Jason L. Eccleston

Host response to translocated microbial products predicts outcomes of patients with HBV or HCV infection

BACKGROUND & AIMS Chronic infection with hepatitis B or C virus (HBV or HCV) is a leading cause of cirrhosis by unknown mechanisms of pathogenesis. Translocation of gut microbial products into the systemic circulation might increase because of increased intestinal permeability, bacterial overgrowth, or impaired clearance of microbial products by Kupffer cells. We investigated whether the extent and progression of liver disease in patients with chronic HBV or HCV infection are associated with microbial translocation and subsequent activation of monocytes. METHODS In a retrospective study, we analyzed data from 16 patients with minimal fibrosis, 68 with cirrhosis, and 67 uninfected volunteers. We analyzed plasma levels of soluble CD14 (sCD14), intestinal fatty acid binding protein, and interleukin-6 by enzyme-linked immunosorbent assay, and lipopolysaccharide (LPS) by the limulus amebocyte lysate assay, at presentation and after antiviral treatment. RESULTS Compared with uninfected individuals, HCV- and HBV-infected individuals had higher plasma levels of LPS, intestinal fatty acid binding protein (indicating enterocyte death), sCD14 (produced upon LPS activation of monocytes), and interleukin-6. Portal hypertension, indicated by low platelet counts, was associated with enterocyte death (P=.045 at presentation, P<.0001 after therapy). Levels of sCD14 correlated with markers of hepatic inflammation (P=.02 for aspartate aminotransferase, P=.002 for ferritin) and fibrosis (P<.0001 for γ-glutamyl transpeptidase, P=.01 for alkaline phosphatase, P<.0001 for α-fetoprotein). Compared to subjects with minimal fibrosis, subjects with severe fibrosis at presentation had higher plasma levels of sCD14 (P=.01) and more hepatic CD14+ cells (P=.0002); each increased risk for disease progression (P=.0009 and P=.005, respectively). CONCLUSIONS LPS-induced local and systemic inflammation is associated with cirrhosis and predicts progression to end-stage liver disease in patients with HBV or HCV infection.

Adult‐onset cystic fibrosis liver disease: Diagnosis and characterization of an underappreciated entity

Cystic fibrosis (CF) liver disease (CFLD), a leading cause of death in CF, is mostly described in pediatric populations. Adult‐onset CFLD lacks sufficient characterization and diagnostic tools. A cohort of CF patients without CFLD during childhood were followed for up to 38 years with serologic testing, imaging, and noninvasive fibrosis markers. Historical CFLD diagnostic criteria were compared with newly proposed CFLD criteria. Thirty‐six CF patients were followed for a median of 24.5 years (interquartile range 15.6‐32.9). By the last follow‐up, 11 (31%) had died. With conventional criteria, 8 (22%) patients had CFLD; and by the new criteria, 17 (47%) had CFLD at a median age of 36.6 years (interquartile range 26.5‐43.2). By the new criteria, those with CFLD had higher median alanine aminotransferase (42 versus 27, P = 0.005), aspartate aminotransferase (AST; 26 versus 21, P = 0.01), direct bilirubin (0.13 versus 0.1, P = 0.01), prothrombin time (14.4 versus 12.4, P = 0.002), and AST‐to‐platelet ratio index (0.31 versus 0.23, P = 0.003) over the last 2 years of follow‐up. Subjects with a FibroScan >6.8 kPa had higher alanine aminotransferase (42 versus 28U/L, P = 0.02), AST (35 versus 25U/L, P = 0.02), AST‐to‐platelet ratio index (0.77 versus 0.25, P = 0.0004), and Fibrosis‐4 index (2.14 versus 0.74, P = 0.0003) and lower platelet counts (205 versus 293, P = 0.02). One CFLD patient had nodular regenerative hyperplasia. Longitudinally, mean platelet counts significantly declined in the CFLD group (from 310 to 230 U/L, P = 0.0005). Deceased CFLD patients had lower platelet counts than those alive with CFLD (143 versus 258 U/L, P = 0.004) or those deceased with no CFLD (143 versus 327U/L, P = 0.006). Conclusion: Adult‐onset CFLD may be more prevalent than previously described, which suggests a later wave of CFLD that impacts morbidity; routine liver tests, radiologic imaging, noninvasive fibrosis markers, and FibroScan can be used algorithmically to identify adult CFLD; and further evaluation in other CF cohorts should be performed for validation. (Hepatology 2017;66:591–601).

