Clinical significance of hepatitis B surface antigen mutants

Hepatitis B virus (HBV) infection is a major public health problem in many countries, with nearly 300 million people worldwide carrying HBV chronic infection and over 1 million deaths per year due to cirrhosis and liver cancer. Several hepatitis B surface antigen (HBsAg) mutations have been described, most frequently due to a single amino acid substitution and seldom to a nucleotide deletion. The majority of mutations are located in the S region, but they have also been found in the pre-S1 and pre-S2 regions. Single amino acid substitutions in the major hydrophilic region of HBsAg, called the “a” determinant, have been associated with immune escape and the consequent failure of HBV vaccination and HBsAg detection, whereas deletions in the pre-S1 or pre-S2 regions have been associated with the development of hepatocellular carcinoma. This review article will focus on the HBsAg mutants and their biological and clinical implications.     

Hepatitis B virus infection in immigrant populations

Hepatitis B virus (HBV) is the most common cause of hepatitis worldwide, with nearly 350 million people chronically infected and 600000 deaths per year due to acute liver failure occurring during acute hepatitis or, more frequently, in HBV-related liver cirrhosis or hepatocellular carcinoma. Ongoing immigration from countries with a high HBV endemicity to those with a low HBV endemicity warrants particular attention to prevent the spread of HBV infection to the native population. This review article analyzes the epidemiology and virological and clinical characteristics of HBV infection in immigrant populations and in their host countries, and suggests prophylactic measures to prevent the spread of this infection. Among the immigrants from different geographical areas, those from South East Asia and sub-Saharan Africa show the highest prevalences of hepatitis B surface antigen (HBsAg) carriers, in accordance with the high endemicity of the countries of origin. The molecular characteristics of HBV infection in immigrants reflect those of the geographical areas of origin: HBV genotype A and D predominate in immigrants from Eastern Europe, B and C in those from Asia and genotype E in those from Africa. The literature data on the clinical course and treatment of HBsAg-positive immigrants are scanty. The management of HBV infection in immigrant populations is difficult and requires expert personnel and dedicated structures for their assistance. The social services, voluntary operators and cultural mediators are essential to achieve optimized psychological and clinical intervention.     

miR-15b/16-2 deletion promotes B-cell malignancies

The central role of the microRNA (miR) 15a/16-1 cluster in B-cell oncogenesis has been extensively demonstrated, with over two-thirds of B-cell chronic lymphocytic leukemia characterized by the deletion of the miR-15a/16-1 locus at 13q14. Despite the well-established understanding of the molecular mechanisms occurring during miR-15a/16-1 dysregulation, the oncogenic role of other miR-15/16 family members, such as the miR-15b/16-2 cluster (3q25), is still far from being elucidated. Whereas miR-15a is highly similar to miR-15b, miR-16-1 is identical to miR-16-2; thus, it could be speculated that both clusters control a similar set of target genes and may have overlapping functions. However, the biological role of miR-15b/16-2 is still controversial. We generated miR-15b/16-2 knockout mice to better understand the cluster’s role in vivo. These mice developed B-cell malignancy by age 15–18 mo with a penetrance of 60%. At this stage, mice showed significantly enlarged spleens with abnormal B cell-derived white pulp enlargement. Flow cytometric analysis demonstrated an expanded CD19+ CD5+ population in the spleen of 40% knockout mice, a characteristic of the chronic lymphocytic leukemia-associated phenotype found in humans. Of note, miR-15b/16-2 modulates the CCND2 (Cyclin D2), CCND1 (Cyclin D1), and IGF1R (insulin-like growth factor 1 receptor) genes involved in proliferation and antiapoptotic pathways in mouse B cells. These results are the first, to our knowledge, to suggest an important role of miR-15b/16-2 loss in the pathogenesis of B-cell chronic lymphocytic leukemia.MicroRNAs (miRNAs) are a class of small noncoding RNAs that modulate gene expression in many physiological and pathological conditions (1). Altered miRNA expression has been reported in several human cancers, and miRNA expression profiles vary according to the considered tumor (2).A role for miRNAs in tumorigenesis and progression was originally documented for the miR-15/16 family (2–5). This group of miRNAs encompasses the miR-15a/16-1 cluster (on chromosome 13q14,) the miR-15b/16-2 cluster (on chromosome 3q25), and the miR-195/497 cluster (on chromosome 17p13).The role of the miR-15a/16-1 cluster in B-cell pathology has been extensively demonstrated (5). The deletion of the miR-15a/16-1 cluster has been reported in over two-thirds of B-cell chronic lymphocytic leukemias (B-CLLs) (5). Our group has demonstrated that the loss of miR-15a/16-1 expression induces higher levels of the antiapoptotic proteins BCL2 and myeloid cell leukemia sequence 1 (BCL2-related) (MCL1) (3, 6). Moreover, this deletion promotes mature B-cell expansion by deregulating the transition from G1 to S phase (7).On the other hand, the biological role of miR-15b/16-2 is still controversial, as this cluster has been reported to behave as either a tumor suppressor [acute promyelocytic leukemia (8, 9) and osteosarcoma (10)] or an oncogene [melanoma (11), up-regulated in the plasma of colorectal cancer (12) and head and neck carcinoma (13)].Because the miR-15a/16-1 and miR-15b/16-2 clusters share miRNAs that are highly similar or, in the case of miR-16, identical, it is possible that they control a similar set of target genes and have overlapping functions.To better characterize the role of miR-15b/16-2 in tumorigenesis and tumor progression, we generated a conventional miR-15b/16-2 knockout mouse model. By the age of 15–18 mo, miR-15b/16-2 knockout mice developed lymphoproliferative disorders closely resembling human B-CLL, with diffuse lymph node enlargement and severe splenomegaly due to the expansion of a CD19+ CD5+ double positive population of neoplastic B cells.     

