Elevated Serum KIM-1 in Sepsis Correlates with Kidney Dysfunction and the Severity of Multi-Organ Critical Illness.

The kidney injury molecule (KIM)-1 is shed from proximal tubular cells in acute kidney injury (AKI), relaying tubular epithelial proliferation. Additionally, KIM-1 portends complex immunoregulation and is elevated after exposure to lipopolysaccharides. It thus may represent a biomarker in critical illness, sepsis, and sepsis-associated AKI (SA-AKI). To characterise and compare KIM-1 in these settings, we analysed KIM-1 serum concentrations in 192 critically ill patients admitted to the intensive care unit. Irrespective of kidney dysfunction, KIM-1 serum levels were significantly higher in patients with sepsis compared with other critical illnesses (191.6 vs. 132.2 pg/mL, p = 0.019) and were highest in patients with urogenital sepsis, followed by liver failure. Furthermore, KIM-1 levels were significantly elevated in critically ill patients who developed AKI within 48 h (273.3 vs. 125.8 pg/mL, p = 0.026) or later received renal replacement therapy (RRT) (299.7 vs. 146.3 pg/mL, p < 0.001). KIM-1 correlated with markers of renal function, inflammatory parameters, hematopoietic function, and cholangiocellular injury. Among subcomponents of the SOFA score, KIM-1 was elevated in patients with hyperbilirubinaemia (>2 mg/dL, p < 0.001) and thrombocytopenia (<150/nL, p = 0.018). In univariate and multivariate regression analyses, KIM-1 predicted sepsis, the need for RRT, and multi-organ dysfunction (MOD, SOFA > 12 and APACHE II ≥ 20) on the day of admission, adjusting for relevant comorbidities, bilirubin, and platelet count. Additionally, KIM-1 in multivariate regression was able to predict sepsis in patients without prior (CKD) or present (AKI) kidney injury. Our study suggests that next to its established role as a biomarker in kidney dysfunction, KIM-1 is associated with sepsis, biliary injury, and critical illness severity. It thus may offer aid for risk stratification in these patients.

Efficacy of allogenous fascia lata grafts in the management of lower eyelid retraction.

PURPOSE: To report on the use of allogenous fascia lata (FL) grafts in patients with lower eyelid retraction (LER). METHODS: In this retrospective study, a consecutive series of 27 patients (39 eyes) with LER who underwent lower eyelid elevation with FL was included. Examinations including measurement of the palpebral fissure vertical height (PFVH), the inferior scleral show distance, the margin reflex distance 2 (MRD 2), and the evaluation of conjunctival hyperemia were conducted at baseline and after a mean postoperative time of 25.9 ± 25.5 (5.0-81.0, median 13.0, last follow-up) months in all patients. RESULTS: At the last follow-up, a significant reduction of the PFVH (11.3 ± 1.7 versus 12.8 ± 2.1 at baseline, p < 0.001), the inferior scleral show distance (0.7 ± 1.0 mm versus 2.1 ± 1.1 at baseline, p < 0.001), and the MRD 2 (6.4 ± 0.9 versus 7.8 ± 1.3 at baseline, p < 0.001) occurred. The conjunctival hyperemia grading score (McMonnies) was significantly reduced (1.8 ± 0.7) at the last follow-up compared to baseline (2.6 ± 0.6, p < 0.001). No case of ectropion or entropion was observed at the last follow-up visit. CONCLUSION: In this case series, lower eyelid elevation with FL grafts as a spacer led to a significant reduction of the PFVH, MRD 2, inferior scleral show distance, and conjunctival hyperemia. No severe surgery-related complications occurred.

Insulin Resistance Is the Main Characteristic of Metabolically Unhealthy Obesity (MUO) Associated with NASH in Patients Undergoing Bariatric Surgery.

