Development and Regression of Cirrhosis

Liver cirrhosis is the ultimate consequence of the wound healing reaction subsequent to a chronic injury, which leads to a complete derangement of the normal hepatic lobular and vascular architecture. Cirrhosis is characterized by patterns of evolution depending on the causative agent and a series of complex underlining mechanisms in which neo-angiogenesis and necro-inflammation play a key role. The importance of the different cell types involved and of the extracellular matrix composition as well as the role of innate immunity, bacterial translocation and oxidative stress are also emerging. A variable degree of regression of fibrosis and even cirrhosis has been described, in experimental models, after suspension of the liver disease causative agent. As some individual features influence the rate of fibrosis progression, genetic and epigenetic factors are likely to influence fibrosis regression. Key Messages: There is increasing awareness that cirrhosis is not a static condition but a dynamic process. Current semi-quantitative scores and clinical classifications are inaccurate and unable to identify the different phases of evolution of the advanced stages of chronic liver diseases (CLDs). The increasing availability of effective etiology-driven therapeutic options for CLDs makes reversion of cirrhosis a more possible prospective. However, the removal of the causing agent, depending on the stage of the disease, does not necessarily eliminate the risk of disease progression, decompensation and development of hepatocellular carcinoma. Also, the non-invasive markers currently validated for the assessment of fibrosis are not suitable for an effective evaluation of fibrosis regression. Conclusions: There is a critical need of a system that would be able to more accurately describe the dynamic development of cirrhosis and the impact of tissue fibrosis, neo-angiogenesis, necro-inflammation and attempted regeneration on its evolution. Effective treatment of CLD can lead to a variable degree of fibrosis regression. New markers able to evaluate this process will need to be detected and validated

Utility of ElastPQ point-shear wave elastography in the work-up of patients with primary sclerosing cholangitis

Background & Aims: Liver stiffness measurement (LSM) and spleen stiffness measurement (SSM) have been shown to be useful tools for assessing the risk of fibrosis and portal hypertension, respectively. However, data on the accuracy of LSM and SSM measured by point-shear wave elastography (pSWE) in patients affected by primary sclerosing cholangitis (PSC) are still lacking. Thus, we aimed to prospectively assess their performance in a cohort of patients with PSC. Methods: We determined the correlation between LSM assessed by a pSWE technique (ElastPQ) and by FibroScan-transient elastography (F-TE). Furthermore, we used receiver-operating characteristic curves and area under the curves (AUROC) to evaluate the performance of LSM by ElastPQ for the staging of fibrosis, using F-TE as a reference standard, and the performance of LSM and SSM by ElastPQ in predicting the presence of oesophageal varices (OVs). Results: One hundred and fifty-two patients with PSC (93 males [61.2%], mean age 46 ± 16 years) were prospectively recruited. ElastPQ and F-TE LSMs were available for all patients, while ElastPQ SSM was available in 109 (72%) patients of whom 35 underwent upper gastrointestinal endoscopy within 1 year of the ultrasound assessment. ElastPQ LSM showed an excellent correlation with F-TE (p <0.001, Spearman's 0.93; Lin's 0.86) and a good diagnostic accuracy for fibrosis staging along all stages of liver fibrosis (AUROCs 0.96, 0.97, 0.97 and 0.99 for fibrosis stages F≥1, F≥2, F≥3 and F=4, respectively), using F-TE as a surrogate of histological fibrosis. ElastPQ SSM showed a good diagnostic performance in predicting the presence of OVs at endoscopy. Conclusions: LSM and SSM by ElastPQ can be used as accurate tools for liver fibrosis risk assessment and fibrosis staging, as well as for predicting the presence of OVs in the work-up of patients with PSC. Impact and implications: Liver and spleen stiffness measurement (LSM and SSM, respectively) by ElastPQ point-shear wave elastography in patients with primary sclerosing cholangitis represent reliable and reproducible tools for non-invasively staging the severity of liver disease and stratifying patients according to their risk of developing liver-related outcomes. In particular, LSM shows good accuracy for staging liver fibrosis and therefore detecting those patients at high risk of having compensated advanced chronic liver disease who require close monitoring. SSM seems to be promising to detect the risk of portal hypertension and therefore of oesophageal varices, enabling the triaging of patients who really need to undergo a screening endoscopy

Collagen proportionate area correlates with histological stage and predicts clinical events in primary sclerosing cholangitis

