the tumor before operation was due to blocking factor in the serum of the patient. Blocking factor and hCG dropped postoperatively. Blocking factor activity in 15 patients with metastatic trophoblastic disease was monitored and, like hCG, was found to be a sensitive indicator of the presence of disease. Its efficacy may be in the small number of patients without hCG but with persistent disease.     

Electron microscopic and biochemical patterns of the normal and malignant trophoblast

The malignant trophoblast in cell culture (BeWo line) known to produce human chorionic gonadtropin (HCG) consists of single cells with cytoplasmic ultrastructures similar to that of the placental cytotrophoblast. One of the striking features of the trophoblastic cells is the excessive accumulation of cytoplasmic glycogen, which may be depleted by epinephrine, and, to a lesser extent, by glucose “starvation.” Glycogenolysis is accompanied by a concomitant increase of endoplasmic reticulum. Hence, the development of this cytoplasmic organelle may reflect at least two different phases of functional activity in trophoblastic cells: (1) hormone synthesis and (2) carbohydrate metabolism. It is cocluded that the cytotrophoblast, in addition to its role as progenitor of syncytium, also actively synthesizes HCG. Hormone synthesis may be reflected by the development of endoplasmic reticulum but is not determined by the phase of differentiation of trophoblastic cells at which syncytium is formed. The enzyme pattern of the BeWo cells resembles that of other malignant tumors. A mucoprotein layer surrounding the BeWo cells is revealed by colloidal iron stain, and its significance is discussed. Present studies indicate that the placenta at term is still an actively functioning organ.