Joseph J. Larson

Nonalcoholic Fatty Liver Disease is Associated with Coronary Artery Calcification

Nonalcoholic fatty liver disease (NAFLD) is related to risk factors of coronary artery disease, such as dyslipidemia, diabetes, and metabolic syndrome, which are closely linked with visceral adiposity. The aim of this study was to investigate whether NAFLD was associated with coronary artery calcification (CAC), which is used as a surrogate marker for coronary atherosclerosis independent of computed tomography (CT)‐measured visceral adiposity. Out of 5,648 subjects who visited one of our health screening centers between 2003 and 2008, we enrolled 4,023 subjects (mean age, 56.9 ± 9.4 years; 60.7% males) without known liver disease or a history of ischemic heart disease. CAC score was evaluated using the Agatston method. On univariate analysis, the presence of CAC (score >0) was significantly associated with age, sex, body mass index, aspartate aminotransferase, alanine aminotransferase, high‐density lipoprotein cholesterol, triglycerides, and increased risk of diabetes, hypertension, smoking, and NAFLD. Increasing CAC scores (0, <10, 10‐100, ≥100) were associated with higher prevalence of NAFLD (odds ratio [OR], 1.84; 95% confidence interval [CI], 1.61‐2.10; P<0.001). Multivariable ordinal regression analysis was adjusted for traditional risk factors, and CT‐measured visceral adipose tissue area in a subgroup of subjects showed that the increased CAC scores were significantly associated with the presence of NAFLD (OR, 1.28, 95% CI, 1.04‐1.59; P = 0.023) independent of visceral adiposity. Conclusion: Patients with NAFLD are at increased risk for coronary atherosclerosis independent of classical coronary risk factors, including visceral adiposity. These data suggest that NAFLD might be an independent risk factor for coronary artery disease. (HEPATOLOGY 2012)

Underestimation of Liver-Related Mortality in the United States

BACKGROUND & AIMS According to the National Center for Health Statistics (NCHS), chronic liver disease and cirrhosis is the 12(th) leading cause of death in the United States. However, this single descriptor might not adequately enumerate all deaths from liver disease. The aim of our study was to update data on liver mortality in the United States. METHODS Mortality data were obtained from the Rochester Epidemiology Project (1999-2008) and the National Death Registry (1979-2008). Liver-specific mortality values were calculated. In contrast to the narrow NCHS definition, updated liver-related causes of death included other specific liver diagnoses (eg, hepatorenal syndrome), viral hepatitis, and hepatobiliary cancers. RESULTS The Rochester Epidemiology Project database contained information on 261 liver-related deaths, with an age- and sex-adjusted death rate of 27.0/100,000 persons (95% confidence interval: 23.7-30.3). Of these, only 71 deaths (27.2%) would have been captured by the NCHS definition. Of cases for which viral hepatitis or hepatobiliary cancer was the cause of death, 96.9% and 94.3% had liver-related immediate causes of death, respectively. In analysis of data from the National Death registry (2008), use of the updated definition increased liver mortality by >2-fold (from 11.7 to 25.7 deaths/100,000, respectively). Using NCHS definitions, liver-related deaths decreased from 18.9/100,000 in 1979 to 11.7/100,000 in 2008-a reduction of 38%. However, using the updated estimate, liver-related deaths were essentially unchanged from 1979 (25.8/100,000) to 2008 (25.7/100,000). Mortality burden was systematically underestimated among non-whites and persons of Hispanic ethnicity. CONCLUSIONS Based on analyses of the Rochester Epidemiology Project and National Death databases, liver-related mortality has been underestimated during the past 2 decades in the United States.

