Association of HIV Infection, Hepatitis C Virus Infection, and Metabolic Factors With Liver Stiffness Measured by Transient Elastography

J Infect Dis. (2013) doi: 10.1093/infdis/jit357 First published online: July 30, 2013

M. Rami Bailony1, Rebecca Scherzer1,2, Gregory Huhn3, Michael W. Plankey4, Marion G. Peters1 and Phyllis C. Tien1,2

+ Author Affiliations

Abstract

Background. Few studies have examined the relationship of human immunodeficiency virus (HIV) monoinfection and its associated perturbations with liver fibrosis.

Methods. Using multivariable linear regression, we examined the demographic, behavioral, metabolic and viral factors associated with transient elastography–measured liver stiffness in 314 participants (165 HIV positive/hepatitis C virus [HCV] negative, 78 HIV positive/HCV positive, 14 HIV negative/HCV positive, 57 HIV negative/HCV negative) in the Women's Interagency HIV Study.

Results. Compared with HIV negative/HCV negative women, HIV positive/HCV positive women had higher median liver stiffness values (7.1 vs 4.4 kPa; P < .001); HIV positive/HCV negative and HIV negative/HCV negative women had similar liver stiffness values (both 4.4 kPa; P = .94). HIV/HCV coinfection remained associated with higher liver stiffness values (74% higher; 95% confidence interval [CI], 49–104) even after multivariable adjustment. Among HCV positive women, waist circumference (per 10-cm increase) was associated with 18% (95% CI, 7.5%–30%) higher liver stiffness values after multivariable adjustment; waist circumference showed little association among HIV positive/HCV negative or HIV negative/HCV negative women. Among HIV positive/HCV negative women, history of AIDS (13%; 95% CI, 4% –27%) and HIV RNA (7.3%; 95% CI, 1.59%–13.3%, per 10-fold increase) were associated with greater liver stiffness.

Conclusions. HCV infection but not HIV infection is associated with greater liver stiffness when infected women are compared with those with neither infection. Our finding that waist circumference, a marker of central obesity, is associated with greater liver stiffness in HIV/HCV-coinfected but not HIV-monoinfected or women with neither infection suggests that in the absence of HCV-associated liver injury the adverse effects of obesity are lessened.

Received February 6, 2013. Accepted May 17, 2013.

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Kids Have Hep C Too

September 5, 2013

Adults are not the only ones who are infected with the Hepatitis C virus. Research shows that a majority of childhood cases are missed.

By Nicole Cutler L.Ac.

After decades of the Hepatitis C virus (HCV) going unnoticed by mainstream institutions, this illness is finally being recognized as a major health problem. An estimated five times more Americans are infected with Hepatitis C than HIV – the virus that causes AIDS, yet HCV is not routinely screened for. This is unfortunate, because the earlier Hepatitis C treatment commences the better chance there is of eliminating the virus. While prevention, detection and treatment of Hepatitis C are just now gaining momentum, these efforts primarily target adults. Hopefully, research released will encourage the medical community to expand Hepatitis C education and awareness to include children.

Continue reading this entire article …..

Women have higher rate of spontaneous clearance of hepatitis C virus

Provided by MedicalXpress

September 12, 2013

A study of patients infected with acute hepatitis C virus (HCV) infection found that women had higher rates of spontaneous viral clearance—undetectable levels of the virus without initiating drug therapy. Findings published in Hepatology, a journal of the American Association for the Study of Liver Diseases, indicate that the gene IL28B (rs12979860) and HCV genotype 1 are also independent predictors of spontaneous HCV clearance.

In 2011, there were 1,229 cases of acute HCV reported to the Centers for Disease Control and Infection (CDC), which represents a 44% increase over 2010. Medical evidence indicates that 25% of those with acute HCV spontaneously clear their infection. Previous prospective studies link female sex, immune responses, neutralizing antibodies and genetics to viral clearance.