hepatitis B virus burden in developing countries

Hepatitis B virus(HBV) infection has shown an intermediate or high endemicity level in low-income countries over the last five decades. In recent years, however, the incidence of acute hepatitis B and the prevalence of hepatitis B surface antigen chronic carriers have decreased in several countries because of the HBV universal vaccination programs started in the nineties. Some countries, however, are still unable to implement these programs, particularly in their hyperendemic rural areas. The diffusion of HBV infection is still wide in several low-income countries where the prevention, management and treatment of HBV infection are a heavy burden for the governments and healthcare authorities. Of note, the information on the HBV epidemiology is scanty in numerous eastern European and Latin-American countries. The studies on molecular epidemiology performed in some countries provide an important contribution for a more comprehensive knowledge of HBV epidemiology, and phylogenetic studies provide information on the impact of recent and older migratory flows.     

Low birth weight and later development of insulin resistance and biochemical/clinical features of polycystic ovary syndrome

Reduced insulin sensitivity in adult life has been reported in subjects born at term small for gestational age (SGA) and in those born prematurely with very low birth weight (LBW) (<1,500 g). We assessed whether LBW (<2,500 g) young women, irrespective of whether they were born SGA or adequate for gestational age (premature AGA), exhibited a reduction in insulin sensitivity through a prospective historical design. The risk of developing biochemical and clinical features of polycystic ovary syndrome was also investigated. The study population included 35 LBW women (19 SGA [BW range, 1,000-2,400 g] and 16 premature AGA [BW range, 1,700-2,440 g]) aged 21.8 +/- 1.8 years and 35 term AGA controls, of similar age, recruited from a neonatal registry. All women underwent clinical, ultrasonographic, hormonal, and metabolic evaluations, including the composite insulin sensitivity index. Women under hormonal contraception (21.4%) were excluded from hormonal and metabolic analyses. Composite insulin sensitivity index was significantly lower in LBW women even when the 2 LBW subgroups, SGA and premature AGA, were analyzed separately (4.4 +/- 2.2 and 4.0 +/- 1.7, respectively) than in controls (6.9 +/- 4.4). The LBW women showed a significantly higher incidence proportion of irregular menses (14/35 [40%] vs 2/35 [5.7%]) and a significantly higher free androgen index (5.8 +/- 3.5 vs 3.9 +/- 3.2). They also showed a nonsignificantly higher proportion of hirsutism, acne, and polycystic ovaries. In conclusion, LBW (<2,500 g) young women, irrespective of whether they were SGA and premature AGA, exhibited a reduction in insulin sensitivity as compared with born at term AGA women. Furthermore, they exhibited an increased risk of developing clinical and biochemical features of polycystic ovary syndrome.     

Epidemiological and clinical aspects of hepatitis B virus infection in Italy over the last 50 years

A relevant gradual reduction of both the incidence rate of acute hepatitis B (AHB) and prevalence of chronic hepatitis B has occurred in Italy in the last 50 years, due to substantial epidemiological changes: Improvement in socioeconomic and hygienic conditions, reduction of the family unit, accurate screening of blood donations, abolition of re-usable glass syringes, hepatitis B virus (HBV)-universal vaccination started in 1991, use of effective well tolerated nucleo(t)side analogues able to suppress HBV replication available from 1998, and educational mediatic campaigns against human immunodeficiency virus infection focusing on the prevention of sexual and parenteral transmission of infections. As an example, AHB incidence has gradually decreased from 10/100000 inhabitants in 1985 to 0.21 in 2020. Unfortunately, the coronavirus disease 2019 (COVID-19) pandemic has interrupted the trend towards HBV eradication. In fact, several HBV chronic carriers living in the countryside have become unable to access healthcare facilities for screening, diagnosis, clinical management, and nucleo(t)side analogue therapy in the COVID-19 pandemic, mainly for anxiety of becoming infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), movement restrictions, and reduced gains from job loss. In addition, one-third of healthcare facilities and personnel for HBV patients have been devolved to the COVID-19 assistance.     

