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Background It is unclear whether the efficacy and long-term outcome of treating patients with hepatitis C virus (HCV)-positive cirrhosis with the new protease inhibitors will extend to those with Child C cirrhosis. Aim To assess the effectiveness of the interferon-free regimens in Child C cirrhotic patients with HCV infection. Methods A systematic Medline search was conducted to retrieve studies describing the treatment of Child C patients with direct-acting agents. Citations from identified studies were cross-referenced and abstracts from European Association for the Study of the Liver ( EASL) and American Association for the Study of Liver Disease ( AASLD) meetings were checked. Extracted data were evaluated using a meta-analysis to calculate a weighted response rate. Results Seven full-text records and two conference abstracts were retained for analysis from the 649 records identified. Data from an Italian real-life trial were also interrogated. Information on treatment outcome was available for 228 of the 240 Child C patients evaluated in the 10 trials. Overall, the weighted mean sustained virological response (SVR12) was 74.9% (95% CI: 65.6-82.4%). Neither duration of treatment (24 or 12 weeks), nor addition of ribavirin influenced these rates. The weighted SVR12 was 65.4% (95% CI: 46.8-80.2) after sofosbuvir/simeprevir, 76.0% (95% CI: 54.4-89.3%) after sofosbuvir/daclatasvir and 83.0% (95% CI: 73.4-89.6) after sofosbuvir/ledipasvir. Some studies did not provide information on the rate of post-treatment relapse or functional improvement. However, in those studies that did provide such data, a relapse was documented in 12.1% of patients and an improvement of ≥2 points on the model for end-stage liver disease ( MELD) score in 61.1% of patients. Conclusion The improvement in MELD scores strongly suggests HCV-positive patients with Child C cirrhosis should be treated with these agents. [ABSTRACT FROM AUTHOR]

Background Several studies have shown that weight changes are common in patients with coeliac disease after starting a gluten-free diet (GFD), but data on the prevalence of metabolic syndrome in this population are still scarce. Aims To assess the prevalence of metabolic syndrome in patients with CD at diagnosis and 1 year after starting GFD. Methods We enrolled all consecutive patients with newly diagnosed coeliac disease (CD) who were referred to our third-level CD Unit. For all patients we collected: waist circumference, BMI, blood pressure, lipid profile (HDL cholesterol, triglycerides) and levels of blood glucose. Diagnosis of metabolic syndrome was made according to the International Diabetes Federation (IDF) criteria for European countries. The prevalence of metabolic syndrome was re-assessed after 12 months of GFD. Results Ninety-eight patients with CD were assessed, two patients with CD (2%) fulfilled the diagnostic criteria for metabolic syndrome at diagnosis and 29 patients (29.5%) after 12 months of GFD ( P < 0.01; OR: 20). With regard to metabolic syndrome sub-categories 1 year after GFD compared to baseline respectively: 72 vs. 48 patients exceeded waist circumference cut-off ( P < 0.01; OR: 2.8); 18 vs. 4 patients had high blood pressure ( P < 0.01; OR: 5.2); 25 vs. 7 patients exceeded glycemic threshold ( P = 0.01; OR: 4.4); 34 vs. 32 patients with CD had reduced levels of HDL cholesterol ( P = 0.7); and 16 vs. 7 patients had high levels of triglycerides ( P = 0.05). Conclusions Patients with coeliac disease show a high risk of metabolic syndrome 1 year after starting a gluten-free diet. We suggest that an in-depth nutritional assessment is undertaken for all patients with coeliac disease. [ABSTRACT FROM AUTHOR]