Morbidity and Mortality Among Older Individuals With Undiagnosed Celiac Disease

BACKGROUND & AIMS Outcomes of undiagnosed celiac disease (CD) are unclear. We evaluated the morbidity and mortality of undiagnosed CD in a population-based sample of individuals 50 years of age and older. METHODS Stored sera from a population-based sample of 16,886 Olmsted County, Minnesota, residents 50 years of age and older were tested for CD based on analysis of tissue transglutaminase and endomysial antibodies. A nested case-control study compared serologically defined subjects with CD with age- and sex-matched, seronegative controls. Medical records were reviewed for comorbid conditions. RESULTS We identified 129 (0.8%) subjects with undiagnosed CD in a cohort of 16,847 older adults. A total of 127 undiagnosed cases (49% men; median age, 63.0 y) and 254 matched controls were included in a systematic evaluation for more than 100 potentially coexisting conditions. Subjects with undiagnosed CD had increased rates of osteoporosis and hypothyroidism, as well as lower body mass index and levels of cholesterol and ferritin. Overall survival was not associated with CD status. During a median follow-up period of 10.3 years after serum samples were collected, 20 cases but no controls were diagnosed with CD (15.2% Kaplan-Meier estimate at 10 years). CONCLUSIONS With the exception of reduced bone health, older adults with undiagnosed CD had limited comorbidity and no increase in mortality compared with controls. Some subjects were diagnosed with CD within a decade of serum collection, indicating that although most cases of undiagnosed CD are clinically silent, some result in symptoms. Undiagnosed CD can confer benefits and liabilities to older individuals.

A revised model for end-stage liver disease optimizes prediction of mortality among patients awaiting liver transplantation.

BACKGROUND & AIMS The Model for End Stage Liver Disease (MELD) was originally developed based on data from patients who underwent the transjugular intrahepatic portosystemic shunt procedure. An updated MELD based on data from patients awaiting liver transplantation should improve mortality prediction and allocation efficiency. METHODS Wait-list data from adult primary liver transplantation candidates from the Organ Procurement and Transplantation Network were divided into a model derivation set (2005-2006; n=14,214) and validation set (2007-2008; n=13,945). Cox regression analysis was used to derive and validate an optimized model that updated coefficients and upper and lower bounds for MELD components and included serum levels of sodium. Main outcomes measure was ability to predict 90-day mortality of patients on the liver transplantation wait list. RESULTS Optimized MELD score updated coefficients and implemented new upper and lower bounds for creatinine (0.8 and 3.0 mg/dL, respectively) and international normalized ratio (1 and 3, respectively). Serum sodium concentrations significantly predicted mortality, even after adjusting for the updated MELD model. The final model, based on updated fit of the 4 variables (ie, bilirubin, creatinine, international normalized ratio, and sodium) had a modest yet statistically significant gain in discrimination (concordance: 0.878 vs 0.865; P<.01) in the validation dataset. Utilization of the new score could affect up to 12% of patients (based on changed score for 459 of 3981 transplants in the validation set). CONCLUSIONS Modification of MELD score to update coefficients, change upper and lower bounds, and incorporate serum sodium levels improved wait-list mortality prediction and should increase efficiency of allocation of donated livers.

Familial Aggregation of Irritable Bowel Syndrome: A Family Case–Control Study

OBJECTIVES:Irritable bowel syndrome (IBS) clusters in families, but previous studies documented family history only from patients. We have shown that patient–relative agreement on IBS status is poor. Thus, we conducted a family case–control study with direct survey of symptoms from family members to better quantitate the aggregation of IBS in families. The aims of this study were to (i) compare the prevalence of IBS in case-relatives with control-relatives, and (ii) determine whether gender, relationship, predominant symptom, and environmental risk factors affect familial aggregation.METHODS:Outpatients with IBS, matched controls, and their first-degree relatives completed a bowel symptom questionnaire. Percent of cases and controls with a family history were compared and odds ratios were computed using χ2-test; recurrence risks to relatives were computed using logistic regression and generalized estimating equations.RESULTS:Data were collected from 477 cases, 297 controls, 1,492 case-relatives, and 936 control-relatives. Probands had a median age of 50 and 78% were women. 50% of case and 27% of control families had at least another relative with IBS yielding an odds ratio of 2.75 (95% CI: 2.01–3.76, P<0.0001). When aggregation estimates were reevaluated stratifying by relative relationship or proband gender, generational and gender effects were not observed. Familial clustering by bowel habit was weakest for diarrhea, and strongest for alternating bowel habits.CONCLUSIONS:IBS aggregates strongly in families. The strength of the association does vary somewhat by relationship to proband, but the lack of association in spouses supports either a possible genetic etiology or a shared household environmental exposure as an underlying cause of IBS.

