Liver cirrhosis in a patient with alcohol dependence and autoimmune hepatitis.

BACKGROUND: Liver cirrhosis is the end-stage entity for a wide variety of chronic liver pathologies. These include viral hepatitis B and C, alcoholic liver disease, non-alcoholic fatty liver disease, hemochromatosis, Wilson disease, autoimmune hepatitis, primary sclerosing cholangitis, and primary biliary cirrhosis. In the majority of cases, liver cirrhosis remains completely asymptomatic until acute decompensation occurs. Patients may present complications of portal hypertension such as gastro-esophageal varices and upper digestive hemorrhage, ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, or hepato-renal syndrome. Establishing the right etiology of cirrhosis is of paramount importance as it helps the treating physician plan the best suitable treatment options and also improves overall outcome. CASE REPORT: We present a case of a chronic alcohol consumer, which, over time, resulted in alcoholic cirrhosis. Initial diagnosis comprised of alcoholic liver disease. However, a further look into the medical history of the patients indicated the presence of underlying autoimmune liver disease, such as autoimmune hepatitis, which might have also contributed to the chronic liver injury. CONCLUSIONS: Multiple factors can lead to liver cirrhosis. Although the most commonly found entity is alcoholism, it cannot be taken as a thumb rule for the only possible etiology. In-depth analysis and proper differential diagnosis should be carefully conducted in order not to miss out on other possible causes. As seen in our case, where an underlying autoimmune hepatitis was found to be the culprit, but due to a long history of alcohol consumption, it was masked at first instance.

Serum biomarkers predictive of cirrhosis in alcoholic liver disease as an alternative to ARFI-SW elastography.

OBJECTIVE: Aspartate aminotransferase to platelet ratio index (APRI) and fibrosis 4 (FIB-4) index are noninvasive biomarkers that evaluate liver stiffness in patients with chronic viral hepatitis and are able to detect advanced hepatic fibrosis and cirrhosis. However, their usefulness in alcoholic liver disease (ALD), when compared with Acoustic Radiation Force Impulse- Shear Wave (ARFI-SW) elastography, is debatable. PATIENTS AND METHODS: We sifted the files of all enrolled patients with ALD that were admitted to our Emergency hospital between January 2019 and December 2020. All patients had undergone ARFI-SW elastography, and APRI and FIB-4 scores were calculated. The performance of APRI and FIB-4 scores in the prediction of cirrhotic patients according to ARFI-SW elastography was evaluated. RESULTS: In total, 120 patients with ALD were evaluated. All of them were male and Caucasian, with a mean age of 55.54±12.4 years. The mean ARFI-SW elastography score was 1.57±0.7 m/s, the median APRI score was 0.68 (0.1-11.6) and the median FIB-4 score was 1.8 (0.2-19.4). Stages of liver fibrosis according to ARFI-SW elastography were evaluated as F0-1 in 21 (10.5%), F2 in 35 (26%), F3 in 52 (17.5%), and F4 in 92 (46%) patients. Based on ARFI-SW elastography fibrosis stage classification, we estimated the optimal APRI and FIB-4 scores to predict the presence of liver cirrhosis (F4) by using ROC curve analysis and the Youden index. The optimal APRI score for F4 patients was calculated as >1.52 [area under the curve (AUC) 0.875, 95% CI 0.809-0.919; p<0.001], giving sensitivity (Se) 81.2%, specificity (Sp) 81.4%, positive predictive value (PPV) 76%, and negative predictive value (NPV) 86.1%. The optimal FIB-4 score for F4 patients was calculated as >2.77 (AUC 0.916, 95% CI 0.814-0.922; p<0.001), giving Se 83.8%, Sp 77%, 81.4 77%, and NPV 84.3%. CONCLUSIONS: APRI and FIB-4 scores can be used as screening tools in ALD for predicting cirrhosis instead of ARFI-SW elastography measurement, which is neither widely available nor an affordable method. Additional prospective studies are required in the future to confirm this finding.

