Burden Of Chronic Liver Disease Research Articles

Metabolic dysfunction-associated fatty liver disease and liver fibrosis: Prevalence and associated factors in the middle-aged and older US population.

The global burden of chronic liver disease is substantial. Limited studies have reported the prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) and liver fibrosis among middle-aged and older people. Therefore, we aimed to determine the nationwide prevalence of and associated factors for MAFLD and fibrosis in adults aged 45-79years from the United States. This cross-sectional study utilized data from the 2017-2018 cycle of the National Health and Nutrition Examination Survey conducted with a nationally representative sample of the civilian, noninstitutionalized US population. Hepatic steatosis and fibrosis were assessed by transient elastography with controlled attenuation parameter and liver stiffness measurement, respectively. A total of 1186 eligible participants aged 45-79years were finally included in the analyses. The estimated prevalence of MAFLD, significant fibrosis (F≥F2), and advanced fibrosis (F≥F3) was 48.6% (95% confidence interval [CI], 43.1%-54.0%), 9.5% (95% CI, 6.8%-12.7%), and 6.7% (95% CI, 4.1%-10.1%), respectively. Multivariable logistic regression revealed an increased MAFLD predisposition in subjects with metabolic disorders including overweight/obesity, abdominal obesity, hypertension, and diabetes mellitus. Moreover, the presence of depression was an independent and strong predictor of MAFLD risk (odds ratio=3.23; 95% CI, 1.37-7.11). Elevated liver enzymes, hypertension, diabetes mellitus, hepatitis virus infection, and steatosis were associated with a high risk of significant fibrosis. Newly defined MAFLD is highly prevalent in the US middle-aged and older population. Approximately 1 in 10 people has significant liver fibrosis. In addition to metabolic disorders, the presence of depression potentially increases the risk of MAFLD.

Genetics, Immunity and Nutrition Boost the Switching from NASH to HCC.

Nonalcoholic fatty liver disease (NAFLD) is the leading contributor to the global burden of chronic liver diseases. The phenotypic umbrella of NAFLD spans from simple and reversible steatosis to nonalcoholic steatohepatitis (NASH), which may worsen into cirrhosis and hepatocellular carcinoma (HCC). Notwithstanding, HCC may develop also in the absence of advanced fibrosis, causing a delayed time in diagnosis as a consequence of the lack of HCC screening in these patients. The precise event cascade that may precipitate NASH into HCC is intricate and it entails diverse triggers, encompassing exaggerated immune response, endoplasmic reticulum (ER) and oxidative stress, organelle derangement and DNA aberrancies. All these events may be accelerated by both genetic and environmental factors. On one side, common and rare inherited variations that affect hepatic lipid remodeling, immune microenvironment and cell survival may boost the switching from steatohepatitis to liver cancer, on the other, diet-induced dysbiosis as well as nutritional and behavioral habits may furtherly precipitate tumor onset. Therefore, dietary and lifestyle interventions aimed to restore patients’ health contribute to counteract NASH progression towards HCC. Even more, the combination of therapeutic strategies with dietary advice may maximize benefits, with the pursuit to improve liver function and prolong survival.

P-15 WAITING LIST FOR LIVER TRANSPLANTATIOS: CLINICAL AND ECONOMIC BURDEN, RETROSPECTIVE STUDY

Burden of disease is an indicator that relates to health status. United States (US) and European epidemiological data have shown that the burden of chronic liver disease has increased significantly in recent decades. There are no studies evaluating the impact of complications of chronic liver disease on the waiting list for deceased donor liver transplantation (LTx). To determine the clinical and economic burden of complications of liver disease in wait-listed patients from the perspective of a transplant center. The study retrospectively analyzed medical records of 104 patients wait-listed for deceased donor LTx from October 2012 to May 2016 and whose treatment was fully provided at the study transplant center. Clinical data were obtained from electronic medical records, while economic data were collected from a hospital management software. To allocate all direct medical costs, two methods were used: full absorption costing and micro-costing. The most common complication was refractory ascites (20.2%), followed by portosystemic encephalopathy (12.5%). The mean number of admissions per patient was 1.37 ± 3.42. Variceal hemorrhage was the complication with longest median length of stay (18 days), followed by hepatorenal syndrome (13.5 days). Hepatorenal syndrome was the costliest complication (mean cost of $3565), followed by spontaneous bacterial peritonitis ($2576) and variceal hemorrhage ($1530). The burden of chronic liver disease includes a great cost for health systems. In addition, it is likely to be even greater as a result of the insidious course of the disease.