Model to estimate survival in ambulatory patients with hepatocellular carcinoma.

Survival of patients with hepatocellular carcinoma (HCC) is determined by the extent of the tumor and the underlying liver function. We aimed to develop a survival model for HCC based on objective parameters including the Model for Endstage Liver Disease (MELD) as a gauge of liver dysfunction. This analysis is based on 477 patients with HCC seen at Mayo Clinic Rochester between 1994 and 2008 (derivation cohort) and 904 patients at the Korean National Cancer Center between 2000 and 2003 (validation cohort). Multivariate proportional hazards models and corresponding risk score were created based on baseline demographic, clinical, and tumor characteristics. Internal and external validation of the model was performed. Discrimination and calibration of this new model were compared against existing models including Barcelona Clinic Liver Cancer (BCLC), Cancer of the Liver Italian Program (CLIP), and Japan Integrated Staging (JIS) scores. The majority of the patients had viral hepatitis as the underlying liver disease (100% in the derivation cohort and 85% in the validation cohort). The survival model incorporated MELD, age, number of tumor nodules, size of the largest nodule, vascular invasion, metastasis, serum albumin, and alpha‐fetoprotein. In cross‐validation, the coefficients remained largely unchanged between iterations. Observed survival in the validation cohort matched closely with what was predicted by the model. The concordance (c)‐statistic for this model (0.77) was superior to that for BCLC (0.71), CLIP (0.70), or JIS (0.70). The score was able to further classify patient survival within each stage of the BCLC classification. Conclusion: A new model to predict survival of HCC patients based on objective parameters provides refined prognostication and supplements the BCLC classification. (HEPATOLOGY 2012)

Patients With Celiac Disease Are Not Followed Up Adequately

BACKGROUND & AIMS Adherence to a gluten-free diet is the only effective treatment for celiac disease. It has been recommended that patients be followed up, make regular visits to the clinic, and undergo serologic analysis for markers of celiac disease, although a follow-up procedure has not been standardized. We determined how many patients with celiac disease are actually followed up. METHODS We collected data on 122 patients with biopsy-proven celiac disease, diagnosed between 1996 and 2006 in Olmsted County, Minnesota (70% women; median age, 42 y), for whom complete medical records and verification of residency were available. We determined the frequency at which patients received follow-up examinations, from 6 months to 5 years after diagnosis. The Kaplan-Meier method was used to estimate event rates at 1 and 5 years. Patients were classified according to categories of follow-up procedures recommended by the American Gastroenterological Association (AGA). RESULTS We estimated that by 1 and 5 years after diagnosis with celiac disease, 41.0% and 88.7% of the patients had follow-up visits, 33.6% and 79.8% were assessed for compliance with a gluten-free diet, 3.3% and 15.8% met with a registered dietitian, 2.5% and 18.1% had an additional intestinal biopsy, and 22.1% and 65.6% received serologic testing for markers of celiac disease, respectively. Among 113 patients (93%) who were followed up for more than 4 years, only 35% received follow-up analyses that were consistent with AGA recommendations. CONCLUSIONS Patients with celiac disease are not followed up consistently. Follow-up examinations often are inadequate and do not follow AGA recommendations. Improving follow-up strategies for patients with celiac disease could improve management of this disease.

Chronic kidney disease and associated mortality after liver transplantation--a time-dependent analysis using measured glomerular filtration rate.