(1) Background: Metabolically healthy obesity (MHO) is a concept that applies to obese patients without any elements of metabolic syndrome (metS). In turn, metabolically unhealthy obesity (MUO) defines the presence of elements of metS in obese patients. The components of MUO can be divided into subgroups regarding the elements of inflammation, lipid and glucose metabolism and cardiovascular disease. MUO patients appear to be at greater risk of developing non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) compared to MHO patients. The aim of this study was to evaluate the influence of different MUO components on NAFLD and NASH in patients with morbid obesity undergoing bariatric surgery. (2) Methods: 141 patients undergoing bariatric surgery from September 2015 and October 2021 at RWTH Aachen university hospital (Germany) were included. Patients were evaluated pre-operatively for characteristics of metS and MUO (HbA1c, HOMA, CRP, BMI, fasting glucose, LDL, TG, HDL and the presence of arterial hypertension). Intraoperatively, a liver biopsy was taken from the left liver lobe and evaluated for the presence of NAFLD or NASH. In ordinal regression analyses, different factors were evaluated for their influence on NAFLD and NASH. (3) Results: Mean BMI of the patients was 52.3 kg/m2 (36-74.8, SD 8.4). Together, the parameters HbA1c, HOMA, CRP, BMI, fasting glucose, LDL, TG, HDL and the presence of arterial hypertension accounted for a significant amount of variance in the outcome, with a likelihood ratio of χ2 (9) = 41.547, p < 0.001, for predicting the presence of NASH. Only HOMA was an independent predictor of NASH (B = 0.102, SE = 0.0373, p = 0.007). Evaluation of steatosis showed a similar trend (likelihood ratio χ2 (9) = 40.272, p < 0.001). Independent predictors of steatosis were HbA1c (B = 0.833, SE = 0.343, p = 0.015) and HOMA (B = 0.136, SE = 0.039, p < 0.001). (4) Conclusions: The above-mentioned model, including components of MUO, was significant for diagnosing NASH in patients with morbid obesity undergoing bariatric surgery. Out of the different subitems, HOMA independently predicted the presence of NASH and steatosis, while HbA1c independently predicted steatosis and fibrosis. Taken together, the parameter of glucose metabolism appears to be more accurate for the prediction of NASH than the parameters of lipid metabolism, inflammation or the presence of cardiovascular disease.

Elongation of the inferior rectus tendon with fascia lata graft for large vertical squint angles in patients with Graves' orbitopathy.

PURPOSE: To investigate the use of fascia lata (FL) grafts for inferior rectus muscle (IRM) tendon elongation in patients with large vertical squint angles with Graves' orbitopathy (GO). METHODS: In this retrospective study, we included a consecutive series of 20 eyes of 13 patients with GO who underwent IRM tendon elongation with FL. Orthoptic and ophthalmologic examinations including measurement of the head posture, the extent of deviation in primary position (PP), elevation, motility, and binocular diplopia at the tangent of Harms were conducted preoperatively and after a mean postoperative time of 10.8 (5.0-35.0) months in all patients. RESULTS: The mean total repositioning distance was 9.3 ± 3.6 (3.5-16.0) mm. Postoperatively, we found a significant increase in elevation (5.4 ± 2.4 vs. 2.7 ± 2.4 mm preoperatively, p = 0.011). A significant reduction in vertical squint angle (2.8 ± 3.7 vs. 20.2 ± 18.8 Δ preoperatively, p = 0.004), chin elevation (2.3 ± 3.7 vs. 12.9 ± 6.3° preoperatively, p < 0.001), extorsion in PP (0.1 ± 3.8 vs. 8.4 ± 7.8° preoperatively, p = 0.002), and in elevation (1.8 ± 4.8 vs. 11.1 ± 10.9° preoperatively, p = 0.004) occurred postoperatively. A mean dose-effect relation of 2.6 ± 2.9 Δ/mm was calculated. Postoperatively, the lower eyelid retraction was significantly increased (1.5 ± 1.4 vs. 0.4 ± 0.5 mm preoperatively, p = 0.005). CONCLUSION: IRM tendon elongation with FL is a feasible and effective procedure without relevant risk for surgery-related complications.

Hepatobiliary phenotypes of adults with alpha-1 antitrypsin deficiency.