Background The new ESPGHAN guidelines for diagnosis of paediatric coeliac disease suggest to avoid biopsy in genetically pre-disposed and symptomatic individuals with positive anti-endomysial antibodies (EMA) and anti-tissue transglutaminases (a- tTG). However, duodenal biopsy remains the gold standard in adult coeliac disease. Aims To establish the cut-off values of a- tTG, which would: predict the presence of duodenal histology (Marsh ≥2) diagnostic for coeliac disease; and predict the presence of villous atrophy (Marsh 3) in adults. Methods We performed an observational prospective study including all consecutive adult patients with suspected coeliac disease. All subjects were tested for EMA and a- tTG. Coeliac disease diagnosis was made in presence of Marsh ≥2, a- tTG >7 U/mL and positive EMA. A ROC curve was constructed to establish the best specificity cut-off of a- tTG levels, which would predict the presence of Marsh ≥2 and Marsh 3 at histology. Results The study included 310 patients with positive antibodies. Histology showed Marsh 1 in 8.7%, Marsh 2 in 3.5%, Marsh 3 in 87.7%. The best cut-off value of a- tTG for predicting Marsh ≥2 was 45 U/mL (sensitivity 70%; specificity 100%; PPV 100%; NPV 24.1%); the best cut-off for predicting villous atrophy was 62.4 U/mL (sensitivity 69%, specificity 100%; PPV 100%; NPV 31%). Conclusions The diagnosis of coeliac disease can be reached without histology in adult patients with positive EMA and a- tTG levels >45 U/mL. An a-tTG level >62.4 was diagnostic for villous atrophy. These results could contribute to improving the diagnosis of coeliac disease by allowing for a significant reduction in diagnosis-related costs. [ABSTRACT FROM AUTHOR]

There is a lack of information on the characteristics of patients with chronic hepatitis C virus infection (HCV) who fail to respond to antiviral treatment. We studied HCV-positive subjects with chronic liver diseases treated with pegylated-interferon (PEG-IFN) and ribavirin (RBV) who failed to clear HCV in routine clinical practice. A total of 2150 consecutive adult patients treated with PEG-IFN plus RBV therapy in 46 Italian centres between 1 July 2004, and 30 June 2005, were studied. Of the 2150 patients, 923 (42.9%) (M/F 585/335, mean age 54.8 years) failed to achieve a serum HCV-RNA clearance. Of these 923 patients, 429 (46.5%) were nonresponders, 298 (32.3%) relapsers, 168 (18.2%) drop-outs for noncompliance or adverse events and 28 (3.0%) were lost during follow-up. Overall, 642 (70.6%) patients received adequate therapy (defined as more than 80% of the drug doses for >80% of the time). Genotypes 1–4 were observed in 76.9% of cases; genotypes 2–3 in 21.2% and mixed in 1.9%, respectively. Multiple logistic regression analysis identified genotypes 1 and 4 as the sole independent predictors of the likelihood of nonresponse to therapy compared with relapse (OR: 4.38; 95% CI = 2.28–8.4). Age older than 65 years was the sole independent factor associated with no adherence to therapy (OR: 2.22; 95% CI = 1.36–3.62). Patients who fail to respond to treatment are a nonhomogeneous population with different features, and the sole factor that discriminates nonresponse from relapse is the distribution of genotypes 1–4. Co-morbidities are unable to determine the type of treatment failure and inadequate adherence to therapy mostly affects patients older than 65 years of age. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) infection is associated with a significant reduction of health related quality of life (QOL), the causes and mechanisms of which are still unknown. To explore whether treatment history could affect QOL, we examined patients with detectable HCV viraemia who had a different therapeutic background. Two hundred sixty-four consecutive subjects with chronic HCV infection and detectable viraemia were enrolled. Of these, 163 were untreated patients, 43 were relapsers, 58 were nonresponders (NR) to nonpegylated interferon (IFN) therapy. To assess QOL, three self-report instruments were employed: the Short Form-36 (SF-36), the Chronic Liver Disease Questionnaire (CLDQ-I) and the World Health Organization Quality of Life assessment (WHOQOL-BREF). Clinical and demographic data were collected, and the QOL scores of HCV-positive patients were compared with those of an Italian normative sample and healthy controls. Further antiviral treatment was offered to untreated and relapsed patients but not to NR. All patient groups displayed lower QOL scores compared with the normative sample and controls. NR displayed lower QOL scores in several areas compared with untreated patients and relapsers. In multivariate regression analyses, being NR and having a physical comorbidity were significantly associated with poorer QOL. Conclusions: Treatment history and expectations and physical comorbidity may affect QOL in HCV-positive patients. Untreated and relapsed patients have comparable levels of QOL and higher scores than NR. [ABSTRACT FROM AUTHOR]