Clozapine and risperidone influence on cortisol and estradiol levels in male patients with schizophrenia.

Estrogens role in schizophrenia patients is a subject, which has gained an increased attention from the medical community. Estrogens have been shown to inhibit dopamine actions, improve neuronal regeneration, and overall, have a protective role in the pathology of schizophrenia. The adjunctive estrogen therapy for men is currently under debate. Antipsychotic medication is known to influence the hypothalamo-hypophyseal - gonadal axis by inducing variable degrees of hyperprolactinemia. Several studies have found that some of the atypical antipsychotics lower cortisol levels in patients and also in healthy controls. We have investigated the effects of clozapine and risperidone on estradiol levels in men with schizophrenia. We have also evaluated the levels of prolactin and cortisol, taking into account the possible influence of antipsychotic drugs on both these hormones. Both prolactin and cortisol also have the potential to regulate sexual hormones biosynthesis. Our study found decreased estradiol levels in men with schizophrenia treated with clozapine and risperidone, while prolactin levels were increased only in the risperidone treated group. Cortisol levels are not statistically significant different between groups.

Venous versus arterial iron administration in haemodialysis. Influence on erythrocytes antioxidant parameters.

Introduction Intravenous iron administration in patients treated by haemodialysis for end stage renal disease can exacerbate oxidative stress by increasing the level of free redox active iron. A way to reduce the impact of iron on oxidative stress in haemodialysis patients may be the administration of iron through arterial extracorporeal circuit. Objective The aim of our study was to compare the influence of iron route of administration (venous versus arterial extracorporeal circuit infusion) on antioxidant parameters in red blood cells of haemodialysis patients in order to clarify if arterial iron administration can have positive impacts related to iron induced oxidative stress. Method Twenty stable patients on regular haemodialysis treatment were selected for the study. They were investigated in a cross-over design at 3 mid-week HD sessions, one week apart, without iron [HD basal] and with either IV infusion of 100mg iron sucrose over the first 20 minutes of HD session, via venous line [HDvenous], or the same solution infused on the arterial extracorporeal circulation [HDarterial]. Blood samples were drawn at 0 min, 40 min and 270 min. Erythrocytes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) activity, non-protein thiol levels and total antioxidant capacity (TEAC) were analysed. Conclusion Haemodialysis significantly decreases the total antioxidant activity in erythrocytes. Iron supplementation, through venous or arterial extracorporeal route has no impact on the total antioxidant activity in red blood cells. Venous iron administration increases GPx activity in erythrocytes suggesting increased lipid peroxidation compared with arterial extracorporeal administration.

Biochemical changes and treatment in glaucoma.

Glaucoma is the second cause of blindness worldwide. This disease is a neurodegenerative disorder characterized by high intraocular pressure, loss of retinal ganglion cells (apoptosis). Even though there is much research done in this field, the results have not yet managed to stop the progression of glaucoma or to heal this pathology. Free oxygen radicals play a major role; they are formed in the aqueous humor and in the vitreous and they produce apoptosis of the neurons in the optic nerve head, degradation of the trabecular meshwork cells. The purpose of the article is to help in trying to understand the physiopathology of glaucoma and the efficacy of its treatments.

The regulator of calcineurin (RCAN1) an important factor involved in atherosclerosis and cardiovascular diseases development.

Atherosclerosis, one of the main causes of cardiovascular diseases, is a complex process that involves manifold factors. Besides the vascular lipids accumulation, inflammatory factors could be considered as a proatherogenic factor - RCAN1. RCAN1 is a regulator of calcineurin, both of them being calcium dependent proteins. Recent studies have shown that RCAN1 has an important role in heart valve development. In the same time researchers found that, the atherosclerotic plaques have an up-regulated RCAN1 gene expression. In the near future, it is desirable to elucidate the RCAN1 function and classify it as a possible biochemical marker to diagnose infancy atherosclerosis.