OBJECTIVE: Alpha-1 antitrypsin deficiency (AATD) is a common, potentially lethal inborn disorder caused by mutations in alpha-1 antitrypsin (AAT). Homozygosity for the 'Pi*Z' variant of AAT (Pi*ZZ genotype) causes lung and liver disease, whereas heterozygous 'Pi*Z' carriage (Pi*MZ genotype) predisposes to gallstones and liver fibrosis. The clinical significance of the more common 'Pi*S' variant remains largely undefined and no robust data exist on the prevalence of liver tumours in AATD. DESIGN: Baseline phenotypes of AATD individuals and non-carriers were analysed in 482 380 participants in the UK Biobank. 1104 participants of a multinational cohort (586 Pi*ZZ, 239 Pi*SZ, 279 non-carriers) underwent a comprehensive clinical assessment. Associations were adjusted for age, sex, body mass index, diabetes and alcohol consumption. RESULTS: Among UK Biobank participants, Pi*ZZ individuals displayed the highest liver enzyme values, the highest occurrence of liver fibrosis/cirrhosis (adjusted OR (aOR)=21.7 (8.8-53.7)) and primary liver cancer (aOR=44.5 (10.8-183.6)). Subjects with Pi*MZ genotype had slightly elevated liver enzymes and moderately increased odds for liver fibrosis/cirrhosis (aOR=1.7 (1.2-2.2)) and cholelithiasis (aOR=1.3 (1.2-1.4)). Individuals with homozygous Pi*S mutation (Pi*SS genotype) harboured minimally elevated alanine aminotransferase values, but no other hepatobiliary abnormalities. Pi*SZ participants displayed higher liver enzymes, more frequent liver fibrosis/cirrhosis (aOR=3.1 (1.1-8.2)) and primary liver cancer (aOR=6.6 (1.6-26.9)). The higher fibrosis burden was confirmed in a multinational cohort. Male sex, age ≥50 years, obesity and the presence of diabetes were associated with significant liver fibrosis. CONCLUSION: Our study defines the hepatobiliary phenotype of individuals with the most relevant AATD genotypes including their predisposition to liver tumours, thereby allowing evidence-based advice and individualised hepatological surveillance.

Association of Alpha-1 Antitrypsin Pi*Z Allele Frequency and Progressive Liver Fibrosis in Two Chronic Hepatitis C Cohorts.

(1) Background: The inherited alpha-1 antitrypsin (A1AT) deficiency variant 'Pi*Z' emerged as a genetic modifier of chronic liver disease. Controversial data exist on the relevance of heterozygous Pi*Z carriage ('Pi*MZ' genotype) as an additional risk factor in patients with chronic viral hepatitis C to develop progressive liver fibrosis. (2) Methods: Two prospectively recruited cohorts totaling 572 patients with therapy-naïve chronic viral hepatitis C (HCV) were analyzed. The Frankfurt cohort included 337 patients and a second cohort from Leipzig included 235 patients. The stage of liver fibrosis was assessed by liver biopsy, AST-to-platelet ratio index (APRI) score and Fibrosis-4 (FIB-4) score (Frankfurt) as well as liver stiffness measurement (LSM) via transient elastography (Leipzig). All patients were genotyped for the Pi*Z variant (rs28929474) of the SERPINA1 gene. (3) Results: In the Frankfurt cohort, 16/337 (4.7%) patients carried the heterozygous Pi*Z allele while 10/235 (4.3%) in the Leipzig cohort were Pi*Z carriers. In both cohorts, there was no higher proportion of Pi*Z heterozygosity in patients with cirrhosis compared to patients without cirrhosis or patients with cirrhosis vs. no liver fibrosis. Accordingly, Pi*Z frequency was not different in histological or serological stages of liver fibrosis (F0-F4) and showed no clear association with LSM. (4) Conclusions: Evaluation in two representative HCV cohorts does not indicate Pi*Z heterozygosity as a clinically relevant disease modifier in chronic HCV infection. However, validation in even larger cohorts with longitudinal follow-up is warranted.

A Radiomics Approach to Predict the Emergence of New Hepatocellular Carcinoma in Computed Tomography for High-Risk Patients with Liver Cirrhosis.

Liver cirrhosis poses a major risk for the development of hepatocellular carcinoma (HCC). This retrospective study investigated to what extent radiomic features allow the prediction of emerging HCC in patients with cirrhosis in contrast-enhanced computed tomography (CECT). A total of 51 patients with liver cirrhosis and newly detected HCC lesions (n = 82) during follow-up (FU-CT) after local tumor therapy were included. These lesions were not to have been detected by the radiologist in the chronologically prior CECT (PRE-CT). For training purposes, segmentations of 22 patients with liver cirrhosis but without HCC-recurrence were added. A total of 186 areas (82 HCCs and 104 cirrhotic liver areas without HCC) were analyzed. Using univariate analysis, four independent features were identified, and a multivariate logistic regression model was trained to classify the outlined regions as "HCC probable" or "HCC improbable". In total, 60/82 (73%) of segmentations with later detected HCC and 84/104 (81%) segmentations without HCC were classified correctly (AUC of 81%, 95% CI 74-87%), yielding a sensitivity of 72% (95% CI 57-83%) and a specificity of 86% (95% CI 76-96%). In conclusion, the model predicted the occurrence of new HCCs within segmented areas with an acceptable sensitivity and specificity in cirrhotic liver tissue in CECT.