Background & Aims: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease in need of accurate biomarkers for stratification and as surrogates for clinical endpoints in trials. Quantitative liver fibrosis assessment by collagen proportionate area (CPA) measurement has been demonstrated to correlate with clinical outcomes in chronic hepatitis C, alcohol-related and non-alcoholic fatty liver disease. We aimed to investigate the ability of CPA to quantify liver fibrosis and predict clinical events in PSC. Methods: Biopsies from 101 PSC patients from two European centres were retrospectively assessed by two expert pathologists in tandem, using grading (Ishak and Nakanuma) and staging (Ishak, Nakanuma, Ludwig) systems recently validated to predict clinical events in PSC. CPA was determined by image analysis of picro-Sirius red-stained sections following a standard protocol. We assessed the correlations between CPA, staging and grading and their associations with three outcomes: (1) time to PSC-related death, liver transplant or primary liver cancer; (2) liver transplant-free survival; (3) occurrence of cirrhosis-related clinical manifestations. Results: CPA correlated strongly with histological stage determined by each scoring system (P < .001) and was significantly associated with the three endpoints. Median time to endpoint-1, endpoint-2 and endpoint-3 was shorter in patients with higher CPA, on Kaplan-Meier analyses (P = .011, P = .034 and P = .001, respectively). Conclusion: Quantitative fibrosis assessment by CPA has utility in PSC. It correlates with established histological staging systems and predicts clinical events. CPA may be a useful tool for staging fibrosis and for risk stratification in PSC and should be evaluated further within prospective clinical trials

Defective spleen function in autoimmune gastrointestinal disorders

Defective spleen function increases susceptibility to bacterial infections which can be prevented by vaccine prophylaxis. Splenic hypofunction can be found in a number of autoimmune disorders; however, no data are available regarding autoimmune atrophic gastritis (AAG), autoimmune enteropathy (AIE) and autoimmune liver disease (AILD). Peripheral blood samples from patients with AAG (n = 40), AIE (n = 3) and AILD (n = 40) were collected. Patients affected by autoimmune disorders already known to be associated with splenic hypofunction, i.e. coeliac disease (CD) and ulcerative colitis (UC), were included as disease controls, while splenectomised patients and healthy subjects were evaluated as positive and negative controls, respectively. Counting of erythrocytes with membrane abnormalities, i.e. pitted red cells, was used as an indicator of spleen function (normal upper limit 4%). Defective splenic function was observed in 22 of the 40 patients with AAG (55.0%), in two of the three patients with AIE (66.6%) and in 35 of the 40 patients with AILD (87.5%). As expected, in untreated CD, refractory CD and UC there was a high prevalence of hyposplenism (43.7%, 88.2% and 54.4%, respectively). Due to the high prevalence of splenic hypofunction, patients with AAG, AILD and AIE should undergo pitted red cell evaluation and, if hyposplenic, they should be candidate to vaccine prophylaxis against encapsulated bacteria

Same donor laparoscopic liver and kidney procurement for sequential living donor liver-kidney transplantation in primary hyperoxaluria type i

Background: Sequential liver-kidney transplantation (SeqLKT) from the same living donor has shown excellent results in children with primary hyperoxaluria type 1 (PH1), yet its experience is limited due to the invasiveness of two major procedures for liver-kidney procurement in a single donor. Despite laparoscopic nephrectomy and hepatic left lateral sectionectomy (LLS) being considered standard procedures in living donation, the sequential use of the two laparoscopic approaches in the same living donor has never been reported. Methods: Herein, we present the first two case series of laparoscopic liver-kidney procurement in the same living donor for SeqLKT in children with PH1 and review of the current literature on this topic. Results: In the first case, a 15-month-old boy received a SeqLKT from his 32-year-old mother, who underwent a laparoscopic LLS and, after 8 months, a laparoscopic left nephrectomy. In the second case, a 34-month-old boy received a SeqLKT from his 40-year-old father who underwent laparoscopic LLS followed by hand-assisted right nephrectomy after 4 months. Both donors had uneventful postoperative courses and were discharged within 5 days from each surgery. The first recipient had no complication; the second child after liver transplantation developed a partial thrombosis of the inferior vena cava, which did not preclude the sequential kidney transplantation. After 12 months, donors and recipients displayed normal liver and renal functions. Conclusions: Sequential laparoscopic liver-kidney procurement in the same living donor is safe and feasible, and might be considered as a possible strategy to promote SeqLKT in children with PH1 from the same living donor

Primary Prophylaxis for Gastrointestinal Bleeding in Children With Biliary Atresia and Portal Hypertension Candidates for Liver Transplantation: A Single-Center Experience