"Knowledge of acute HCV clearance is limited given that patients are typically asymptomatic during the initial stages of infection and at-risk populations, such as people who inject drugs, are often marginalized," explains lead author Dr. Jason Grebely at The Kirby Institute, University of New South Wales in Australia. "Our research aims to advance understanding of time to and predictors of HCV clearance to improve early therapeutic intervention options."

Researchers used data from the InC3 Study—a collaboration of nine prospective studies from Australia, Canada, the Netherlands, and the U.S. funded by the National Institutes of Health and led by Professor Kimberly Page from the University of California San Francisco—which included participants with HCV and human immunodeficiency virus (HIV) who were recruited between 1985 and 2010. The present study included 632 individuals diagnosed with acute HCV with 35% of the group being female and 82% Caucasian. Roughly 96% of participants had injected drugs, 47% were infected with HCV genotype 1 and 5% were co-infected with HIV.

Results show that 173 of the 632 participants had spontaneously cleared the virus during follow-up. At one year post-infection, 25% had HCV clearance. The average time to clearance among those who cleared HCV was 16.5 weeks, with 34%, 67% and 83% demonstrating clearance at 3, 6 and 12 months, respectively.

"Our findings indicate that females, those with the IL28B gene, and those with HCV genotype 1 are independent predictors of spontaneous clearance of acute HCV," concludes Prof. Kimberly Page. "Further research is necessary to understand the effect of sex in controlling HCV infection."

Explore further: Only half newly reported HCV cases receiving follow-up test

More information: "The Effects of Female Sex, Viral Genotype and Il28b Genotype on Spontaneous Clearance of Acute Hepatitis C Virus Infection." Jason Grebely, Kimberly Page, Rachel Sacks-Davis, Maarten Schim van der Loeff, Thomas M. Rice, Julie Bruneau, Meghan D. Morris, Behzad Hajarizadeh, Janaki Amin, Andrea L. Cox, Arthur Y. Kim, Barbara H. McGovern, Janke Schinkel, Jacob George, Naglaa H. Shoukry, Georg M. Lauer, Lisa Maher, Andrew R. Lloyd, Margaret Hellard, Gregory J. Dore and Maria Prins on behalf of the InC3 Study Group. Hepatology; ( DOI: 10.1002/hep.26639 ); Published Online: August 2, 2013.

Journal reference: Hepatology

Provided by Wiley

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Promising AIDS Vaccine Being Developed

Image Credit: Thinkstock.com

September 11, 2013

Brett Smith for redOrbit.com – Your Universe Online

A promising new AIDS vaccine being developed at Oregon Health & Science University has demonstrated the capacity to effectively remove all traces of an AIDS-causing virus from non-human primates, according to a newly published report in the journal Nature.

The vaccine is being tested on a primate form of HIV, called simian immunodeficiency virus (SIV), which causes AIDS in monkeys. After working further to refine the vaccine, OHSU scientists said they hoped an HIV-form of the potential vaccine could soon be tested in human subjects.

“To date, HIV infection has only been cured in a very small number of highly-publicized but unusual clinical cases in which HIV-infected individuals were treated with anti-viral medicines very early after the onset of infection or received a stem cell transplant to combat cancer,” said Dr. Louis Picker, associate director of the OHSU Vaccine and Gene Therapy Institute. “This latest research suggests that certain immune responses elicited by a new vaccine may also have the ability to completely remove HIV from the body.”

In conjunction with researchers at two other American institutions, the Picker lab’s approach uses the cytomegalovirus (CMV), a common virus carried by a large percentage of the population that typically causes no symptoms. The researchers found that pairing CMV with SIV had a unique and desirable effect. CMV engineered to express SIV proteins results in the generation and indefinite maintenance of so-called “effector memory” T-cells that are designed to seek out and destroying SIV-infected cells.

T-cells are a vital component of the body’s immune system. Unfortunately, T-cells drawn out as an immune system response to conventional vaccines of SIV are not able to eradicate the virus. However, the SIV-specific T-cells elicited by the altered CMV were different. About half of the monkeys given highly pathogenic SIV after being vaccinated with the modified vaccine still became infected with SIV, but over time their bodies eliminated all traces of the virus.