BACKGROUND & AIMS The accuracy of creatinine-based estimated GFR (eGFR) in assessing the prevalence of chronic kidney disease (CKD) and associated mortality after liver transplantation (LTx) is unknown. Using measured GFR (mGFR) by iothalamate clearance, we determined the prevalence of the entire spectrum of renal dysfunction and the impact of CKD on mortality after LTx. METHODS A database that prospectively tracks all LTx recipients at this academic transplant program from 1985 to 2012 was queried to identify all adult primary LTx recipients. Our post-LTx protocol incorporates GFR measurement by iothalamate clearance at regular intervals. A multistate model was used to assess the prevalence of CKD, kidney transplant, and death after LTx. Time-dependent Cox regression analysis was performed to evaluate the impact of mGFR and eGFR changes on survival. RESULTS A total of 1211 transplant recipients were included. At the time of LTx, the median age was 54 years, 60% were male and 86% were Caucasian. At 25 years after LTx, 54% of patients died, 9% underwent kidney transplantation, whereas 7%, 21%, and 18% had mGFR >60, 59-30, and <30 ml/min/1.73 m(2) respectively. The risk of death increased when mGFR decreased below 30 ml/min/1.73 m(2): HR = 2.67 (95% CI = 1.80-3.96) for GFR = 29-15 ml/min/1.73 m(2) and HR = 5.47 (95% CI = 3.10-9.65) for GFR <15 ml/min/1.73 m(2). Compared to mGFR, eGFR underestimated mortality risk in LTx recipients with an eGFR of 30-90 ml/min/1.73 m(2). CONCLUSIONS An overwhelming majority of LTx recipients develop CKD. The risk of death increases exponentially when GFR <30 ml/min/1.73 m(2). Creatinine-based eGFR underestimates the mortality risk in a large proportion of patients.

Biliary Tract Cancers in Olmsted County, Minnesota, 1976-2008

OBJECTIVES:The epidemiology of biliary tract cancers has changed in the United States in the past several decades. The aim of this study is to evaluate biliary tract cancers with regard to the incidence rates, etiology, treatment, and survival in Olmsted County between 1976 and 2008.METHODS:Community residents over 20 years of age with a newly diagnosed biliary tract cancers were identified using the Rochester Epidemiology Project. Clinical information, including tumor stage, treatment, and survival status was abstracted from the medical records. The incidence rate was calculated considering the entire population of Olmsted County to be at risk and adjusted by age and sex according to US Census 2000 population. Temporal trends of patient survival with biliary tract cancers were assessed.RESULTS:A total of 116 subjects met the study criteria. The age-sex-adjusted incidence rate of intrahepatic cholangiocarcinoma (ICC) increased from 0.3 to 2.1 (P=0.02) but one of gall bladder (GB) cancer decreased from 4.0 to 2.2 (P=0.04) per 100,000 person-years between 1976 and 2008 (P<0.01). Overall incidence rates of remaining biliary tract cancers have not changed. Overall 59% of patients presented with stage 3 or 4 cancers and a median survival was 6.3 months. Survival in patients with biliary tract cancer has minimally improved from median survival of 4.2–7.7 months between 1976 and 2008 (P=0.05).CONCLUSIONS:In Olmsted County, the incidence of ICC and GB cancer has increased and decreased, respectively. The prognosis remains poor in community residents diagnosed with biliary tract cancers.

Impact of MELD on waitlist outcome of retransplant candidates.

Under the current allocation system for liver transplantation (LTx), primary and retransplantation (ReTx) are treated identically. The aims of this study were (1) to compare the risk of death between ReTx and primary LTx candidates at a given MELD score and (2) to gauge the impact of the MELD‐based allocation system on the waitlist outcome of ReTx candidates. Based on data of all waitlist registrants in the United States between 2000 and 2006, unique adult patients with chronic liver disease were identified and followed forward to determine mortality within six months of registration. There were a total of 45,943 patients waitlisted for primary LTx and 2081 registered for ReTx. In the MELD era (n = 30,175), MELD was significantly higher among ReTx candidates than primary LTx candidates (median, 21 vs. 15). Within a range of MELD scores where most transplantation took place, mortality was comparable between ReTx and primary candidates after adjusting for MELD. The probability for LTx increased significantly following implementation of the MELD‐based allocation in both types of candidates. We conclude that by and large, primary and ReTx candidates fare equitably under the current MELD‐based allocation system, which has contributed to a significant increase in the probability of LTx.