Hepatic Encephalopathy: From Metabolic to Neurodegenerative.

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome of both acute and chronic liver disease. As a metabolic disorder, HE is considered to be reversible and therefore is expected to resolve following the replacement of the diseased liver with a healthy liver. However, persisting neurological complications are observed in up to 47% of transplanted patients. Several retrospective studies have shown that patients with a history of HE, particularly overt-HE, had persistent neurological complications even after liver transplantation (LT). These enduring neurological conditions significantly affect patient's quality of life and continue to add to the economic burden of chronic liver disease on health care systems. This review discusses the journey of the brain through the progression of liver disease, entering the invasive surgical procedure of LT and the conditions associated with the post-transplant period. In particular, it will discuss the vulnerability of the HE brain to peri-operative factors and post-LT conditions which may explain non-resolved neurological impairment following LT. In addition, the review will provide evidence; (i) supporting overt-HE impacts on neurological complications post-LT; (ii) that overt-HE leads to permanent neuronal injury and (iii) the pathophysiological role of ammonia toxicity on astrocyte and neuronal injury/damage. Together, these findings will provide new insights on the underlying mechanisms leading to neurological complications post-LT.

Increasing prevalence of NAFLD/NASH among children, adolescents and young adults from 1990 to 2017: a population-based observational study

ObjectiveTo describe the prevalence and variations of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH) among children and adolescents (CADs) and young adults (YADs).DesignA population-based observational study.SettingAnnual cases and prevalence of NAFLD/NASH...

Trends in the Economic Burden of Chronic Liver Diseases and Cirrhosis in the United States: 1996-2016.

The management of chronic liver diseases (CLDs) and cirrhosis is associated with substantial healthcare costs. We aimed to estimate trends in national healthcare spending for patients with CLDs or cirrhosis between 1996 and 2016 in the United States. National-level healthcare expenditure data developed by the Institute for Health Metrics and Evaluations for the Disease Expenditure Project and prevalence of CLDs and cirrhosis derived from the Global Burden of Diseases Study were used to estimate temporal trends in inflation-adjusted US healthcare spending, stratified by setting of care (ambulatory, inpatient, emergency department, and nursing care). Joinpoint regression was used to evaluate temporal trends, expressed as annual percent change (APC) with 95% confidence intervals (CIs). Drivers of change in spending for ambulatory and inpatient services were also evaluated. Total expenditures in 2016 were $32.5 billion (95% CI, $27.0-$40.4 billion). Over 65% of spending was for inpatient or emergency department care. From 1996 to 2016, there was a 4.3%/year (95% CI, 2.8%-5.8%) increase in overall healthcare spending for patients with CLDs or cirrhosis, driven by a 17.8%/year (95% CI, 14.5%-21.6%) increase in price and intensity of hospital-based services. Total healthcare spending per patient with CLDs or cirrhosis began decreasing after 2008 (APC -1.7% [95% CI, -2.1% to -1.2%]), primarily because of reductions in ambulatory care spending (APC -9.1% [95% CI, -10.7% to -7.5%] after 2011). Healthcare expenditures for CLDs or cirrhosis are substantial in the United States, driven disproportionately by acute care in-hospital spending.

Undiagnosed liver diseases.

The landscape of chronic liver disease has drastically changed over the past 20 years, largely due to advances in antiviral therapy and the rise of metabolic syndrome and associated non-alcoholic fatty liver disease (NAFLD). Despite advances in the diagnosis and treatment of a variety of liver diseases, the burden of chronic liver disease is increasing worldwide. The first step to addressing any disease is accurate diagnosis. Here, we discuss liver diseases that remain undiagnosed, either because they are difficult to diagnose or due to hepatic manifestations of an unrecognized systemic disease. Additionally, their underlying etiology may remain unknown or they represent previously uncharacterized and therefore novel liver diseases. Our goal is to provide a framework for approaching undiagnosed liver diseases which elude standard hepatic diagnostic work-up and whose patterns of disease are often overlooked.