Influence of GSH synthesis inhibition on temporal distribution of NAD+/NADH during vascular endothelial cells proliferation.

Pathological conditions states such as stroke, diabetes mellitus, hypertension, dyslipidemia are associated with increased levels of free radicals that alter normal function of the vascular endothelium and perturb vascular homeostasis. The redox couples reduced glutathione (GSH)/oxidized glutathione (GSSG), NADH/NAD+, and NADPH/NADP+ play major functions in the intracellular redox balance. Any decrease in tissue or systemic GSH levels under the aforementioned pathologies would enhance oxidative damage to the vascular endothelium. Beside their role as coenzyme that participate in cellular metabolism, pyridine nucleotides serve also as substrate for enzymes involved in DNA repair and longevity. There is scant data on NAD+/NADH kinetics and distribution during human cells proliferation. Here, we determined the influence of cellular GSH status on the early dynamics of nuclear-to-cytosol (N-to-C) NAD+ and nuclear NADH kinetics (6 h interval) over 72 h of endothelial cell proliferation. The IHEC cell line was used as a surrogate for human brain micro vascular endothelial cells. Inhibition of GSH synthesis by buthionine sulfoximine (BSO) and sustained low cellular GSH significantly increased nuclear NADH levels (p<0.01), which correlated with lower nuclear GSH and prolonged cell cycle S-phase. When BSO was removed the pattern of nuclear NAD+ resembled that of control group, but nuclear NADH concentrations remained elevated, as in GSH deficient cells (p<0.01). The coincidence of high nuclear NADH and lower nuclear NAD+ with S-phase prolongation are suggestive of CtBP and NAD+-dependent DNA repair enzyme activation under conditions of decreased cellular GSH. These results provide important insights into GSH control of vascular endothelial growth and restitution, key processes in the restoration of the endothelium adjacent to the post-injury lesion site.

Increase in total antioxidant capacity of plasma despite high levels of oxidative stress in uncomplicated type 2 diabetes mellitus.

OBJECTIVE: Oxidative stress is implicated in the pathophysiology of diabetes mellitus and its chronic complications. The aim of this study was to evaluate plasma antioxidant status in patients with uncomplicated type 2 diabetes, in order to understand the interactions between its components and the diabetic milieu. METHODS: Plasma samples were collected from 15 patients with type 2 diabetes receiving oral antidiabetic agents and from 18 healthy control subjects without diabetes. Glycosylated haemoglobin was measured as an indicator of blood glucose control. Total and residual antioxidant activities were measured. Lipid peroxides were measured as indicators of plasma oxidative stress. Copper and caeruloplasmin were also assayed as possible pro-oxidants. RESULTS: Antioxidant activities, lipid peroxide level, copper concentration and caeruloplasmin activity were significantly increased in the plasma of patients with diabetes compared with control subjects. CONCLUSIONS: The total antioxidant capacity of plasma was increased, despite high levels of oxidative stress, in patients with uncomplicated type 2 diabetes. Increased levels of copper and caeruloplasmin characterized the diabetic milieu, despite an absence of chronic complications.

Can ageing be slowed?: Hormetic and redox perspectives.

Redox metabolism has long been considered to play important roles in aging and the development of age-related diseases. Both dietary and pharmacological manipulations of redox metabolism have been associated with the extension of lifespan. Increasing new evidence s also suggests that the process of aging may derive from imperfect clearance of oxidatively damaged material. The accumulation of this molecular "garbage", relatively indigestible, further hinders cellular functions, induces progressive failure of maintenance and repair and increases the probability of death. One important trend in anti-aging strategy is, therefore, to prevent or even revert the accumulation of these oxidatively altered molecules by stimulating the maintenance and repair systems through hormesis. A promising approach for slowing down ageing and achieving a healthy senescence is represented by repeated exposure to various mild stresses (caloric restriction, moderate exercise, nutritional or pharmacological hormetins). This article reviews the potential therapeutic tools available to date for increasing longevity and obtaining and successful ageing from the redox and hormetic perspective.

