Tamar H. Taddei

The underrecognized progressive nature of N370S Gaucher disease and assessment of cancer risk in 403 patients

Mutations in GBA1 gene that encodes lysosomal glucocerebrosidase result in Type 1 Gaucher Disease (GD), the commonest lysosomal storage disorder; the most prevalent disease mutation is N370S. We investigated the heterogeneity and natural course of N370S GD in 403 patients. Demographic, clinical, and genetic characteristics of GD at presentation were examined in a cross‐sectional study. In addition, the relative risk (RR) of cancer in patients compared with age‐, sex‐, and ethnic‐group adjusted national rates of cancer was determined. Of the 403 patients, 54% of patients were homozygous (N370S/N370S) and 46% were compound heterozygous for the N370S mutation (N370S/other). The majority of N370S/N370S patients displayed a phenotype characterized by late onset, predominantly skeletal disease, whereas the majority of N370S/other patients displayed early onset, predominantly visceral/hematologic disease, P < 0.0001. There was a striking increase in lifetime risk of multiple myeloma in the entire cohort (RR 25, 95% CI 9.17–54.40), mostly confined to N370S homozygous patients. The risk of other hematologic malignancies (RR 3.45, 95% CI 1.49–6.79), and overall cancer risk (RR 1.80, 95% CI 1.32–2.40) was increased. Homozygous N370S GD leads to adult‐onset progressive skeletal disease with relative sparing of the viscera, a strikingly high risk of multiple myeloma, and an increased risk of other cancers. High incidence of gammopathy suggests an important role of the adaptive immune system in the development of GD. Adult patients with GD should be monitored for skeletal disease and cancers including multiple myeloma. Am. J. Hematol., 2009.

Inherited metabolic disease of the liver

Purpose of review The past decade has seen extraordinary growth in our understanding of the pathophysiology of Wilson disease, genetic hemochromatosis and α-1 antitrypsin deficiency as we continue to elucidate the molecular and cellular machinery involved in their pathogenesis. The continued progress in the elaboration of the molecular biology, genetics, epidemiology, and management of these prototypical inherited metabolic diseases will be the focus of this review. Recent findings Wilson disease and genetic hemochromatosis involve defects in metal transport with copper and iron accumulation in hepatocytes, respectively. In α-1 antitrypsin deficiency, hepatocytes accumulate defective α-1 antitrypsin that misfolds. As a more complete picture of the molecular biology of the proteins and genes involved in transport has evolved, so has our understanding of the etiopathogenesis of these disorders and the variety of phenotypes observed. Finally, new ideas regarding the clinical management of these disorders will emerge with elucidation of the cellular basis for these diseases. Summary The recent developments detailed in this article have important implications for the future diagnosis and treatment of these diseases. Recent discoveries link molecular defects with alterations in the functional machinery of the cell, and provide new avenues for advancing the diagnosis and treatment of these disorders.

Impact of body mass index on graft failure and overall survival following liver transplant

Abstract:  Goals:  To assess the influence of body mass index (BMI) in the outcome of liver transplantation.

Identifying barriers to hepatocellular carcinoma surveillance in a national sample of patients with cirrhosis