Summary Background : The consumption of unfiltered coffee, containing bioactive diterpenes, causes an increase in plasma homocysteine concentration. A slight increase in plasma homocysteine is also caused by large quantities of filtered coffee. Coffee terpenes also raise plasma glutathione in mice. Aim : To verify the effect of Italian-style coffee consumption on the plasma concentration of glutathione and homocysteine in healthy subjects. Methods : Twenty-two volunteers consumed five cups of coffee per day for 1 week and maintained their usual diet. Five subjects were enrolled as controls. The intervention trial was preceded and followed by seven coffee-free days. Results : Plasma glutathione increased by 16% (P < 0.05) on coffee consumption, and returned to the original concentration after the washout period. The increase in plasma homocysteine concentration (13% after 1 week of coffee intake) was not significant. No differences in glutathione or homocysteine concentration were observed in the control group. No variation of plasma hydroperoxide concentration was detectable. Conclusions : A coffee intake regimen, representing the average consumption of coffee drinkers in Italy, increased the plasma concentration of glutathione, but no significant increase in the plasma homocysteine concentration was detected. [ABSTRACT FROM AUTHOR]

Linked Content This article is linked to Steenbergen et al paper. To view this article visit https://doi.org/10.1111/apt.13964. [ABSTRACT FROM AUTHOR]

Background: While mucosal healing has been proved to predict relevant clinical outcomes in Crohn's disease (CD), little is known about the long-term significance of transmural healing., Aims: To prospectively assess the 1-year clinical outcomes in CD patients achieving transmural healing following treatment with biologics, and to compare them with those in patients reaching only mucosal healing or no healing., Methods: Observational longitudinal study, evaluating 1-year outcomes in terms of steroid-free clinical remission, rate of hospitalisation and need for surgery in a group of CD patients treated with anti-tumour necrosis factor (TNF) alpha for 2 years. Bowel sonography was used in all patients to determine transmural healing., Results: Of 218 patients who completed a 2-year treatment course with anti-TNF alpha, 68 (31.2%) presented transmural (plus mucosal) healing (bowel wall thickness ≤3 mm at bowel sonography), 60 (27.5%) mucosal healing only, and 90 (41.3%) did not achieve any intestinal healing. Transmural healing was associated with a higher rate of steroid-free clinical remission (95.6%), lower rates of hospitalisation (8.8%) and need for surgery (0%) at 1 year compared to mucosal (75%, 28.3% and 10%, respectively) and no healing (41%, 66.6% and 35.5%, respectively) (P < 0.001). Furthermore, transmural healing was associated with longer intervals until clinical relapse (HR, hazard ratio 0.87, P = 0.01), hospitalisation (HR 0.88, P = 0.002) and surgery (HR 0.94, P = 0.008) than mucosal healing. Also among patients discontinuing treatment with biologics, transmural healing predicted better clinical outcomes at 1 year than mucosal healing (P = 0.01)., Conclusions: Transmural healing is an ambitious and powerful treatment goal associated, to a greater extent than mucosal healing, with improvement of all clinical outcomes. Additionally, transmural healing is associated with better long-term clinical outcomes than mucosal healing also after discontinuation of biologics., (© 2019 John Wiley & Sons Ltd.)