The researchers said the ‘virus hunters’ of the affected primates’ bodies were given a much better targeting system by the new vaccine candidate – along with better weapons to locate and destroy their elusive enemy.

“Through this method we were able to teach the monkey’s body to better ‘prepare its defenses’ to combat the disease,” Picker said. “Our vaccine mobilized a T-cell response that was able to overtake the SIV invaders in 50 percent of the cases treated.”

“Moreover, in those cases with a positive response, our testing suggests SIV was banished from the host,” he added. “We are hopeful that pairing our modified CMV vector with HIV will lead to a similar result in humans.”

The vaccine researchers said they are now investigating the potential reasons why only a fraction of the animals treated had a positive reaction to the vaccine. They added that the effectiveness of the vaccine candidate could potentially be boosted.

Speaking in front of the 246th gathering of the American Chemical Society in Indianapolis, Stanford chemist Paul Wender said AIDS might be curable in two years thanks to prostratin, a drug candidate made from the bark of a Samoan tree.

Wender said preliminary tests are currently being done on animals, but blood from AIDS patients who have been on immunosuppressive therapy is also being tested and the results appear positive.

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Infected health worker sparks UK-wide hep C investigation

Provided by Nursing Times

September, 2013 | By Steve Ford

Around 3,000 patients have been contacted in Wales over the risk they may have been infected with hepatitis C by a retired healthcare worker who worked in obstetrics and gynaecology.

To date, two patients in Wales have been identified as having hepatitis C, which is known to have been transmitted from the healthcare worker. 

In a written statement, the Welsh Government said today that it had it been made aware of a “serious incident” reported by Aneurin Bevan University Health Board, involving a retired healthcare worker who has been diagnosed with hepatitis C.

The healthcare worker’s main employment in Wales was between May 1984 and July 2003 at Caerphilly District Miners’ Hospital, but also for a short time at the former East Glamorgan Hospital and Wrexham Maelor Hospital. 

During the healthcare worker’s career, time was also spent working in England, Scotland and Northern Ireland. 

Aneurin Bevan University Health Board is writing to at least 3,000 patients this week and a further 2,000 patients next week, who have been identified as having definitely or possibly received certain procedures from the healthcare worker.

The healthcare worker also worked at other hospitals across the UK prior to working in Wales, including 11 hospitals in England between 1975 and 1983.

Similar “lookback” exercises to contact patients are taking place in parallel across all affected hospitals in England, Scotland and Northern Ireland.

Public Health England said less than 400 women in England have so far been identified as having definitely or possibly had operations conducted by the affected healthcare worker.

People who receive a letter are being offered counselling and advice on what to do next. 

A confidential telephone helpline number has been set up and clinics established to provide testing for those that have received a letter.

The identity of the healthcare worker is not being released due to confidentiality rights, the Welsh Government said. The individual had no symptoms and was unaware of the infection until after they retired.

In a statement, Public Health England medical director Dr Paul Cosford said he wanted to “emphasise that the risk of infection is very small”.

Women who came into contact with the infected individual via an obstetric or gynaecological operation, or while giving birth, were being offered testing “purely as a precaution”, he said.

“Around one in 250 adults in England have chronic hepatitis C infection and it does not automatically lead to health problems. Treatment can help clear the infection in up to 80% cases,” he added.

Since 2007, all staff new to the NHS should be offered a hepatitis C test and anyone performing surgical procedures for the first time should be tested by their employing trust or health board. 

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Hepatitis C virus therapy is associated with lower health care costs not only in noncirrhotic patients but also in patients with end-stage liver disease

Alimentary Pharmacology & Therapeutics

Volume 38, Issue 7, pages 784–793, October 2013

Original Article

S. C. Gordon^1,*, F. M. Hamzeh², P. J. Pockros³, R. S. Hoop², A. R. Buikema⁴, E. J. Korner², N. A. Terrault⁵

Article first published online: 25 AUG 2013

DOI: 10.1111/apt.12454

© 2013 John Wiley & Sons Ltd

Summary

Background

The effect of anti-viral treatment on downstream costs for hepatitis C virus (HCV)-infected patients is unknown.