Upper Gi Endoscopy-indications and Findings at Tertiary Care Hospital Hyderabad/Jamshoro

Objective: To document different indications and findings of upper GI Endoscopy in our endoscopy suite.
 Methods: A descriptive study of 500 patients who underwent upper gastrointestinal (UGI) endoscopy was conducted in the Endoscopy Unit of PNS DRIGH LUMHS Jamshoro and Civil Hospital Hyderabad from April to September 2020. Included patients underwent UGI endoscopy. Demographic data including indications and endoscopic findings of the patients was collected via study proforma.
 Results: Total five hundred patients were studied; their mean age was 42.4±16.8 years. Out of all 52.8% were males. Upper GI bleed was the commonest indication (33.2%) followed by dysphagia (21.6%), epigastrium pain (10%), surveillance and screening of varices (9% and 8.2% respectively). The most common endoscopic findings were esophageal varices (32.2 %), gastritis (18.8%), and normal (11.4%). In patients with esophageal varices, 77.4% had chronic liver disease with positive serology for HCV and HBV in 63.4% and 23% respectively.
 Conclusion: The most common indication was upper GI bleed with esophageal varices for upper GI endoscopy. The underlying etiology of varices reflects the high burden of chronic liver disease due to viral hepatitis.

Natural History of NAFLD.

The epidemiology and the current burden of chronic liver disease are changing globally, with non-alcoholic fatty liver disease (NAFLD) becoming the most frequent cause of liver disease in close relationship with the global epidemics of obesity, type 2 diabetes and metabolic syndrome. The clinical phenotypes of NAFLD are very heterogeneous in relationship with multiple pathways involved in the disease progression. In the absence of a specific treatment for non-alcoholic steatohepatitis (NASH), it is important to understand the natural history of the disease, to identify and to optimize the control of factors that are involved in disease progression. In this paper we propose a critical analysis of factors that are involved in the progression of the liver damage and the occurrence of extra-hepatic complications (cardiovascular diseases, extra hepatic cancer) in patients with NAFLD. We also briefly discuss the impact of the heterogeneity of the clinical phenotype of NAFLD on the clinical practice globally and at the individual level.

Prevalence of liver fibrosis and associated risk factors in the Korean general population: a retrospective cross-sectional study

ObjectivesThe health burden of chronic liver disease is increasing worldwide. Its main histological consequence is liver fibrosis, and eventually cirrhosis. This process is rarely diagnosed at the pre-cirrhotic stage due...

The Growing Burden of Disability Related to Chronic Liver Disease in the United States: Data From the Global Burden of Disease Study 2007-2017.

Chronic liver disease (CLD) causes significant morbidity and mortality in the United States with regional variations. Comparable and consistent state‐level measures of CLD‐related morbidity and disability among U.S. states have not been well studied. Our aim was to assess the CLD burden within the United States between 2007 and 2017 based on the most common causes of CLD: hepatitis B virus, hepatitis C virus (HCV), alcoholic liver disease (ALD), and nonalcoholic fatty liver disease (NAFLD). The Global Burden of Disease database was used for the years 2007‐2017. International Classification of Diseases, Tenth Revision, codes were used to identify liver cancer (LC) and cirrhosis. Disability‐adjusted life years (DALYs) were computed by the summation of years of life lost and years lived with disability. All rates reported here were age‐standardized rates per 100,000 population. In 2017, there were 167,324 incident CLDs, 21% from LC and 79% from cirrhosis; this number was 30% higher than in 2007. The highest rate increases were seen in Kentucky, New York, and Pennsylvania. In 2017, there were 90,046 CLD‐related deaths, which was 34% higher than in 2007. Highest rank increases were seen in Kentucky, Montana, and Washington. The rate of CLD incidence and death due to NAFLD was higher than other causes of CLD. In 2017, CLD caused 2.33 million DALYs, which was 27% higher than in 2007 and was mainly driven by HCV (37.2%), ALD (27.7%), and NAFLD (10.6%). California, Texas, and Florida had the highest DALYs; however, the highest CLD‐DALY rates per 100,000 population were seen in New Mexico, District of Columbia, and Oklahoma. Conclusion: The CLD‐related burden is increasing in the majority of U.S. states at an unprecedented rate. The impact of this burden on individual states is heterogeneous, and there are important disparities among states that merit further investigation.