Background & Aims: Advances in direct-acting antiviral treatment of HCV have reinvigorated public health initiatives aimed at identifying affected individuals. We evaluated the possible impact of only diagnosed and linked-to-care individuals on overall HCV burden estimates and identified a possible strategy to achieve the WHO targets by 2030., Methods: Using a modelling approach grounded in Italian real-life data of diagnosed and treated patients, different linkage-to-care scenarios were built to evaluate potential strategies in achieving the HCV elimination goals., Results: Under the 40% linked-to-care scenario, viraemic burden would decline (60%); however, eligible patients to treat will be depleted by 2025. Increased case finding through a targeted screening strategy in 1948-1978 birth cohorts could supplement the pool of diagnosed patients by finding 75% of F0-F3 cases. Under the 60% linked-to-care scenario, viraemic infections would decline by 70% by 2030 but the patients eligible for treatment will run out by 2028. If treatment is to be maintained, a screening strategy focusing on 1958-1978 birth cohorts could capture 55% of F0-F3 individuals. Under the 80% linked-to-care scenario, screening limited in 1968-1978 birth cohorts could sustain treatment at levels required to achieve the HCV elimination goals., Conclusion: In Italy, which is an HCV endemic country, the eligible pool of patients to treat will run out between 2025 and 2028. To maintain the treatment rate and achieve the HCV elimination goals, increased case finding in targeted, high prevalence groups is required., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Metabolic disorders are well-known risk factors for HCC. Conversely, their impact on the natural history of HCC is not established. This study aimed at evaluating the impact of metabolic disorders on clinical features, treatment and survival of HCC patients regardless of its aetiology., Methods: We analysed the ITA.LI.CA database regarding 839 HCC patients prospectively collected. The following metabolic features were analysed: BMI, diabetes, arterial hypertension, hypercholesterolaemia and hypertriglyceridaemia. According to these features, patients were divided into 3 groups: 0-1, 2 and 3-5 metabolic features., Results: As compared with patients with 0-1 metabolic features, patients with 3-5 features showed lower percentage of HCC diagnosis on surveillance (P = .021), larger tumours (P = .038), better liver function (higher percentage of Child-Pugh class A [P = .007] and MELD < 10 [P = .003]), higher percentage of metastasis (P = .024) and lower percentage of portal vein thrombosis (P = .010). The BCLC stage and treatment options were similar among the 3 groups, with the exception of a less frequent access to loco-regional therapies for BCLC stage B patients with 3-5 features (P = .012). Overall survival and survival according to BCLC stage and/or treatment did not significantly differ among the 3 groups. Only using a probabilistic sensitivity analysis, diabetic patients showed a lower survival (P = .046). MELD score, HCC morphology, nodule size, BCLC stage, portal vein thrombosis and metastasis were independent predictors of lead-time adjusted survival., Conclusions: Our "real world" study suggests that metabolic disorders shape the clinical presentation of HCC but do not seem to play a major role in setting patient survival., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We investigated the role of HFE C282Y, H63D, and TMPRSS6 A736V variants in the pathogenesis of iron deficiency anemia (IDA) in celiac disease (CD) patients, at diagnosis and after 1 year of gluten-free diet (GFD). Demographic and clinical features were prospectively recorded for all CD patients between 2013 and 2017. C282Y, H63D, and A736V variants were evaluated for CD patients and controls. Finally, 505 consecutive CD patients and 539 age-matched control subjects were enrolled. At diagnosis, 229 CD subjects had IDA (45.3%), with a subgroup of anemic patients (45.4%) presented persistent IDA at follow-up. C282Y allele frequency was significantly increased in CD compared with controls (1.1% vs 0.2%, P = .001), whereas H63D and A736V allele frequencies were similar among patients and controls (P = .92 and .84, respectively). At diagnosis, C282Y variant in anemic CD patients was significantly increased compared to nonanemic group (2% and 0.5%, P = .04). At follow-up, A736V was significantly increased in IDA persistent than in IDA not persistent (57.7% vs 35.2%, P < .0001). CD patients with H63D mutation showed higher Hb, MCV, serum iron, and ferritin levels than subjects without HFE mutations. Decreased hepcidin values were observed in anemic compared to nonanemic subjects at follow-up (1.22 ± 1.14 vs 2.08 ± 2.15, P < .001). This study suggests a protective role of HFE in IDA CD patients and confirms the role of TMPRSS6 in predicting oral iron response modulating hepcidin action on iron absorption. Iron supplementation therapeutic management in CD could depend on TMPRSS6 genotype that could predict persistent IDA despite iron supplementation and GFD., (© 2017 Wiley Periodicals, Inc.)