Hepatocellular carcinoma (HCC) is a leading cause of morbidity and mortality in cirrhosis patients. This provides an opportunity to target the highest‐risk population, yet surveillance rates in the United States and Europe range from 10% to 40%. The goal of this study was to identify barriers to HCC surveillance, using data from the Veterans Health Administration, the largest provider of liver‐related health care in the United States. We included all patients 75 years of age or younger who were diagnosed with cirrhosis from January 1, 2008, until December 31, 2010. The primary outcome was a continuous measure of the percentage of time up‐to‐date with HCC surveillance (PTUDS) based on abdominal ultrasound (secondary outcomes included computed tomography and magnetic resonance imaging). Among 26,577 patients with cirrhosis (median follow‐up = 4.7 years), the mean PTUDS was 17.8 ± 21.5% (ultrasounds) and 23.3 ± 24.1% when any liver imaging modality was included. The strongest predictor of increased PTUDS was the number of visits to a specialist (gastroenterologist/hepatologist and/or infectious diseases) in the first year after cirrhosis diagnosis; the association between visits to a primary care physician and increasing surveillance was very small. Increasing distance to the closest Veterans Administration center was associated with decreased PTUDS. There was an inverse association between ultrasound lead time (difference between the date an ultrasound was ordered and requested exam date) and the odds of it being performed: odds ratio = 0.77, 95% confidence interval 0.72‐0.82 when ordered > 180 days ahead of time; odds ratio = 0.90, 95% confidence interval 0.85‐0.94 if lead time 91‐180 days. Conclusions: The responsibility for suboptimal surveillance rests with patients, providers, and the overall health care system; several measures can be implemented to potentially increase HCC surveillance, including increasing patient–specialist visits and minimizing appointment lead time. (Hepatology 2017;65:864‐874).

Systemic therapy in hepatocellular carcinoma

Many potential systemic therapies are being investigated for the treatment of hepatocellular carcinoma (HCC). The incidence of this malignancy is rising sharply and the vast majority of patients present at advanced stages. Although the earlier dismal results with cytotoxic chemotherapies made way for the development of locoregional therapies that provided improved overall survival, truly personalized therapy will require the selection of phenotypically similar stages of disease and populations, an understanding of the complex molecular and genetic pathways leading to HCC, and a keen understanding of the pathobiology of cirrhosis. Only then will we understand how to offer a particular patient at a specific stage of disease the appropriate therapy to truly prolong survival.

Development and Performance of an Algorithm to Estimate the Child-Turcotte-Pugh Score From a National Electronic Healthcare Database.

BACKGROUND & METHODS The Child-Turcotte-Pugh (CTP) score is a widely used and validated predictor of long-term survival in cirrhosis. The CTP score is a composite of 5 subscores, 3 based on objective clinical laboratory values and 2 subjective variables quantifying the severity of ascites and hepatic encephalopathy. To date, no system to quantify CTP score from administrative databases has been validated. The Veterans Outcomes and Costs Associated with Liver Disease study is a multicenter collaborative study to evaluate the outcomes and costs of hepatocellular carcinoma in the U.S. Veterans Health Administration. We developed and validated an algorithm to calculate electronic CTP (eCTP) scores by using data from the Veterans Health Administration Corporate Data Warehouse. METHODS Multiple algorithms for determining each CTP subscore from International Classification of Diseases version 9, Common Procedural Terminology, pharmacy, and laboratory data were devised and tested in 2 patient cohorts. For each cohort, 6 site investigators (Boston, Bronx, Brooklyn, Philadelphia, Minneapolis, and West Haven VA Medical Centers) were provided cases from which to determine validity of diagnosis, laboratory data, and clinical assessment of ascites and encephalopathy. The optimal algorithm (designated eCTP) was then applied to 30,840 cirrhotic patients alive in the first quarter of 2008 for whom 5-year overall and transplant-free survival data were available. The ability of the eCTP score and other disease severity scores (Charlson-Deyo index, Veterans Aging Cohort Study index, Model for End-Stage Liver Disease score, and Cirrhosis Comorbidity) to predict survival was then assessed by Cox proportional hazards regression. RESULTS Spearman correlations for administrative and investigator validated laboratory data in the HCC and cirrhotic cohorts, respectively, were 0.85 and 0.92 for bilirubin, 0.92 and 0.87 for albumin, and 0.84 and 0.86 for international normalized ratio. In the HCC cohort, the overall eCTP score matched 96% of patients to within 1 point of the chart-validated CTP score (Spearman correlation, 0.81). In the cirrhosis cohort, 98% were matched to within 1 point of their actual CTP score (Spearman, 0.85). When applied to a cohort of 30,840 patients with cirrhosis, each unit change in eCTP was associated with 39% increase in the relative risk of death or transplantation. The Harrell C statistic for the eCTP (0.678) was numerically higher than those for other disease severity indices for predicting 5-year transplant-free survival. Adding other predictive models to the eCTP resulted in minimal differences in its predictive performance. CONCLUSION We developed and validated an algorithm to extrapolate an eCTP score from data in a large administrative database with excellent correlation to actual CTP score on chart review. When applied to an administrative database, this algorithm is a highly useful predictor of survival when compared with multiple other published liver disease severity indices.