Serum transferrin as a biomarker of hepatocyte nuclear factor 4 alpha activity and hepatocyte function in liver diseases.

BACKGROUND: Serum transferrin levels represent an independent predictor of mortality in patients with liver failure. Hepatocyte nuclear factor 4 alpha (HNF4α) is a master regulator of hepatocyte functions. The aim of this study was to explore whether serum transferrin reflects HNF4α activity. METHODS: Factors regulating transferrin expression in alcoholic hepatitis (AH) were assessed via transcriptomic/methylomic analysis as well as chromatin immunoprecipitation coupled to DNA sequencing. The findings were corroborated in primary hepatocytes. Serum and liver samples from 40 patients with advanced liver disease of multiple etiologies were also studied. RESULTS: In patients with advanced liver disease, serum transferrin levels correlated with hepatic transferrin expression (r = 0.51, p = 0.01). Immunohistochemical and biochemical tests confirmed reduced HNF4α and transferrin protein levels in individuals with cirrhosis. In AH, hepatic gene-gene correlation analysis in liver transcriptome revealed an enrichment of HNF4α signature in transferrin-correlated transcriptome while transforming growth factor beta 1 (TGFß1), tumor necrosis factor α (TNFα), interleukin 1 beta (IL-1ß), and interleukin 6 (IL-6) negatively associated with transferrin signature. A key regulatory region in transferrin promoter was hypermethylated in patients with AH. In primary hepatocytes, treatment with TGFß1 or the HNF4α inhibitor BI6015 suppressed transferrin production, while exposure to TNFα, IL-1ß, and IL-6 had no effect. The correlation between hepatic HNF4A and transferrin mRNA levels was also seen in advanced liver disease. CONCLUSIONS: Serum transferrin levels constitute a prognostic and mechanistic biomarker. Consequently, they may serve as a surrogate of impaired hepatic HNF4α signaling and liver failure.

Low Serum Levels of Soluble Receptor Activator of Nuclear Factor κ B Ligand (sRANKL) Are Associated with Metabolic Dysregulation and Predict Long-Term Mortality in Critically Ill Patients.

Soluble receptor activator of nuclear factor κ B ligand (sRANKL) is a member of the tumor necrosis factor receptor superfamily, and therefore, involved in various inflammatory processes. The role of sRANKL in the course of bone remodeling via activation of osteoclasts as well as chronic disease progression has been described extensively. However, the potential functional importance of sRANKL in critically ill or septic patients remained unknown. Therefore, we measured sRANKL serum concentrations in 303 critically ill patients, including 203 patients with sepsis and 100 with non-sepsis critical illness. Results were compared to 99 healthy controls. Strikingly, in critically ill patients sRANKL serum levels were significantly decreased at intensive care unit (ICU) admission (p = 0.011) without differences between sepsis and non-sepsis patients. Inline, sRANKL was correlated with markers of metabolic dysregulation, such as pre-existing diabetes and various adipokines (e.g., adiponectin, leptin receptor). Importantly, overall mortality of critically ill patients in a three-year follow-up was significantly associated with decreased sRANKL serum concentrations at ICU admission (p = 0.038). Therefore, our study suggests sRANKL as a biomarker in critically ill patients which is associated with poor prognosis and overall survival beyond ICU stay.

Serum keratin 19 (CYFRA21-1) links ductular reaction with portal hypertension and outcome of various advanced liver diseases.