An apparent homozygous deletion in maltase-glucoamylase, a lesson in the evolution of SNP arrays☆ , ☆☆

Single nucleotide polymorphism (SNP) arrays possess clinical potential due to their high throughput capacity, sensitivity and versatility. We used such an array to perform a genome-wide SNP analysis of a patient with a multi-system undiagnosed disease involving peripheral neuropathies and food intolerances. The patient had a homozygous deletion within the gene encoding maltase-glucoamylase (MGAM), an intestinal starch digestion enzyme, predicting absence of enzyme activity and potential starch indigestion. We then performed validation testing using a functional MGAM analysis that involved starch ingestion followed by measuring blood glucose and insulin levels as well as hydrogen breath levels. Gastrointestinal tissue was also obtained via endoscopy and immunohistochemical staining for intestinal MGAM was performed. Our results strongly suggest the presence and functioning of MGAM which disproved deficiency predictions based on SNP array analysis findings, classifying the deletion as a functional polymorphism. This study highlights a current clinical limitation of SNP arrays, i.e., distinguishing deleterious genomic alterations from misleading functional polymorphisms. We conclude that novel findings from SNP arrays should be clinically validated and published.

Markers of Microbial Translocation Are Elevated in Hepatitis B (HBV) and Hepatitis C (HCV) Infection; A Window Into Biology and Surrogate Markers for Detecting Disease Progression

Purpose: In patients with HBeAgpositive chronic hepatitis B (CHB), one of the primary endpoints of therapy is HBeAg seroconversion; however, there is inconsistent data on the durability of HBeAg seroconversion following consolidation therapy. Our goal is to investigate the rate of recurrent HBV viremia in CHB patients after HBeAg seroconversion. Methods: We retrospectively studied 88 consecutive CHB patients who achieved treatment-induced HBeAg seroconversion among the 458 HBeAg-positive patients treated with various antiviral regimens at 3 GI and liver clinics in the U.S. between 3/1998 and 9/2010. HBeAg seroconversion was defined as loss of HBeAg and development of hepatitis B e antibody (anti-HBe). Recurrent HBV viremia was defined as reappearance of detectable HBV DNA (>100 IU/mL) from nadir in two consecutive laboratory tests. Results: Patients were stratified into two groups: Group I 49 patients who remained on therapy, and Group II 39 patients who discontinued therapy following HBeAg seroconversion. In both groups, the majority of patients were Asian (94-95%) and male (62-69%). Antiviral medications in which patients achieved HBeAg seroconversion included: lamivudine (23%), adefovir (34%), entecavir (36%), tenofovir (4%), adefovir+lamivudine (1%), and entecavir+tenofovir (2%). Median treatment duration before HBeAg seroconversion was similar in Group I and Group II (18 [1-86] vs. 21 [5-63] months, p=0.99). At the time of HBeAg seroconversion, compared to Group I, Group II was younger (37±10 vs. 41±12 years), had lower mean HBV DNA levels (0.27±0.78 vs. 0.95±1.69 log10 IU/mL), and median ALT levels (24 [8-60] vs. 30 [593] U/L). In Group II, the median duration of consolidation therapy before treatment discontinuation was 12 months (range, 1-55), in which 10 completed <6 months, 10 completed 6-11 months, and 19 completed ≥12 months. At time of treatment discontinuation, all patients in Group II had undetectable HBV DNA. The rate of recurrent HBV viremia was significantly higher in Group II compared to Group I (90% vs. 0%, p<0.0001). After a median of 3 (1-42) months off therapy, the mean HBV DNA level detected at time of recurrent HBV viremia was 4.11±1.92 log10 IU/mL. Conclusion: The majority of patients (90%) who discontinued therapy after achieving HBeAg seroconversion with undetectable HBV DNA by PCR experienced recurrent HBV viremia. Patients who remained on therapy achieved and maintained undetectable level of HBV DNA. Patients should be monitored closely for recurrent HBVwhen therapy is discontinued, despite achieving HBeAg seroconversion.