Background. Cirrhosis for biliary atresia (BA) is associated with risk of gastrointestinal bleeding (GB) from gastroesophageal varices due to portal hypertension. Primary prophylaxis of GB is controversial in children who are candidates for liver transplantation (LT). The aim of the study was to define the management of gastroesophageal varices and to identify the benefit of primary prophylaxis for GB in BA children waiting for LT.Methods. A retrospective single-center study including all BA children listed for LT in 2008-2016. Clinical, endoscopical, and biochemical data were analyzed.Results. Of 82 children, 50 (61%) did not receive primary prophylaxis and did not present any episode of bleeding, 16 (19.5%) underwent primary prophylaxis, and 16 (19.5%) presented spontaneous GB and received secondary prophylaxis. Children without primary prophylaxis and GB were younger than patients with primary prophylaxis and those with GB (7.7 years [range, 4.1-37.9 years] vs 11.2 years [range, 5.1-43 years]; P = .03 vs 10.7 years [range, 6.9-39.9 years], respectively; P = .004). Seventy-five percent of GB occurred in children older than 8 months. Fifteen (93.8%) children with GB presented esophageal varices (grade III = 10 [62.5%]) and 10 (62.5%) required endoscopic treatments, consisting mainly of sclerotherapy. Median time to LT was similar for children with or without bleeding (2 months [range, 0-17.7 months] vs 2.2 months [0-17.9 months], respectively; P = .89). After 45.5 months (range, 13.7-105.5 months) of follow-up, the overall patient survival was 97.6%. At the intention-to-treat analysis, the survival rate was 100% for patients without bleeding episode and 87.5% for children with GB (P = .16).Conclusions. Despite the risk of GB being not clinically predictable in children with BA waiting for LT, our experience suggests that primary prophylaxis of GB might be unnecessary in children younger than 6 months, while it should be considered in older children. Thus, the occurrence of GB does not delay the timing of transplantation

Life-saving vascular access after combined liver and kidney transplantation: A challenging access to the right atrium

Exhaustion of vascular accesses is a major complication in patients undergoing hemodialysis, especially in pediatric setting. We report the case of a boy treated for loss of hemodialysis access after a combined liver-kidney transplantation and transient renal dysfunction. An interventional dilatation of calcific superior vena cava allowed to insert a stable central venous line for dialysis until full graft recovery. Careful management of central lines allows to spare the main vessels and reduces the need for unusual accesses

Serological markers of extracellular matrix remodeling predict transplant‐free survival in primary sclerosing cholangitis

BACKGROUND: Primary sclerosing cholangitis is a progressive liver disease with a remarkably variable course. Biomarkers of disease activity or prognostic models predicting outcome at an individual level are currently not established. AIM: To evaluate the prognostic utility of four biomarkers of basement membrane and interstitial extracellular matrix remodeling in patients with primary sclerosing cholangitis. METHODS: Serum samples were available from 138 large‐duct primary sclerosing cholangitis patients (of which 102 [74%] with IBD) recruited 2008‐2012 and 52 ulcerative colitis patients (controls). The median follow‐up time was 2.2 (range 0‐4.3) years. Specific biomarkers of type III and V collagen formation (PRO‐C3 and PRO‐C5, respectively) and type III and IV collagen degradation (C3M and C4M, respectively) were assessed. The Enhanced Liver Fibrosis test, including procollagen type III N‐terminal peptide, tissue inhibitor of metalloproteinase‐1 and hyaluronic acid was assessed for comparison. RESULTS: All markers were elevated in primary sclerosing cholangitis compared to ulcerative colitis patients (P < 0.001). PRO‐C3 showed the largest difference between the two groups with a threefold increase in primary sclerosing cholangitis compared to ulcerative colitis patients. Patients with high baseline serum levels of all markers, except C3M, had shorter survival compared to patients with low baseline serum levels (P < 0.001). Combining PRO‐C3 and PRO‐C5 the odds ratio for predicting transplant‐free survival was 47 compared to the Enhanced Liver Fibrosis test's odds ratio of 11. CONCLUSIONS: Extracellular matrix remodeling is elevated in primary sclerosing cholangitis patients compared to ulcerative colitis patients. Furthermore, the interstitial matrix marker PRO‐C3 was identified as a potent prognostic marker and an independent predictor of transplant‐free survival in primary sclerosing cholangitis

A disease-associated gene desert directs macrophage inflammation through ETS2

Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health1. This is compounded by the limited efficacy of available treatments1 and high failure rates during drug development2, highlighting an urgent need to better understand disease mechanisms. Here we show how functional genomics could address this challenge. By investigating an intergenic haplotype on chr21q22—which has been independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu’s arteritis3–6—we identify that the causal gene, ETS2, is a central regulator of human inflammatory macrophages and delineate the shared disease mechanism that amplifies ETS2 expression. Genes regulated by ETS2 were prominently expressed in diseased tissues and more enriched for inflammatory bowel disease GWAS hits than most previously described pathways. Overexpressing ETS2 in resting macrophages reproduced the inflammatory state observed in chr21q22-associated diseases, with upregulation of multiple drug targets, including TNF and IL-23. Using a database of cellular signatures7, we identified drugs that might modulate this pathway and validated the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this illustrates the power of functional genomics, applied directly in primary human cells, to identify immune-mediated disease mechanisms and potential therapeutic opportunities