Common variable immunodeficiency disorder-related liver disease is common and results in portal hypertension and an increased risk of death.

BACKGROUND: Common variable immunodeficiency disorder (CVID) manifests with recurrent infections and inflammatory complications, including liver disease. We report the clinical features, natural history, and outcomes of patients with CVID-related liver disease (CVID-rLD) from a tertiary immunology and hepatology center. METHODS: Two hundred eighteen patients were identified; CVID-rLD was defined by persistently abnormal liver function tests or evidence of chronic liver disease (CLD) or portal hypertension (PHTN) by radiological or endoscopic investigation, after exclusion of other causes. Patients with CVID-rLD were investigated and managed following a joint pathway between immunology and hepatology services. Data, including clinical parameters, investigations, and outcomes, were retrospectively collected. RESULTS: A total of 91/218 (42%) patients had evidence of CVID-rLD, and 40/91 (44%) had PHTN. Patients with CVID-rLD were more likely to have other noninfectious complications of CVID (85/91, 93.4% vs. 75/127, 59.1%, p<0.001) including interstitial lung disease, gut disease, and autoimmune cytopenias. Nodular regenerative hyperplasia (NRH) was identified in 63.8% of liver biopsies, and fibrosis in 95.3%. Liver stiffness measurements (LSMs) were frequently elevated (median 9.95 kPa), and elevated LSM was associated with PHTN. All-cause mortality was higher in those with CVID-rLD (24/91, 26.4% vs. 14/127, 11%, p=0.003), which was the only organ complication associated with mortality (HR 2.24, 1.06-4.74, p=0.04). Factors predicting mortality in CVID-rLD included PHTN, increasing fibrosis, and LSM. CONCLUSIONS: Liver disease is a common complication of CVID as part of complex, multi-organ involvement and is associated with high rates of PHTN and an increased hazard of mortality.

Common variable immunodeficiency disorder (CVID)-related liver disease: assessment of the main histological aspects using novel semiquantitative scoring systems, image analysis and correlation with clinical parameters of liver stiffness and portal hypertension.

AIMS: We aimed to investigate the relationship between T-cell-mediated sinusoidal injury, nodular regenerative hyperplasia like changes (NRH-LC) and fibrosis, clinical measures of fibrosis and portal hypertension, and progression rate in common variable immunodeficiency disorder (CVID)-related liver disease. METHODS: This is a retrospective single-centre study. Liver biopsies from CVID patients with liver disease were reviewed to assess for NRH-LC, fibrosis and elastosis, including collagen and elastin proportionate areas. CD3 positive T-cells infiltration and sinusoidal endothelial changes by CD34 expression were quantified by image analysis and a semiquantitative method, respectively. These findings were correlated with liver stiffness measurements (LSM) and hepatic venous pressure gradient (HVPG). RESULTS: NRH-LC and pericellular elastosis were present in most biopsies (32/40 and 38/40, respectively). All biopsies showed fibrosis, which was limited to pericellular in 21/40 (52.5%) and included bridging fibrous septa in 19/40 (47.5%). 28/40 liver biopsies showed enhanced sinusoidal expression of CD34. There were more CD3 positive cells in biopsies with NRH-LC compared with those without. There was no significant correlation between LSM, HVPG and fibrosis/elastosis scores. Five of seven patients with at least two biopsies showed progression in fibrosis stage. CONCLUSIONS: NRH-LC and fibrosis in CVID patients often coexist along with the presence of sinusoidal endothelial changes and sinusoidal lymphocytic infiltration. Fibrosis progresses over time, and significant fibrosis can be observed in young patients (<30 years old), potentially reflecting a more aggressive form of CVID-related liver disease. Further studies are necessary to investigate the relationship between histological findings, clinical measures of fibrosis and portal hypertension and outcome.

Colorectal cancer in the young, many questions, few answers.

At a time where the incidence of colorectal cancer, a disease predominantly of developed nations, is showing a decline in those 50 years of age and older, data from the West is showing a rising incidence of this cancer in young individuals. Central to this has been the 75% increase in rectal cancer incidence in the last four decades. Furthermore, predictive data based on mathematical modelling indicates a 124 percent rise in the incidence of rectal cancer by the year 2030 - a statistic that calls for collective global thought and action. While predominance of colorectal cancer (CRC) is likely to be in that part of the large bowel distal to the splenic flexure, which makes flexible sigmoidoscopic examination an ideal screening tool, the cost and benefit of mass screening in young people remain unknown. In countries where the incidence of young CRC is as high as 35% to 50%, the available data do not seem to indicate that the disease in young people is one of high red meat consuming nations only. Improvement in our understanding of genetic pathways in the aetiology of CRC, chiefly of the MSI, CIN and CIMP pathway, supports the notion that up to 30% of CRC is genetic, and may reflect a familial trait or environmentally induced changes. However, a number of other germline and somatic mutations, some of which remain unidentified, may play a role in the genesis of this cancer and stand in the way of a clear understanding of CRC in the young. Clinically, a proportion of young persons with CRC die early after curative surgery, presumably from aggressive tumour biology, compared with the majority in whom survival after operation will remain unchanged for five years or greater. The challenge in the future will be to determine, by genetic fingerprinting or otherwise, those at risk of developing CRC and the determinants of survival in those who develop CRC. Ultimately, prevention and early detection, just like for those over 50 years with CRC, will determine the outcome of CRC in young persons. At present, aside from those with an established familial tendency, there is no consensus on screening young persons who may be at risk. However, increasing awareness of this cancer in the young and the established benefit of prevention in older persons, must be a message that should be communicated with medical students, primary health care personnel and first contact doctors. The latter constitutes a formidable challenge.