BACKGROUND: Keratins (Ks) represent tissue-specific proteins. K18 is produced in hepatocytes while K19, the most widely used ductular reaction (DR) marker, is found in cholangiocytes and hepatic progenitor cells. K18-based serum fragments are commonly used liver disease predictors, while K19-based serum fragments detected through CYFRA21-1 are established tumor but not liver disease markers yet. Since DR reflects the severity of the underlying liver disease, we systematically evaluated the usefulness of CYFRA21-1 in different liver disease severities and etiologies. METHODS: Hepatic expression of ductular keratins (K7/K19/K23) was analyzed in 57 patients with chronic liver disease (cohort i). Serum CYFRA21-1 levels were measured in 333 Austrians with advanced chronic liver disease (ACLD) of various etiologies undergoing hepatic venous pressure gradient (HVPG) measurement (cohort ii), 231 French patients with alcoholic cirrhosis (cohort iii), and 280 hospitalized Germans with decompensated cirrhosis of various etiologies (cohort iv). RESULTS: (i) Hepatic K19 levels were comparable among F0-F3 fibrosis stages, but increased in cirrhosis. Hepatic K19 mRNA strongly correlated with the levels of other DR-specific keratins. (ii) In ACLD, increased serum CYFRA21-1 associated with the presence of clinically significant portal hypertension (CSPH; HVPG ≥ 10 mmHg) (OR = 5.87 [2.95-11.68]) and mortality (HR = 3.02 [1.78-5.13]; median follow-up 22 months). (iii) In alcoholic cirrhosis, elevated serum CYFRA21-1 indicated increased risk of death/liver transplantation (HR = 2.59 [1.64-4.09]) and of HCC (HR = 1.74 [1.02-2.96]) over the long term (median follow-up 73 months). (iv) In decompensated cirrhosis, higher serum CYFRA21-1 predicted 90-day mortality (HR = 2.97 [1.92-4.60]) with a moderate accuracy (AUROC 0.64), independently from established prognostic scores. CONCLUSIONS: Hepatic K19 mRNA and serum CYFRA21-1 levels rise in cirrhosis. Increased CYFRA21-1 levels associate with the presence of CSPH and reliably indicate mortality in the short and long term independently of conventional liver biochemistry markers or scoring systems. Hence, the widely available serum CYFRA21-1 constitutes a novel, DR-related marker with prognostic implications in patients with different settings of advanced liver disease.

Non-Invasive Assessment and Management of Liver Involvement in Adults With Alpha-1 Antitrypsin Deficiency.

Alpha-1 antitrypsin deficiency (AATD) is a systemic disorder affecting mainly the lung and the liver and is caused by mutations in SERPINA1, the AAT gene. A homozygous "Pi*Z" mutation (Pi*ZZ genotype) may cause liver fibrosis on its own independently of pulmonary AATD manifestation, while heterozygous Pi*Z carriage (Pi*MZ genotype) is considered a strong risk factor for development of liver cirrhosis in patients with concomitant liver disease such as alcoholic and non-alcoholic liver disease. In Pi*ZZ homozygotes, liver disease constitutes the second leading cause of death and is highly heterogeneous. About 35% of Pi*ZZ individuals display significant liver fibrosis on biopsy (i.e., fibrosis stage ≥ 2 on scale 0-4). Among non-invasive methods for liver fibrosis assessment, liver stiffness measurement (LSM) via vibration-controlled transient elastography (VCTE) has been most widely evaluated. Based on these data, Pi*ZZ adults have 20x increased odds of developing advanced liver fibrosis (i.e., fibrosis stage ≥ 3) than adults without AAT mutation. Risk factors for accelerated fibrosis progression are male sex, age ≥ 50 years, alcohol misuse, obesity, diabetes mellitus, or metabolic syndrome. Unlike VCTE, other ultrasound- and magnetic resonance-based elastography methods have been assessed in small cohorts of Pi*ZZ individuals and remain to be comprehensively validated. Among blood-based fibrosis tests, AST-to-platelet ratio index (APRI) correlates moderately with histologic fibrosis stage and LSM. Given APRI's wide availability, it can be used for risk stratification as an adjunct to LSM or when LSM is not at hand. Despite recent efforts, AATD-related liver disease, especially for genotypes other than Pi*ZZ, remains greatly understudied. AATD individuals should be offered liver biochemistry, liver ultrasound, and non-invasive fibrosis assessment at the time of diagnosis to detect potential complications and for proper risk stratification. If signs of AATD-related liver disease occur (i.e., pathologic fibrosis test or repeatedly elevated liver enzymes), patients should be referred to a health care center specialized in AATD-related liver disease and be screened for potentially treatable comorbidities. To exclude the latter, they may need a liver biopsy. Moreover, every health care provider of an AATD individual should be aware of the potential liver manifestation, counsel their patient on modifiable hepatic risk factors, and offer them regular liver check-ups.

Liver Phenotypes of European Adults Heterozygous or Homozygous for Pi∗Z Variant of AAT (Pi∗MZ vs Pi∗ZZ genotype) and Noncarriers.