Aim

To evaluate follow-up costs in patients with chronic HCV, stratified by liver disease severity.

Methods

Using a US private insurance database, mean all-cause per-patient-per-month (PPPM) US (2010) medical costs were calculated for HCV-infected persons who did and did not receive anti-HCV treatment between January 2002 and August 2010. Analysis was stratified by liver disease severity [noncirrhotic disease (NCD), compensated cirrhosis (CC) or end-stage liver disease (ESLD)] defined by ICD-9 and CPT codes.

Results

A total of 33 309 patients were included (78% NCD, 7% CC and 15% ESLD); 4111 individuals (12%) received anti-HCV treatment during the 2-year baseline period. Mean PPPM follow-up health care costs were significantly lower among treated patients with NCD ($900 vs. $1378 in untreated patients, P < 0.001) and ESLD ($3634 vs. $5071, P < 0.001) groups but not in the CC group ($1404 vs. $1795, P < 0.071; t-test). In a multivariable model adjusted for demographic characteristics, comorbidities, index date and geographical region, incremental cost ratios for total health care costs differed significantly (P < 0.001) between treated and untreated patients in the NCD and ESLD groups but not in the CC group. From this model, mean PPPM total health care costs between treated and untreated patients were $885 and $1370 in the NCD, $1369 and $1802 in the CC, and $3547 and $5137 in the ESLD groups, respectively.

Conclusions

Anti-HCV therapy was associated with lower follow-up US health care costs, and these savings were independent of baseline patient comorbidities and stage of disease.

Introduction

Most patients with chronic hepatitis C virus (HCV) infection in the United States were born between 1945 and 1964 and acquired HCV between 1960 and 1980.[1] As a result, the prevalence of the long-term cirrhotic complications of chronic HCV infection in this cohort, including hepatocellular carcinoma (HCC) and other liver-related morbidity and mortality, is increasing.[2-4] This trend has important implications for the health care system in the United States. HCV infection is the leading indication for liver transplantation and the most common cause of HCC.[5-9] Patients with detectable HCV infection have a significantly increased risk of dying from hepatic and extrahepatic causes, including cardiovascular disease, than patients who are HCV negative.[10-12]

Effective treatment is available for chronic HCV infection, but only a small proportion of patients receive treatment.[13-15] This is due to both underdiagnosis and undertreatment and reflects a lack of awareness on the part of patients, barriers to accessing treatment, and the complexity and tolerability of current treatment.[15-17] The prospect of more effective and better tolerated therapies has led some physicians to recommend treatment deferral.[18] Among those patients who do receive treatment and have advanced fibrosis, achievement of a sustained virological response significantly reduces the cumulative rate of HCC, transplantation and liver-related death.[19-21]

Hepatitis C virus infection increases health care costs,[22-24] and we and others have shown that health care costs increase in a stepwise fashion as HCV-related liver disease progresses.[23, 25] Thus, it seems plausible that treatment of HCV infection may delay or halt disease progression and would be associated with significant reductions in health care costs. However, there are few data that support this assumption. Using a large comprehensive health care database of patients with chronic HCV infection, we evaluated the impact of anti-HCV treatment on health care costs in patients with chronic HCV infection stratified by liver disease severity.

Methods

In a prior study, we tested the hypothesis that direct medical costs increase with disease severity, and the study provided estimates of those costs.[25] During this study, we also observed that treated patients appeared to have lower costs than untreated patients. Therefore, in the present analysis, we tested the hypothesis that patients who are treated for their HCV infection have lower downstream direct medical costs regardless of demographic characteristics or comorbidities than patients who are not treated.