Starting Dose of Sorafenib for the Treatment of Hepatocellular Carcinoma: A Retrospective, Multi-Institutional Study

Purpose Sorafenib is currently the only Food and Drug Administration-approved first-line therapy for patients with advanced hepatocellular carcinoma. There are few data examining how sorafenib starting dose may influence patient outcomes and costs. Patients and Methods We retrospectively evaluated 4,903 patients from 128 Veterans Health Administration hospitals who were prescribed sorafenib for hepatocellular carcinoma between January 2006 and April 2015. After 1:1 propensity score matching to account for potential treatment bias, hazard ratios (HRs) were calculated using Cox regression and were tested against a noninferiority margin of HR = 1.1. A matched multivariate logistic regression was performed to adjust for potential confounders. The primary end point was overall survival (OS) of patients who were prescribed standard starting dosage sorafenib (800 mg/d per os) versus that of patients who were prescribed reduced starting dose sorafenib (< 800 mg/d per os). Results There were 3,094 standard dose sorafenib patients (63%) and 1,809 reduced starting dose sorafenib patients (37%). Reduced starting dose sorafenib patients had more Barcelona Clinic Liver Cancer stage D ( P < .001), higher Model for End-Stage Liver Disease Sodium scores ( P < .001), higher Child-Turcotte-Pugh scores ( P < .001), and higher Cirrhosis Comorbidity Index scores ( P = .01). Consequently, reduced starting dose sorafenib patients had lower OS (median, 200 v 233 days, HR = 1.10). After propensity score matching and adjusting for potential confounders, there was no longer a significant OS difference (adjusted hazard ratio [HRadj], 0.92; 95% CI, 0.83 to 1.01), and this fell significantly below the noninferiority margin ( P < .001). Reduced starting dose sorafenib patients experienced significantly lower total cumulative sorafenib cost and were less likely to discontinue sorafenib because of gastrointestinal adverse effects (8.7% v 10.8%; P = .047). Conclusion The initiation of sorafenib therapy at reduced dosages was associated with reduced pill burden, reduced treatment costs, and a trend toward a decreased rate of discontinuing sorafenib because of adverse events. Reduced dosing was not associated with inferior OS relative to standard dosing.

Increased T-Cell Sinusoidal Lymphocytosis in Liver Biopsies in Patients With Chronic Hepatitis C and Mixed Cryoglobulinemia