BACKGROUND & AIMS: Homozygosity for the Pi∗Z variant of the gene that encodes the alpha-1 antitrypsin peptide (AAT), called the Pi∗ZZ genotype, causes a liver and lung disease called alpha-1 antitrypsin deficiency. Heterozygosity (the Pi∗MZ genotype) is a risk factor for cirrhosis in individuals with liver disease. Up to 4% of Europeans have the Pi∗MZ genotype; we compared features of adults with and without Pi∗MZ genotype among persons without preexisting liver disease. METHODS: We analyzed data from the European Alpha-1 Liver Cohort, from 419 adults with the Pi∗MZ genotype, 309 adults with the Pi∗ZZ genotype, and 284 individuals without the variant (noncarriers). All underwent a comprehensive evaluation; liver stiffness measurements (LSMs) were made by transient elastography. Liver biopsies were analyzed to define histologic and biochemical features associated with the Pi∗Z variant. Levels of serum transaminases were retrieved from 444,642 participants, available in the United Kingdom biobank. RESULTS: In the UK biobank database, levels of serum transaminases were increased in subjects with the Pi∗MZ genotype compared with noncarriers. In the Alpha-1 Liver Cohort, adults with Pi∗MZ had lower levels of gamma-glutamyl transferase in serum and lower LSMs than adults with the Pi∗ZZ variant, but these were higher than in noncarriers. Ten percent of subjects with the Pi∗MZ genotype vs 4% of noncarriers had LSMs of 7.1 kPa or more (adjusted odds ratio, 4.8; 95% confidence interval, 2.0-11.8). Obesity and diabetes were the most important factors associated with LSMs ≥7.1 kPa in subjects with the Pi∗MZ genotype. AAT inclusions were detected in liver biopsies of 63% of subjects with the Pi∗MZ genotype, vs 97% of subjects with the Pi∗ZZ genotype, and increased with liver fibrosis stages. Subjects with the Pi∗MZ genotype did not have increased hepatic levels of AAT, whereas levels of insoluble AAT varied among individuals. CONCLUSIONS: Adults with the Pi∗MZ genotype have lower levels of serum transaminases, fewer AAT inclusions in liver, and lower liver stiffness than adults with the Pi∗ZZ genotype, but higher than adults without the Pi∗Z variant. These findings should help determine risk of subjects with the Pi∗MZ genotype and aid in counseling.

Mild Iron Overload as Seen in Individuals Homozygous for the Alpha-1 Antitrypsin Pi*Z Variant Does Not Promote Liver Fibrogenesis in HFE Knockout Mice.

The presence of the homozygous 'Pi*Z' variant of alpha-1 antitrypsin (AAT) ('Pi*ZZ' genotype) predisposes to liver fibrosis development, but the role of iron metabolism in this process remains unknown. Therefore, we assessed iron metabolism and variants in the Homeostatic Iron Regulator gene (HFE) as the major cause of hereditary iron overload in a large cohort of Pi*ZZ subjects without liver comorbidities. The human cohort comprised of 409 Pi*ZZ individuals and 254 subjects without evidence of an AAT mutation who were recruited from ten European countries. All underwent a comprehensive work-up and transient elastography to determine liver stiffness measurements (LSM). The corresponding mouse models (Pi*Z overexpressors, HFE knockouts, and double transgenic [DTg] mice) were used to evaluate the impact of mild iron overload on Pi*Z-induced liver injury. Compared to Pi*Z non-carriers, Pi*ZZ individuals had elevated serum iron, transferrin saturation, and ferritin levels, but relevant iron overload was rare. All these parameters were higher in individuals with signs of significant liver fibrosis (LSM ≥ 7.1 kPa) compared to those without signs of significant liver fibrosis. HFE knockout and DTg mice displayed similar extent of iron overload and of fibrosis. Loss of HFE did not alter the extent of AAT accumulation. In Pi*ZZ individuals, presence of HFE mutations was not associated with more severe liver fibrosis. Taken together, Pi*ZZ individuals display minor alterations in serum iron parameters. Neither mild iron overload seen in these individuals nor the presence of HFE mutations (C282Y and H63D) constitute a major contributor to liver fibrosis development.

Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis.