Background & Aims: Despite the excellent efficacy of direct-acting antivirals (DAA) reported in clinical trials, virological failures can occur, often associated with the development of resistance-associated substitutions (RASs). This study aimed to characterize the presence of clinically relevant RASs to all classes in real-life DAA failures., Methods: Of the 200 virological failures that were analyzed in 197 DAA-treated patients, 89 with pegylated-interferon+ribavirin (PegIFN+RBV) and 111 without (HCV-1a/1b/1g/2/3/4=58/83/1/6/24/25; 56.8% treatment experienced; 65.5% cirrhotic) were observed. Sanger sequencing of NS3/NS5A/NS5B was performed by home-made protocols, at failure (N=200) and whenever possible at baseline (N=70)., Results: The majority of the virological failures were relapsers (57.0%), 22.5% breakthroughs, 20.5% non-responders. RAS prevalence varied according to IFN/RBV use, DAA class, failure type and HCV genotype/subtype. It was 73.0% in IFN group vs 49.5% in IFN free, with the highest prevalence of NS5A-RASs (96.1%), compared to NS3-RASs (75.9% with IFN, 70.5% without) and NS5B-RASs (66.6% with IFN, 20.4% without, in sofosbuvir failures). In the IFN-free group, RASs were higher in breakthrough/non-responders than in relapsers (90.5% vs 40.0%, P<.001). Interestingly, 57.1% of DAA IFN-free non-responders had a misclassified genotype, and 3/4 sofosbuvir breakthroughs showed the major-RAS-S282T, while RAS-L159F was frequently found in sofosbuvir relapsers (18.2%). Notably, 9.0% of patients showed also extra target RASs, and 47.4% of patients treated with ≥2 DAA classes showed multiclass resistance, including 11/11 NS3+NS5A failures. Furthermore, 20.0% of patients had baseline-RASs, which were always confirmed at failure., Conclusions: In our failure setting, RAS prevalence was remarkably high in all genes, with a partial exception for NS5B, whose limited resistance is still higher than previously reported. This multiclass resistance advocates for HCV resistance testing at failure, in all three genes for the best second-line therapeutic tailoring., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: Evidence indicates that intestinal microbiota may participate in both the induction and the progression of liver damage. The aim of our research was the detection and evaluation of the effects of chronic treatment with a symbiotic formulation on CCl4 -induced rat liver fibrosis., Results: CCl4 significantly increased gastric permeability in respect to basal values, and the treatment with symbiotic significantly decreased it. CCl4 per se induced a decrease in intestinal permeability. This effect was also seen in fibrotic rats treated with symbiotic and was still evident when normal rats were treated with symbiotic alone (P < 0.001 in all cases). Circulating levels of pro-inflammatory cytokine TNF-α were significantly increased in rats with liver fibrosis as compared with normal rats, while symbiotic treatment normalized the plasma levels of TNF-α and significantly enhanced anti-inflammatory cytokine IL 10. TNF-α, TGF-β, TLR4, TLR2, iNOS and α-SMA mRNA expression in the liver were up-regulated in rats with CCl4 -induced liver fibrosis and down-regulated by symbiotic treatment. Moreover, IL-10 and eNOS mRNA levels were increased in the CCL4 (+) symbiotic group. Symbiotic treatment of fibrotic rats normalized serum ALT, AST and improved histology and liver collagen deposition. DGGE analysis of faecal samples revealed that CCl4 administration and symbiotic treatment either alone or in combination produced modifications in faecal profiles vs controls., Conclusions: Our results provide evidence that in CCl4 -induced liver fibrosis, significant changes in gastro-intestinal permeability and in faecal flora occur. Treatment with a specific symbiotic formulation significantly affects these changes, leading to improvement in both liver inflammation and fibrosis., (© 2013 John Wiley & Sons A/S.)