Claims data

Deidentified medical and pharmacy claims enrolment information and mortality data were obtained for commercial health plan members enrolled between January 1, 2002, and August 31, 2010, in a large US private insurance database affiliated with OptumInsight (Eden Prairie, MN, USA).[25] The study database included claims for all prescription medications and medical services submitted by providers to constituent health plans for payment.

Data were collected from all available health care sites including physicians' offices, emergency departments and hospitals for all types of services. Claims analyses were based on amounts paid by health plans and patient responsibility amounts; costs paid by other health plans and Medicare were not included. In-patient stays were identified using a combination of AMA site codes, revenue codes and provider specialty codes, which indicated stays in an acute care or long-term care facility. ER visits were identified by a combination of AMA site codes and CPT codes indicating emergency department visits. Office visits and outpatient visits were identified using AMA site codes indicating each type of visit.

Patients included in the analysis were commercial health plan members with chronic HCV infection as evidenced by HCV-specific ICD-9 codes from January 1, 2003, to August 31, 2010. Codes that support the diagnosis of chronic HCV infection were also required for inclusion. The requirement for ≥1 HCV-specific ICD-9 code and ≥1 code on a nondiagnostic claim allowed for the exclusion of patients who only had rule-out codes for HCV infection. The complete list of ICD-9 codes used to identify patients with chronic HCV infection is included in Table 1.

Table 1. HCV diagnostic codes used to identify patients with chronic HCV infectiona

Inclusion criteria (one of the following)	Description (ICD-9-CM code)
HCV, hepatitis C virus. a From January 1, 2003, to August 31, 2010.
Single claim with one of these chronic HCV diagnosis codes	Chronic hepatitis C with hepatic coma (070.44) Chronic hepatitis C without mention of hepatic coma (070.54)
Two claims with one of these unspecified HCV diagnosis codes on separate dates of service	Hepatitis C carrier (V02.62) Unspecified viral hepatitis C without hepatic coma (070.70)Unspecified viral hepatitis C with hepatic coma (070.71)
Two claims with one of these acute and unspecified HCV diagnosis codes spaced ≥6 months apart	Acute hepatitis C with hepatic coma (070.41)Acute hepatitis C without mention of hepatic coma (070.51)Hepatitis C carrier (V02.62)Unspecified viral hepatitis C without hepatic coma (070.70)Unspecified viral hepatitis C with hepatic coma (070.71)

Disease severity groups

Patients were assigned to one of three disease severity categories according to predefined criteria established by a consensus panel of three clinical hepatologists: noncirrhotic disease (NCD), compensated cirrhosis (CC) or end-stage liver disease (ESLD). Patients included in the NCD cohort had no codes associated with conditions or procedures related to cirrhosis, decompensated cirrhosis, HCC or liver transplantation. Patients included in the CC group were required to have a diagnostic code indicating the presence of cirrhosis, whereas those included in the ESLD group were required to have diagnostic or procedural codes associated with decompensated cirrhosis, HCC or liver transplantation. A complete list of conditions used to assign patients to one of the three disease severity groups is in Table 2.[25]

Table 2. Conditions or procedures used to assign patients to liver disease severity groupsa

Noncirrhotic disease	Compensated cirrhosis	End-stage liver disease
Patients were assigned to the highest level severity category for which they had a qualifying condition or procedure. a Assignment to a liver disease severity group was based on diagnosis or procedure codes.
No listed conditions or procedures	Cirrhosis	Liver transplant
		Hepatocellular carcinoma
		Liver failure, including hepatorenal syndrome
		Hepatic encephalopathy
		Portal hypertension
		Oesophageal varices
		Other gastrointestinal haemorrhage
		Ascites
		Other sequelae of chronic liver disease
		Abdominal paracentesis procedures
		Shunts and catheter procedures
		Treatment of varices
		Portal decompression procedures

Patients in each disease severity group were assigned an index date. For patients in the NCD group, the index date was assigned as the date of the first claim with an HCV-related diagnostic code after the patient was continuously enrolled in the health plan for ≥2 years. For patients in the CC group, the index date was assigned as the date of the first claim for cirrhosis; for patients in the ESLD group, the index date was assigned as the date of the first claim for a condition or procedure indicating ESLD. Patients had been observed for ≥2 years before the index date to measure baseline comorbidities and treatment and for ≥30 days after and including the index date to measure outcomes. By definition, patients in the CC group had NCD during the baseline period and patients in the ESLD group had either cirrhosis or NCD during the baseline period.