COVID-19 pandemic and future burden of chronic liver diseases

COVID-19 pandemic and future burden of chronic liver diseases

Nonalcoholic Fatty Liver Disease-Related Chronic Kidney Disease.

Nonalcoholic fatty liver disease has become the main concern of hepatologists around the world and the main research topic for identifying effective and safe therapy. Advances in the treatment of chronic viral hepatitis in recent years have opened the way towards reducing mortality in patients with chronic liver disease. This goal has not yet been reached, as the burden of chronic liver disease remains a future major health problem as the incidence of the nonalcoholic fatty liver disease continues to rise. The proportion of patients with liver cirrhosis and those with hepatocellular carcinoma due to nonalcoholic liver disease on the liver transplant waiting list has increased in the last years. The upward trend in the incidence and prevalence of the disease in recent decades raises concern over a possible global epidemic, especially as the disease is still underestimated and underdiagnosed. Chronic kidney disease presented an increase in incidence and prevalence during the last years, and it has been associated not only with increased morbidity and mortality but also with high costs for the health system. During the last decade, several studies have shown the association between nonalcoholic fatty disease and chronic kidney disease, two major worldwide health problems.

Public Health Perspectives on Combating Liver Disease

Watch a video presentation of this article Although not one of the World Health Organization’s top four chronic disease priorities, the global burden of chronic liver disease is significant. In 2016, the death toll from cirrhosis alone was 1.2 million, which was not far behind that of tuberculosis (1.3 million) and diabetes (1.5 million). Beyond its mortality impact, chronic liver disease is associated with enormous health care cost and disability-adjusted life years. In addition, it disproportionately affects low- and middle-income countries and vulnerable subpopulations. This series in Clinical Liver Diseases presents a public health perspective on combating chronic liver disease. Chronic liver disease is a unique kind of public health problem. As the consequence of infectious etiologies (hepatitis B and hepatitis C), as well as lifestyle behaviors (alcohol consumption and obesity), it spans both communicable and noncommunicable categories of disease. Its epidemiology varies widely between and even within countries, and is subject to the lifestyle behaviors, socioeconomic factors, cultural influences, and historical events promoting each etiology. Lastly, unlike other chronic diseases, the direct clinical sequelae of liver disease encompass nonmalignant and malignant complications. Public health approaches require efforts on all fronts: prevention, screening, and treatment. Although there is not a set recipe for success, it is useful to learn about best practices from various regions of the world. To that end, in these public health series perspectives on liver diseases, Shantan Cheemerla et al. present an overview of the global burden of chronic liver disease, Andrew Yeoman discusses potential strategies on population-level liver disease detection, Luis Diaz et al. propose local solutions to the alcohol liver disease problem in Latin America, and we present best practice examples for combating hepatitis B from the Sago prefecture in Japan (Yuichiro Eguchi et al.) and hepatitis C among incarcerated persons in Canada (Sofia Bartlett et al.).

Health-related quality of life in Cuban patients with chronic liver disease: A real-world experience

Introduction and objectivesPatient-reported outcomes (PROs) are important for comprehensive assessment of chronic liver disease (CLD). Latin America and the Caribbean have a high burden of CLD, but PROs are lacking. We assessed health-related quality of life (HRQL) in Cuban patients with compensated CLD. Materials and methodsA cross sectional study performed of adult patients with a diagnosis of chronic viral infection B and C (HBV, HCV), non-alcoholic fatty liver diseases (NAFLD) and autoimmune liver diseases (AILD) including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and overlap syndrome (AIH+PBC). PROs were collected using: Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Work Productivity and Activity-Specific Health Problem (WPAI: SHP), and the Chronic Liver Disease Questionnaire (CLDQ)-disease-specific. Results543 patients enrolled, n=91 (HBV), n=188 (HCV), n=221 (NAFLD), n=43 (AILD). Of those with AILD, 22 had AIH, 14 PBC, and 7 overlap AIH/PBC. Mean age was 53.5 years, 64.1% female, 69.2% white, and 58.0% employed. Patients with HCV and AILD had more severe liver disease. A significant impairment in PROs was observed in HCV group whereas the AILD patients had more activity impairment. CLDQ-HRQL scores were significantly lower for patients with NAFLD and AILD compared to HBV. Male gender and exercising ≥90min/week predicted better HRQL. The strongest independent predictors of HRQL impairment were fatigue, abdominal pain, anxiety, and depression (p<0.05). ConclusionsHRQL for Cuban patients with compensated CLD differs according to the CLD etiology. Patients with HCV and AILD had the worst PRO scores most likely related to severe underlying liver disease and/or extrahepatic manifestations.