Familial aggregation, linkage and case-control studies support the role of germline genes in the aetiology of lymphoid malignancies. To further examine the role of genetic variation underlying susceptibility, we analysed 1536 single nucleotide polymorphisms in 152 genes involved in apoptosis, DNA repair, immune response and oxidative stress pathways among a unique sample of 165 unrelated familial cases including patients with chronic lymphocytic leukaemia (CLL), Waldenström macroglobulinaemia (WM) and Hodgkin lymphoma (HL), and 107 spouse controls. We confirmed previous studies showing a polymorphism in the IL10 promoter (rs1800890/-3575T>A) to be associated with non-Hodgkin lymphoma, as this allele was found to be associated with both CLL and WM. We also confirmed the role of IL6 variation to be associated with HL. Polymorphisms in TNFSF10 were associated with both CLL and WM. Future replication and functional studies are needed to clarify the role of these genetic variants. Finally, our data further support the close association of WM and CLL.

Monoclonal B cell lymphocytosis (MBL) was detected in four unaffected first-degree relatives (FDR) in a familial chronic lymphocytic leukaemia (CLL) kindred. The proband remains untreated and two male siblings have died. The four unaffected siblings have been followed for a five-year period. All four FDR developed a kappa(+)CD5(+) MBL detected by flow cytometry. Poymerase chain reaction (PCR) for IGHV rearrangement showed evidence of oligoclonality in three of these individuals. Single cell PCR of flow cytometric sorted kappa(+) cells combined with Ig kappa light chain gene sequencing revealed further evidence of monoclonality in two of these individuals. Three of these individuals all showed evidence of hyper-somatic mutations. The B-cell repertoire in unaffected FDR in familial CLL offers a new area to investigate the interface between the immune system and lymphoid neoplasm.

Monoclonal B-cell lymphocytosis (MBL) is a recently described laboratory finding in otherwise healthy individuals. In MBL, a light chain-restricted, clonal B-cell population, often with a chronic lymphocytic leukaemia (CLL) phenotype, is identified by flow cytometry. Although the prognostic significance remains unclear, there is an increased incidence in ageing populations and those with a family history of CLL. During the past decade of MBL study, three families have come to our attention in which prospective sibling haematopoietic stem cell donors were found to have an MBL. These families raise complex bioethical issues with regard to disclosure of research data, eligibility for clinical trials and potential donor transfer of MBL. These issues are explored in this report. Identification of MBL among prospective sibling transplant donors will become a common occurrence in transplant practice as transplantation is increasingly offered to older individuals and those with CLL.

Although the familial aspect of chronic lymphocytic leukaemia (CLL) has been appreciated for decades, it is only with the recent confluence of improved molecular and gene technologies and world-wide collaborative networks that accelerated progress has become apparent. In this summary we highlight selected themes in the genetics of CLL emphasizing the opportunities and challenges of this malignancy.