Spleen and Liver Volumetrics as Surrogate Markers of Hepatic Venous Pressure Gradient in Patients With Noncirrhotic Portal Hypertension

Noncirrhotic portal hypertension (NCPH) is a rare disease that may lead to serious clinical consequences. Currently, noninvasive tools for the assessment of NCPH are absent. We investigated the utility of spleen and liver volumetrics as a marker of the presence and severity of portal hypertension in this population. A cohort of NCPH patients evaluated between 2003 and 2015 was retrospectively studied. The association of spleen and liver volumes with the hepatic venous pressure gradient (HVPG) level was evaluated using locally weighted scatterplot smoothing curves. A cohort of patients with viral hepatitis‐related liver disease was used as controls. Of the 86 patients with NCPH evaluated during the study period, 75 (mean age, 35 ± 17; 73% males) were included in the final analysis. Patients with portal hypertension had significantly higher spleen and liver to body mass index (BMI) ratios compared to patients with HVPG <5 mm Hg (39.5 ± 27.9 versus 22.8 ± 10.6 cm3/kg/m2, P = 0.003; 91.1 ± 40.1 versus 71.4 ± 16.7 cm3/kg/m2, P = 0.014, for spleen/BMI and liver/BMI, respectively). In contrast to the patients with viral hepatitis, a positive linear correlation was observed in the NCPH cohort between spleen/BMI and liver/BMI (above a cutoff of 25 and 80 cm3/kg/m2, respectively) and HVPG level. Additionally, only in the NCPH cohort was an increase in spleen/BMI range quartile predictive of a higher prevalence of portal hypertension and clinically significant portal hypertension (trend, P = 0.014 and 0.031, respectively). Conclusion: Spleen and liver volumetrics may have utility in the assessment of NCPH as a noninvasive biomarker that can be performed using routine radiologic examinations. Further studies are needed to validate these findings. (Hepatology Communications 2018; 00:000‐000)

Adult presentation of intestinal malrotation

We present an interesting case of congenital malrotation that was not discovered until adulthood. The patient presented with chronic, non-specific gastrointestinal symptoms which were subsequently alleviated with surgical correction of the congenital malrotation. Malrotation is less often considered in the adult patient and the associated presentation and imaging abnormalities of this case offer a valuable opportunity for thought and brief review.

Gastrointestinal: Adult presentation of intestinal malrotation

We present an interesting case of congenital malrotation that was not discovered until adulthood. The patient presented with chronic, non-specific gastrointestinal symptoms which were subsequently alleviated with surgical correction of the congenital malrotation. Malrotation is less often considered in the adult patient and the associated presentation and imaging abnormalities of this case offer a valuable opportunity for thought and brief review.