Protection of erythrocyte membrane against oxidative damage by geriforte in healthy human subjects.

The influence of Geriforte, an Ayurvedic natural supplement, on the antioxidant defense systems in human erythrocytes and plasma was investigated in an open human clinical study. The ability of Geriforte to inhibit the azo-bis 2-amidinopropane dihydrochloride (AAPH) dependent lysis of erythrocytes was also evaluated. Geriforte supplementation increased the activity of erythrocyte catalase (265.745 +/- 15.768 vs. 352,329 +/- 18.480 K/g Hb/mL, p < 0.01) and reduced the free radical mediated cytotoxicity induced by azo-bis 2-amidinopropane dihydrochloride (AAPH), which was measured by erythrocyte membrane stability assay (0.0439 +/- 0.0069 vs. 0.1291 +/- 0.0396 C50- AAPH (mM), p < 0.05). The intervention did not change significantly the activity of erythrocyte superoxide dismutase and the plasma levels of antioxidant agents. The results indicate that Geriforte possesses cytoprotective properties on erythrocytes against oxidative challenge and specific antioxidant activity, which involves mainly the intracellular protective systems and the membranes.

So many options but one choice: the human body prefers alpha-tocopherol. A matter of stereochemistry.

alpha-Tocopherol belongs to the group of vitamin E vitamers. Recent years findings indicate that alpha-tocopherol is more than just a simple fat-soluble anti-oxidant as it was found that it can also regulate gene expression. From all vitamin E vitamers human body preferentially retains alpha-tocopherol, but the reasons for this preference are still elusive. Different studies indicated that human body, through the action of two hepatic proteins, alpha-tocopherol transfer protein (alpha-TTP) and cytochrome P450 4F2 (CYP4F2), is able to make subtle structural differences between different vitamin E forms. This is an example of stereochemistry used as a discrimination factor between molecules with different biological activities.

The oxidative hypothesis of senescence.

The oxidative hypothesis of senescence, since its origin in 1956, has garnered significant evidence and growing support among scientists for the notion that free radicals play an important role in ageing, either as "damaging" molecules or as signaling molecules. Age-increasing oxidative injuries induced by free radicals, higher susceptibility to oxidative stress in short-lived organisms, genetic manipulations that alter both oxidative resistance and longevity and the anti-ageing effect of caloric restriction and intermittent fasting are a few examples of accepted scientific facts that support the oxidative theory of senescence. Though not completely understood due to the complex "network" of redox regulatory systems, the implication of oxidative stress in the ageing process is now well documented. Moreover, it is compatible with other current ageing theories (e.g, those implicating the mitochondrial damage/mitochondrial-lysosomal axis, stress-induced premature senescence, biological "garbage" accumulation, etc). This review is intended to summarize and critically discuss the redox mechanisms involved during the ageing process: sources of oxidant agents in ageing (mitochondrial -electron transport chain, nitric oxide synthase reaction- and non-mitochondrial- Fenton reaction, microsomal cytochrome P450 enzymes, peroxisomal beta -oxidation and respiratory burst of phagocytic cells), antioxidant changes in ageing (enzymatic- superoxide dismutase, glutathione-reductase, glutathion peroxidase, catalase- and non-enzymatic glutathione, ascorbate, urate, bilirubine, melatonin, tocopherols, carotenoids, ubiquinol), alteration of oxidative damage repairing mechanisms and the role of free radicals as signaling molecules in ageing.

IL-6 - STAT-3 - hepcidin: linking inflammation to the iron metabolism.

Recently discovered peptide hormone hepcidin is the key regulator of systemic iron homeostasis. Iron metabolism is regulated in response to variations in hepcidin plasma levels. Hepcidin levels that are inappropriately low or high result in iron overload or iron deficiency, respectively. The early studies showed that hypoxia, iron concentration, and inflammation influence hepcidin levels, but the exact mechanism remained elusive. Very recently, different research groups discovered that IL-6, through the Jak/STAT-3 signaling pathway, is involved in regulation of hepcidin levels in response to inflammatory stimuli. In this review we present a general view of hepcidin biology, with emphasis on regulation in inflammatory conditions.