Treatment cohorts

Within each disease severity group, two treatment cohorts were identified: (i) patients treated during the baseline period (treated cohort) and (ii) patients not treated during the baseline period (untreated cohort). To ensure that patients in the treated cohort had completed a treatment regimen during the baseline period, only patients with evidence of treatment in both the baseline and follow-up periods were excluded. Patients in the untreated cohort who received treatment in the follow-up period were retained in the main analysis but excluded as part of a sensitivity analysis.

Outcomes

For each patient, follow-up health care costs were calculated based on health plan – paid amounts reported on all claims submitted for payment during the follow-up period. Indirect costs were not included. Costs were adjusted to 2010 US$ using the annual medical care component of the consumer price index to account for inflation during the study.

Both all-cause and HCV-related costs were measured. Costs were considered HCV related if any HCV-related ICD-9 code or CPT code was listed in a primary or secondary position on the claim (Tables 1 and 2).

Follow-up costs are reported as per-patient-per-month (PPPM, 2010 US$) to adjust for the variable amount of time that patients were enrolled in the health plan following the index date.

Statistical analyses

Analyses were conducted from a health plan perspective. Follow-up health care costs were compared between the treated and untreated cohorts within each disease severity group. Mean differences in all-cause and HCV-related follow-up costs between treated and untreated patients were evaluated by t-test. In addition, follow-up costs were modelled using multivariable methods to further adjust for demographics, geographical location and comorbidities. Comorbidity covariates included in the models were those that might influence treatment decisions as determined by clinical hepatologists (SCG, NAT, PJP): Quan-Charlson comorbidity score (a validated comorbidity index that predicts 10-year mortality[26]), HIV/AIDS, cancer (excluding HCC and superficial skin tumours or cancer in situ), alcohol and substance abuse, psychiatric disorders, diabetes, cardiovascular disease and chronic obstructive pulmonary disease (COPD). All comorbidities were identified based on ICD-9 codes reported during the baseline period.

In the multivariable analyses, costs were modelled using a generalised linear model with a log link to account for the highly skewed nature of health care cost data.[27] Adjusted costs were predicted for the treated and untreated cohorts within each disease severity group using a recycled prediction method.[28]

Because some patients in the untreated cohort received treatment during the follow-up period, a sensitivity analysis was conducted that excluded these patients to determine whether the observed differences in follow-up costs might be attributable to the cost of treatment.

Results

A total of 25 966 with NCD, 2219 with CC and 5124 with ESLD were included in this analysis (Figure 1). Among patients with NCD, 12% (n = 3001) were treated in the baseline period. Among patients with CC and ESLD, 12% (n = 261) and 17% (n = 849), respectively, were treated during the baseline period, before the initial diagnosis of their respective liver disease severity level. Among patients not treated in the baseline period, 13% of patients with NCD (n = 3014), 30% of patients with CC (n = 595) and 12% of patients with ESLD (n = 505) were treated during the follow-up period. The mean duration of follow-up in treated and untreated patients was 773 and 734 days, respectively, among patients with NCD; 609 and 652 days, respectively, among patients with CC; and 646 and 680 days, respectively, among patients with ESLD.

Figure 1. US patients (n = 33 309) included in the analysis, by liver disease severity, for the period January 1, 2002, to August 31, 2010. Patients treated during both baseline and follow-up were excluded (1916 patients with noncirrhotic disease, 166 patients with compensated cirrhosis and 353 patients with end-stage liver disease). HCV, hepatitis C virus.