Changes in the Global Burden of Chronic Liver Diseases From 2012 to 2017: The Growing Impact of NAFLD.

Chronic hepatitis B virus (HBV), hepatitis C virus (HCV), nonalcoholic fatty liver disease (NAFLD), and alcohol-associated liver disease (ALD) are main causes of chronic liver disease. We assessed the global incidence, mortality, and disability-adjusted life-years (DALYs) related to chronic liver disease (primary liver cancer [LC] and cirrhosis). We obtained data from the 2017 Global Burden of Disease study. In 2017, there were 2.14million liver-related deaths (2.06-2.30million), representing an 11.4% increase since 2012 (16.0% increase in LC deaths; 8.7% increase in cirrhosis deaths). LC and cirrhosis accounted for 38.3% and 61.7%, respectively, of liver deaths (LC and cirrhosis deaths were related to HBV [39% and 29%], HCV [29% and 26%], ALD [16% and 25%], and NAFLD [8% and 9%]). Between 2012 and 2017, age-standardized incidence rate, age-standardized death rate (ASDR), and age-standardized DALY rate increased for LC from 11.1 to 11.8, 10.1 to 10.2, and 250.4 to 253.6 per 100,000, respectively. Although age-standardized incidence rate for cirrhosis increased from 66.0 to 66.3, ASDR and age-standardized DALY rate decreased from 17.1 to 16.5 and 532.9 to 510.7, respectively. The largest increase in ASDR for LC occurred in Eastern Europe (annual percent change [APC]=2.18% [0.89%-3.49%]), whereas the largest decrease occurred in high-income Asia Pacific (APC=-2.88% [-3.58 to -2.18%]). ASDR for LC-NAFLD and ALD increased annually by 1.42% (1.00%-1.83%) and 0.53% (0.08-0.89), respectively, whereas there were no increases for HBV (P=0.224) and HCV (P=0.054). ASDR for cirrhosis-NAFLD increased (APC=0.29% [0.01%-0.59%]) but decreased for ALD (APC=-0.44% [-0.78% to -0.40%]), HCV (APC=-0.50% [-0.81% to -0.18%]), and HBV (APC=-1.43% [-1.71% to -0.40%]). From 2012 to 2017, the global burden of LC and cirrhosis has increased. Viral hepatitis remains the most common cause of liver deaths, and NAFLD is the most rapidly growing contributor to liver mortality and morbidity.

The Growing Burden of Disability Related to Nonalcoholic Fatty Liver Disease: Data From the Global Burden of Disease 2007-2017.

Chronic liver disease (CLD) is a growing cause of morbidity and mortality worldwide. The burden of CLD varies according to etiology and geographic location. We assessed the global burden of disability from the most important complications of CLD (cirrhosis and liver cancer [LC]) according to the most common etiologies between 2007 and 2017. We obtained years living with disability (YLD), years of life lost (YLL), and disability‐adjusted life‐years (DALYs) data from the Global Burden of Disease 2017 study. Between 2007 and 2017, LC DALYs decreased by 4.52% and cirrhosis DALYs decreased by 10.58%. Nevertheless, in 2017, CLD caused 62.16 million DALYs (33.4% LC and 66.5% cirrhosis), of which 96.8% came from YLL (34.1% LC and 65.9% cirrhosis) and 3.2% from YLD (11.6% LC and 88.4% cirrhosis). In 2017, Asia accounted for 66% of all DALYs globally. Central Asia, Africa regions, Southeast Asia, and Eastern Europe had the highest liver‐related DALYs (≥1,000 per 100,000), whereas the lowest rates (≤500 per 100,000) were seen in high‐income regions, such as Asia Pacific, North America, Western Europe, and Australasia. In 2007, hepatitis B virus caused the majority (47.5%) of liver‐related DALYs, followed by hepatitis C virus (23.7%), alcoholic liver disease (14.2%), and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) (6.4%). In 2017, these rates shifted to 45.7%, 24.1%, 4.8%, and 7.1%, respectively. Between 2007 and 2017, cirrhosis‐related DALYs due to NAFLD/NASH increased by 23.4%, whereas the increment was 37.5% for LC‐related DALYs due to NAFLD/NASH. Conclusion: DALYs due to viral hepatitis still account for the largest proportion of CLD‐related DALYs. Although DALYs from all other liver diseases have remained stable in the last decade, DALYs related to NAFLD/NASH are growing. National, regional, and global policies are needed to address the disability burden of NAFLD across the world.