Oxidative stress parameters in hemodialysis patients with or without diabetes.

Oxidative stress (imbalance of antioxidant and prooxidants in favour of the later) is considered to be a feature of diabetes and chronic renal failure. Carbonyl stress defined as accumulation of reactive carbonyl compounds due to excess production or disturbed clearance from the body is thought to amplify oxidative stress in these conditions. The accumulation of carbonyl compounds can be also a consequence of oxidative stress. A vicious cycle can thus be formed. We have studied the association between carbonyl stress markers (dicarbonyl compounds, Amadori products) and oxidative stress markers (total plasmatic thiols and malondialdehyde level) in hemodialysed patients with or without diabetes taking into account the levels of possible excess substrates (glucose and triglycerides). We have concluded that hemodialysed diabetes patients are more susceptible to oxidative stress than hemodialysed patients without diabetes.

Hepcidin the link between inflammation and anemia in chronic renal failure.

A chronic inflammatory state characterized the patients with chronic renal failure. The causes of this situation are multiple and inter-connected. The break of the equilibrium between pro-inflammatory agents and anti-inflammatory ones in haemodialysis patients leads to anemia of chronic inflammation, characterized by a functional iron deficiency. Very recently it was discovered a peptide produced by the liver, named hepcidin, that provides a good link between inflammation and metabolism of iron, rendering more understandable the interdependence of inflammation and anemia.

A spectrophotometric assay of folic acid concentrations in rats: correlations with age and organ.

Spectrophotometric assays have been used to determine FA concentration in tissue homogenates from various organs (liver, kidneys, brain, spleen) in white rats; these studies were undertaken to test the age--and organ--dependent variations of FA concentrations in tissue homogenates. The results showed a marked decrease of FA concentration in the adult group of rats when related to the young group, and in the aged group when compared to the adults respectively. Analysing the determined values of folates in tissue homogenates of various organs (in rats belonging to the same group of age), the highest concentration has been found in the liver homogenate, followed in decreasing order by kidneys and to a much greater distance, by the brain and spleen.

Folic acid age correlation established on folates determinations in cell homogenates.

From the available data, there has resulted that folic acid quantity in homogenate, coming from various organs, collected from young animals is much larger than for the other age categories. These results may be correlated with intense cell proliferation and development processes that take place in the young tissues as compared to rather low values established from grown-ups and old ranges. When comparing the folates quantity found in homogenate resulting from various organs we may ascertain that, if the folates are related to grams of tissue under the test, they are more in spleen than in kidneys, liver and brains respectively. If the folates are reported to tissue protein milligrams it may be ascertained that a larger quantity of folates is found in the brains than in the other studied organs that may be due to big dilution of the proteins in the brains.

Histochemical localization of folic acid in the cells.

Smears, fresh cryotome sections (dried at 4 degrees C for 24 h), and deparaffinized sections were used for the "in situ" localization of folic acid. After irradiation with ultraviolet light, folic acid breaks down into a pteridine and a diazotizable amine. After oxidation and a brief hydrolysis, glyoxylic acid formed from the pteridine can be vizualized by a coupling agent, indicating the sites of folic acid in the cell.

The kinetics of the histochemical method for dihydrofolate dehydrogenase (dihydrofolate reductase).

The purpose of the present investigation is to report some histochemical and cytospectrophotometric observations providng more objective evidence for the specific activity of the histochemical method for dihydrofolate reductase activity (5.6.7.8-tetrahydrofolate: E.C. 1.5.1.3). Kinetic factors of the enzymic reaction, such as fixation, pH, coenzymes, substrate concentration, Michaelis constant, temperature, time of incubation, aerobiosis, and anaerobiosis, activators and inhibitors, were investigated.