Mo1001 Nodular Regenerative Hyperplasia: Many Ways to Get There

Introduction: Nodular Regenerative Hyperplasia (NRH) is a rare noncirrhotic portal hypertensive liver disease characterized by the diffuse transformation of hepatic parenchyma into regenerative nodules without fibrosis. Although the specific etiology has yet to be elucidated, NRH has been associated with various diseases, conditions and medications. Thus, whether NRH occurs from a single unifying pathophysiologic process or multiple different processes is still uncertain. Aims: To characterize biochemical, radiological, and histologic markers of liver disease in patients (pts) with and without NRH in multiple disease cohorts. Methods: Pts with chronic granulomatous disease (CGD), sickle cell disease (SCD), systemic mast cell disease (SMCD), common variable immunodeficiency disease (CVID) and sporadic cases of NRH underwent hepatologic evaluation and liver biopsy for clinical care purposes were evaluated with biomarkers of liver disease, radiologic imaging and histopathologic analysis. Results: 137 pts were evaluated and 56 (41%) were diagnosed with NRH histologically. Of those with NRH, 11 (20%) had CGD, 22 (39%) SCD, 7 (13%) SMCD, 12 (21%) CVID and 4 (7%) sporadic disease. Age at biopsy across all NRH cohorts was significantly older compared to the non-NRH population (mean 40 vs. 33 years, p=0.0128). Patients with NRH had significantly higher alkaline phosphatase (197 vs. 190 U/L, p=0.01), increased liver volumes (2152 vs. 1166 cm3, p=0.01) and increased spleen volumes (after excluding SCD) (1071 vs. 410 cm3, p=0.01), which negatively correlated with platelets ( ρ -0.58, p= 0.002). In the SCD cohort, pts with NRH had increased gamma-glutamyltransferase (128 vs. 67 U/L, p=0.03) and increased lactate dehydrogenase (432 vs. 322 U/L, p=0.01). On histologic evaluation, SCD-NRH pts had increased lobular inflammation (p=0.04). SMCDNRH pts had increased portal and peri-portal inflammation (p=0.005 and p=0.01, respectively), veno-occlusive changes (p=0.04), portal venopathy (p=0.001) and sinusoidal dilation (p=0.03). Conclusions: Despite parallels in clinical disease presentation, histopathologic examination of NRH in separate disease cohorts suggests different mechanistic pathways. Given the potential for multiple etiologies, NRH may be more common than previously thought. Further investigation should focus on the underlying disease process as it may provide a window into biology.

848 Cystic Fibrosis Liver Disease -Development of a Novel Criteria to Identify a Second Wave of Liver Disease in Adults

Introduction: Cystic fibrosis liver disease (CFLD) is the 3rd leading cause of death in cystic fibrosis (CF) patients, contributing to 2.5-5% of overall mortality. Onset of CFLD has been mostly described in pediatric populations, but with improving life expectancy, adult onset CFLD is increasingly recognized with an estimated prevalence of 2-37%. Criteria for the diagnosis of adult CFLD are lacking and inconsistent; with few studies evaluating noninvasive biomarkers and radiographic data for classification systems. Aims: To characterize adult CFLD and develop a set of novel criteria for the diagnosis of adult CFLD utilizing biochemical, clinical and radiographic markers in an adult CF cohort followed at the NIH Clinical Center for up to 37 years (yrs). Methods: Patients with CF were evaluated with hepatic biomarkers of inflammation, synthetic function, portal hypertension, radiologic imaging, and transient elastography (TE). Charts were extracted for clinical data. Utilizing these biomarkers along with TE, APRI, and FIB-4, criteria were defined for the diagnosis CFLD. Patients who met CFLD criteria were compared to CF patients without evidence of liver disease. Results: 36 patients with CF (33% F508 homozygous, 23% F508 heterozygous) were studied (65% males, 97% white). The median age of CF diagnosis was 11 yrs, and the median follow-up duration was 23 yrs (range 2 to 37). At the time of last follow-up (mean age=46 yrs), 11 (31%) had died (respiratory failure=3, infection=3, complications of transplantation=2, or other causes=3). 17 of 36 (47%) patients met criteria for CFLD (mean age of diagnosis=31 yrs). Patients with CFLD had significantly higher mean ALT (44.3 vs 28.1, p=0.01), direct bilirubin (0.2 vs 0.1, p =0.04), PT (14.4 vs 12.8, p=0.01), and APRI (0.6 vs 0.2, p=0.04) over the last year of follow-up. In the CFLD group, 4 patients had radiographic evidence of advanced liver disease and 1 patient had nodular regenerative hyperplasia and experienced hepatic decompensation. On longitudinal comparison, platelet counts significantly declined in the CFLD group (312 to 237 U/L, p=0.007) as compared to patients without CFLD (328 to 297 U/L, p=0.11). Conclusions: By evaluating non-invasive markers of liver disease, a novel criteria can be employed to identify adult CFLD. These biomarkers not only suggest that a second wave of liver disease exists in adult CF patients, but also that it may be more prevalent than previously described. Further evaluation of this diagnostic criteria in other CF cohorts should be performed to evaluate its utility in adult CFLD.