Mixed cryoglobulinemia (MC) has a strong association with hepatitis C virus (HCV) infection and is associated with a higher degree of fibrosis and poor response to therapy. Currently, there are no known histological findings on liver biopsy that correlate with the presence of MC in HCV-infected patients, although we have occasionally noted prominent sinusoidal lymphocytosis in MC patients. The goal of this study is to determine whether sinusoidal lymphocytosis is a histological marker of MC in liver biopsies from patients with chronic hepatitis C. The liver clinic database at our institution was searched for chronic hepatitis C patients with MC who underwent liver biopsy during 1999–2005. Ten such cases were identified and were included in the study. Ten chronic hepatitis C MC-negative cases were matched for age and stage of fibrosis to serve as controls. Histological features (sinusoidal lymphocytes, inflammatory activity, acidophil bodies, and fibrosis stage) were evaluated in each biopsy. Clinical and laboratory data (serum protein electrophoresis, liver enzymes, hepatitis C viral load, treatment status, comorbidities, etc.) were also recorded. Formalin-fixed, paraffin-embedded sections were submitted for immunohistochemical analysis using antibodies against CD3, CD20, CD4, CD8, and CD68. Sinusoidal lymphocytes were counted in 5 hpf (40×) on hematoxylin and eosin (H&E) stain, and on CD3 and CD20 immunostains. The number of CD68+ Kupffer cells was also counted in a similar fashion. In the MC-positive versus MC-negative cases, mean fibrosis stage (2.4 vs. 2.4), inflammatory grade (1.7 vs. 2.1), lymphocyte count (359 vs. 128/5 hpf), and Kupffer cell count (239 vs. 220/5 HPF) were assessed. There was a significant increase in sinusoidal T-cell lymphocytes (P < 0.05) in MC-positive cases as compared to MC-negative cases. Nearly all sinusoidal lymphocytes were CD8-positive cells in both groups. Other histological parameters did not differ in the two groups. MC-positive cases tended to have a lower viral load as compared to controls (P = 0.059). The role of sinusoidal T cells in the pathogenesis of MC is currently unknown. It is unclear if the presence of these cells implies ongoing antigenic stimulation that may lead to increased risk of lymphoma. This feature may be an important clue to predict the presence of MC, an HCV-associated phenomenon that has important implications for response to treatment and disease progression.

Comparing Child-Pugh, MELD, and FIB-4 to Predict Clinical Outcomes in Hepatitis C Virus-Infected Persons: Results From ERCHIVES

Background Identifying hepatitis C virus (HCV)-positive persons at high risk of early complications can help prioritize treatment decisions. We conducted this study to compare Child-Turcotte-Pugh (CP), MELD, and FIB-4 scores for predicting clinical outcomes and to identify those at low risk of complications. Methods Within electronically retrieved cohort of HCV-infected veterans, we identified HCV-positive persons and excluded those with human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), prevalent hepatic decompensation (HD), hepatocellular carcinoma (HCC), and those treated for HCV. We calculated incidence rates for HD, HCC, and all-cause mortality at 1, 3, and 5 years after HCV diagnosis. Using receiver operating characteristic (ROC) curves, we determined the optimal cut-off values for each score for these outcomes. Results Among 21 116 persons evaluated, 89.7% were CP Class-A, 79.9% had MELD<9, and 43.4% had FIB-4<1.45. AUROC for HD at 1, 3, and 5 years was higher for FIB-4 (0.84-0.86) compared with MELD (0.70-0.76) (P < .001). AUROC for HCC at 1, 3, and 5 years was 0.81-0.82 for FIB-4 but 0.61-0.68 for CP and MELD scores. (P < .001) AUROC for all-cause mortality at 3 and 5 years was 0.65-0.68. The optimal cut-off scores to identify persons at low risk of complications were as follows: CP <5; MELD <8; FIB-4 <3 for HD and HCC, and <2 for all-cause mortality, below which <1.5% developed HD and HCC and ≤2.5% died at 3 years. Conclusions FIB-4 score is a better predictor of HD and HCC in HCV-positive persons. A score of <3 is associated with a low risk of HD and HCC 1 and 3 years after HCV diagnosis.

HIV, Aging, and Viral Coinfections: Taking the Long View

Viral suppression of human immunodeficiency virus (HIV) with combination antiviral therapy (cART) has led to increasing longevity but has not enabled a complete return to health among aging HIV-infected individuals (HIV+). Viral coinfections are prevalent in the HIV+ host and are implicated in cancer, liver disease, and accelerated aging. We must move beyond a simplistic notion of HIV becoming a “chronic controllable illness” and develop an understanding of how viral suppression alters the natural history of HIV infection, especially at the intersection of HIV with other common viral coinfections in the context of an altered, aging immune system.