Serum and Bile Lipids in Young Women with Radiolucent Gallstones

To investigate the relationship between blood and bile lipids, serum cholesterol, high density lipoprotein cholesterol, and triglycerides were correlated with cholesterol saturation index of bile in 21 women-10 with radiolucent gallstones and 11 without stones. All of the women had regular menstrual cycles, were normolipidemic, and on a hospital diet. On the same morning, blood and the darkest duodenal bile were taken after cholecystokinin (CCK) stimulation. Standard laboratory procedures were used to analyze serum and bile lipids. We found: 1) statistically significant (t test, p less than 0.05) but only slight hypercholesterolemia (+ 12%) in patients with gallstones; 2) a negative correlation of serum cholesterol with cholesterol saturation index of bile, both in the control group (r = -0.654, p less than 0.05) and in gallstone patients (r = -0.665, p less than 0.05); 3) a correlation of high density lipoprotein cholesterol with cholesterol saturation index only in normal women (r = -0.619, p less than 0.05); 4) conversely, a correlation of triglycerides with the same index in only gallstone patients (r = 0.641, p less than 0.05). With the stepwise multiple regression analysis (independent variables: diagnosis of gallstones, serum cholesterol, HDL cholesterol, triglycerides; dependent variable: biliary cholesterol saturation index), only gallstone diagnosis and serum cholesterol influenced significantly (F test, p less than 0.05) the biliary cholesterol saturation index. These findings suggest that young women with radiolucent gallstones are slightly hypercholesterolemic, that in women both with and without gallstones there is a negative correlation between serum cholesterol and biliary cholesterol saturation, but women with gallstones have a higher cholesterol saturation index of the bile than women without gallstones with the same level of cholesterol in the blood.     

Frontal gray matter atrophy in middle aged adults with type 1 diabetes is independent of cardiovascular risk factors and diabetes complications

AimsTo determine if regional gray matter volume (GMV) differences in middle-aged adults with and without type-1 diabetes (T1D) are localized in areas most vulnerable to aging, e.g. fronto-subcortical networks; and if these differences are explained by cardiovascular risk factors and diabetes complications.MethodsRegional GMV was computed using 3 T MRI of 104 adults with a childhood onset of T1D (mean age: 49 ± 7 and duration: 41 ± 6 years) and 151 adults without diabetes (mean age: 40 ± 6). A Bonferroni threshold (n = 45, p ≤ 0.001) was applied to account for multiple between-group comparisons and analyses were repeated in an age- and gender-matched subset of participants with T1D and controls (n = 44 in each group, mean age [SD] and range: 44.0, [4.3], 17.4 and 44.6 [4.3], 17.0, respectively).ResultsCompared to controls, T1D patients had smaller GMV in the frontal lobe (6% to 19% smaller) and adjacent supramarginal and postcentral gyri (8% to 13% smaller). Between-group differences were independent of age, waist circumference, systolic blood pressure, fasting total cholesterol and smoking status and were similar in sensitivity analyses restricted to age- and gender-matched participants. Associations between GMV and diabetes complications were not significant.ConclusionsThese findings extend the notion of accelerated brain aging in T1D to middle-aged adults. The pathophysiology of frontal gray matter atrophy and its impact on future development of disability and dementia need further study, especially as middle-aged T1D patients progress to older age.     

Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia

Isolated methylmalonic acidemia (MMA), caused by deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT), is often complicated by end stage renal disease that is resistant to conventional therapies, including liver transplantation. To establish a viable model of MMA renal disease, Mut was expressed in the liver of Mut^−/− mice as a stable transgene under the control of an albumin (INS-Alb-Mut) promoter. Mut^−/−;Tg^INS-Alb-Mut mice, although completely rescued from neonatal lethality that was displayed by Mut^−/− mice, manifested a decreased glomerular filtration rate (GFR), chronic tubulointerstitial nephritis and ultrastructural changes in the proximal tubule mitochondria associated with aberrant tubular function, as demonstrated by single-nephron GFR studies. Microarray analysis of Mut^−/−;Tg^INS-Alb-Mut kidneys identified numerous biomarkers, including lipocalin-2, which was then used to monitor the response of the GFR to antioxidant therapy in the mouse model. Renal biopsies and biomarker analysis from a large and diverse patient cohort (ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT00078078","term_id":"NCT00078078"}}NCT00078078) precisely replicated the findings in the animals, establishing Mut^−/−;Tg^INS-Alb-Mut mice as a unique model of MMA renal disease. Our studies suggest proximal tubular mitochondrial dysfunction is a key pathogenic mechanism of MMA-associated kidney disease, identify lipocalin-2 as a biomarker of increased oxidative stress in the renal tubule, and demonstrate that antioxidants can attenuate the renal disease of MMA.