Monoclonal B-cell lymphocytosis (MBL) has been the subject of more intensive investigation for the last 10 years. The increased presence of MBL in unaffected, first-degree relatives with familial chronic lymphocytic leukaemia (CLL) suggest that it is surrogate marker for early disease. In normal population studies, MBL is found to be increased in ageing subjects. Consensus criteria for the diagnosis of MBL have been proposed. The differential diagnosis has been further clarified and the prevalence of MBL is most prominent in the elderly. The aetiology of MBL is unknown but probably involves immune mechanism of senescence or altered response. Environmental health studies suggest that exposure to certain toxins may lead to MBL but further work is needed. MBL is a precursor to CLL but may also regress, remain stable or progress to clinical CLL.

Previously thought to be best described as a plasma cell disorder, Waldenström macroglobulinaemia (WM) is now understood to be a distinct clinicobiological entity. WM shares B-cell origin and certain other features with both chronic lymphocytic leukaemia (CLL) and multiple myeloma (MM). WM and CLL arise from B-cells at discrete stages in their maturation process, and MM arises from B-cells that have fully differentiated into plasma cells. While MM has a well-known precursor condition, monoclonal gammopathy of undetermined significance (MGUS), CLL and WM may also have associated precursor states, monoclonal B-cell lymphocytosis (MBL) and IgM MGUS, respectively. This review explores the features that link or distinguish these haematolymphoid malignancies, with special attention to emerging data regarding IgM MGUS and its unique relationship to WM, and identifies important gaps in our understanding of the putative precursor conditions, MBL and IgM MGUS.

Chronic lymphocytic leukaemia (CLL) has a strong hereditary component, but an understanding of predisposition genes is poor. Anticipation with familial CLL has been reported, although the molecular mechanism is unknown. Expansion of trinucleotide repeat sequences underlies anticipation observed in neurodegenerative disease. A polymerase chain reaction-based assay was used to analyse the stability of ten CCG- and CAG-trinucleotide repeat tracts in 18 CLL families and 140 patients with the sporadic form of the disease. The study suggests that anticipation, if it occurs in CLL, is not linked to CCG- and CAG-repeat expansion, however, variation in repeat length at certain loci (FRA16A) may permit identification of susceptible family members. In addition, polymorphisms with prognostic significance were identified. These were high length (but not expanded) repeats at FRA11B (P = 0.01), ATXN1 (P = 0.032) and ATXN3 (P = 0.022), all associated with poor risk disease.

A subset of chronic lymphocytic leukaemia (CLL) shows familial aggregation. Studies show an increased risk for CLL and other lymphoproliferative disease among first-degree relatives of affected individuals. A genome-wide scan of 18 CLL families in 2003 detected LOD or non-parametric linkage scores > or = 1.0 on chromosomes 1, 3, 6, 12, 13 and 17. Follow-up study with 28 families showed no evidence of linkage at 1p22.1-p21.2, 3q22.1, 3q26.2, 6q22.31-q23.2, 12q24.23, 14q32.13, 17p13.3. Chromosome 13q21.33 remains a region of interest with a P-value of 0.013 (marker D13S1291) and warrants additional molecular investigation as a susceptibility region for CLL.

Very low levels of circulating monoclonal B-cell subpopulations can now be detected in apparently healthy individuals using flow cytometry. We propose the term 'monoclonal B-cell lymphocytosis' (MBL) to describe this finding. The aim of this document is to provide a working definition of MBL for future clinical, epidemiological and laboratory studies. We propose that the detection of a monoclonal B-cell population by light chain restriction is sufficient to define this condition in individuals not meeting the diagnostic criteria for other B-lymphoproliferative disorders. The majority of individuals with MBL will have cells that are indistinguishable from chronic lymphocytic leukaemia (CLL). However, this blood cell clonal expansion of CD5+ or CD5- B-lymphocytes is age-dependent and immunophenotypic heterogeneity is common. Longitudinal studies are required to determine whether MBL is a precursor state to CLL or other B-lymphoproliferative disease in a situation analogous to a monoclonal gammopathy of undetermined significance and myeloma. Future studies of MBL should be directed towards determining its relationship to clinical disease, particularly in individuals from families with a genetic predisposition to developing CLL.