OBJECTIVE: Homozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants ('Pi*Z' and 'Pi*S'), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse. DESIGN: We analysed multicentric case-control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi*Z and Pi*S variants was performed. RESULTS: The Pi*Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (p<0.0001). Accordingly, the Pi*Z variant increased the risk of NAFLD subjects to develop cirrhosis (adjusted OR=7.3 (95% CI 2.2 to 24.8)). Likewise, the Pi*Z variant presented in 6.2% of alcohol misusers with cirrhosis but only in 2.2% of alcohol misusers without significant liver injury (p<0.0001). Correspondingly, alcohol misusers carrying the Pi*Z variant were prone to develop cirrhosis (adjusted OR=5.8 (95% CI 2.9 to 11.7)). In contrast, the Pi*S variant was not associated with NAFLD-related cirrhosis and only borderline with alcohol-related cirrhosis (adjusted OR=1.47 (95% CI 0.99 to 2.19)). CONCLUSION: The Pi*Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a weak risk in alcohol misusers. As 2%-4% of Caucasians are Pi*Z carriers, this finding should be considered in genetic counselling of affected individuals.

Comparison of non-invasive assessment of liver fibrosis in patients with alpha1-antitrypsin deficiency using magnetic resonance elastography (MRE), acoustic radiation force impulse (ARFI) Quantification, and 2D-shear wave elastography (2D-SWE).

PURPOSE: Although it has been known for decades that patients with alpha1-antitrypsin deficiency (AATD) have an increased risk of cirrhosis and hepatocellular carcinoma, limited data exist on non-invasive imaging-based methods for assessing liver fibrosis such as magnetic resonance elastography (MRE) and acoustic radiation force impulse (ARFI) quantification, and no data exist on 2D-shear wave elastography (2D-SWE). Therefore, the purpose of this study is to evaluate and compare the applicability of different elastography methods for the assessment of AATD-related liver fibrosis. METHODS: Fifteen clinically asymptomatic AATD patients (11 homozygous PiZZ, 4 heterozygous PiMZ) and 16 matched healthy volunteers were examined using MRE and ARFI quantification. Additionally, patients were examined with 2D-SWE. RESULTS: A high correlation is evident for the shear wave speed (SWS) determined with different elastography methods in AATD patients: 2D-SWE/MRE, ARFI quantification/2D-SWE, and ARFI quantification/MRE (R = 0.8587, 0.7425, and 0.6914, respectively; P≤0.0089). Four AATD patients with pathologically increased SWS were consistently identified with all three methods-MRE, ARFI quantification, and 2D-SWE. CONCLUSION: The high correlation and consistent identification of patients with pathologically increased SWS using MRE, ARFI quantification, and 2D-SWE suggest that elastography has the potential to become a suitable imaging tool for the assessment of AATD-related liver fibrosis. These promising results provide motivation for further investigation of non-invasive assessment of AATD-related liver fibrosis using elastography.

The CXCR4 antagonist POL5551 is equally effective as sirolimus in reducing neointima formation without impairing re-endothelialisation.

Impaired endothelial recovery after the implantation of drug-eluting stents is a major concern because of the increased risk for late stent thrombosis. The disruption of the chemokine axis CXCL12/CXCR4 inhibits neointima formation by blocking the recruitment of smooth muscle progenitor cells. To directly compare a CXCR4-targeting treatment strategy with drugs that are currently used for stent coating, we studied the effects of the CXCR4 antagonist POL5551 and the drug sirolimus on neointima formation. Apolipoprotein E-deficient mice were treated with POL5551 or sirolimus continuously for 28 days after a carotid wire injury. POL5551 inhibited neointima formation by 63% (for a dosage of 2 mg/kg/day) and by 70% (for a dosage of 20 mg/kg/day). In comparison, sirolimus reduced the neointimal area by 69%. In contrast to treatment with POL5551 during the first three days after injury, injection of POL5551 (20 mg/kg) once per day for 28 days diminished neointimal hyperplasia by 53%. An analysis of the cellular composition of the neointima showed a reduction in the relative smooth muscle cell (SMC) and macrophage content in mice that had been treated with a high dose of POL5551. In contrast, the diminished SMC content after sirolimus treatment was associated with a neointimal enrichment of macrophages. Furthermore, endothelial recovery was impaired by sirolimus, but not by POL5551. Therefore, the inhibition of CXCR4 by POL5551 is equally effective in preventing neointima formation as sirolimus, but POL5551 might be more beneficial because treatment with it results in a more stable lesion phenotype and because it does not impair re-endothelialisation.