Innovative strategies for reducing the burden of chronic liver disease

Alcohol consumption is increasing in the UK, bringing an increased incidence of cirrhosis, which in turn can lead to hepatic encephalopathy. This complication of cirrhosis can be devastating for patients and their families, and incurs a large health economic burden to the NHS. Cirrhosis is, of course, preventable. As disease prevention is at the heart of the NHS Long Term Plan, it can be used as the basis of a 10-year plan to avoid the complications of chronic liver disease.

Thrombospondin1 as a potential therapeutic target for human nonalcoholic fatty liver disease.

Thrombospondin1 as a potential therapeutic target for human nonalcoholic fatty liver disease.

Trends in the Burden of Chronic Liver Disease Among Hospitalized US Adults

One factor associated with the rapidly increasing clinical and economic burden of chronic liver disease (CLD) is inpatient health care utilization. To understand trends in the hospitalization burden of CLD in the US. This cross-sectional study of hospitalized adults in the US used data from the National Inpatient Sample from 2012 to 2016 on adult CLD-related hospitalizations. Data were analyzed from June to October 2019. Hospitalizations identified using a comprehensive review of CLD-specific International Classification of Diseases, Ninth Revision, Clinical Modification and International Statistical Classification of Diseases, Tenth Revision, Clinical Modification codes. Survey-weighted annual trends in national estimates of CLD-related hospitalizations, in-hospital mortality, and hospitalization costs, stratified by demographic and clinical characteristics. This study included 1 016 743 CLD-related hospitalizations (mean [SD] patient age, 57.4 [14.4] years; 582 197 [57.3%] male; 633 082 [62.3%] white). From 2012 to 2016, the rate of CLD-related hospitalizations per 100 000 hospitalizations increased from 3056 (95% CI, 3042-3069) to 3757 (95% CI, 3742-3772), and total inpatient hospitalization costs increased from $14.9 billion (95% CI, $13.9 billion to $15.9 billion) to $18.8 billion (95% CI, $17.6 billion to $20.0 billion). Mean (SD) patient age increased (56.8 [14.2] years in 2012 to 57.8 [14.6] years in 2016) and, subsequently, the proportion with Medicare also increased (41.7% [95% CI, 41.1%-42.2%] to 43.6% [95% CI, 43.1%-44.1%]) (P for trend < .001 for both). The proportion of hospitalizations of patients with hepatitis C virus was similar throughout the period of study (31.6% [95% CI, 31.3%-31.9%]), and the proportion with alcoholic cirrhosis and nonalcoholic fatty liver disease showed increases. The mortality rate was higher among hospitalizations with alcoholic cirrhosis (11.9% [95% CI, 11.7%-12.0%]) compared with other etiologies. Presence of hepatocellular carcinoma was also associated with a high mortality rate (9.8% [95% CI, 9.5%-10.1%]). Cost burden increased across all etiologies, with a higher total cost burden among hospitalizations with alcoholic cirrhosis ($22.7 billion [95% CI, $22.1 billion to $23.2 billion]) or hepatitis C virus ($22.6 billion [95% CI, $22.1 billion to $23.2 billion]). Presence of cirrhosis, complications of cirrhosis, and comorbidities added to the CLD burden. Over the study period, the total estimated national hospitalization costs in patients with CLD reached $81.1 billion. The inpatient CLD burden in the US is likely increasing because of an aging CLD population with increases in concomitant comorbid conditions.