The baseline characteristics of treated and untreated patients in each of the three disease severity groups are in Table 3. Among patients with NCD and ESLD, the mean age was significantly lower (P < 0.001) among patients who received anti-HCV treatment compared with untreated patients; however, among patients with CC, the mean age was significantly higher among treated patients (P = 0.026). In the NCD group, both the proportion of male patients (P = 0.006) and the mean Quan-Charlson comorbidity score (P < 0.001) were significantly higher among treated vs. untreated patients. In addition, significantly fewer treated patients with NCD had associated ICD-9 codes for HIV/AIDS (P < 0.001), diabetes mellitus (P < 0.001), cardiovascular disease (P < 0.001) and COPD (P = 0.007) compared with untreated patients with NCD.

Table 3. (Click to view table) Patient and treatment characteristics by disease severity

Of note, a lower proportion of treated patients had associated ICD-9 codes for alcohol/substance abuse compared with untreated patients in both the NCD (P < 0.001) and CC groups (P = 0.047). In contrast, significantly more treated patients within each of the three disease severity groups had associated ICD-9 codes for psychiatric disease (NCD, P = 0.002; CC, P = 0.024; ESLD, P < 0.001; Table 3).

Unadjusted mean PPPM health care costs

Mean PPPM total health care costs, medical costs and HCV-related health care costs during the follow-up period were highest in patients with ESLD and lowest in patients with NCD (Table 4). Mean PPPM total health care costs were significantly greater in untreated patients both in the NCD group (P < 0.001) and the ESLD group (P < 0.001) (Table 4). Mean PPPM medical costs were significantly higher among untreated patients in the NCD (P < 0.001) and ESLD (P < 0.001) groups but not in the CC group (P = 0.947). Mean PPPM HCV-related health care costs were also significantly higher among untreated patients in each of the three disease severity groups (NCD, P < 0.001; CC, P = 0.003; ESLD, P < 0.001; Table 4).

Table 4. (Click to view table) Mean follow-up all-cause PPPM costs (2010 US$) by treatment history and  liver disease severity

A proportion of patients who were not treated during the baseline period received treatment in the follow-up period (13% of NCD, 30% of CC and 12% of ESLD). To determine if differences in costs during the follow-up period were attributable to follow-up treatment costs, patients receiving treatment in the follow-up period were excluded in a sensitivity analysis, with similar results. Specifically, unadjusted costs were significantly lower among patients who received treatment in the NCD and ESLD groups, with no statistically significant difference in cost between treated and untreated patients in the CC group (data not shown).

Adjusted health care cost models

After adjustment for demographic characteristics, comorbidities, index year, geographical region and treatment, there were statistically significant differences (P < 0.001) in incremental total health care costs between treated and untreated patients within the NCD and ESLD groups but not within the CC group (P = 0.057) (Table 5, Figure 2).

Table 5. (Click to view table) reated PPPM minus untreated PPPM

Figure 2. Predicted total costs [per-patient-per-month (PPPM), 2010 US$] by baseline treatment in patients with noncirrhotic disease (NCD), compensated cirrhosis (CC) and end-stage liver disease (ESLD). Covariates adjusted for in the analysis included age, sex, geographical region, index year, baseline comorbidities and baseline treatment for hepatitis C virus infection. ^■, treated; □, untreated.

Patients with NCD who received anti-HCV treatment were estimated to have total health care costs that were approximately 35% lower (cost ratio, 0.646; 95% CI, 0.586–0.712) than that for untreated patients with NCD (Figure 2). Medical costs (cost ratio, 0.713; 95% CI, 0.631–0.806) and HCV-related total costs (cost ratio, 0.380; 95% CI, 0.329–0.439) were also significantly lower in treated than in untreated patients (Figure 2).

Similarly, patients in the ESLD group who received anti-HCV treatment during the baseline period were estimated to have total health care costs that were approximately 30% lower (cost ratio, 0.691; 95% CI, 0.579–0.824) when compared with that of untreated patients with ESLD during the follow-up period (Table 5). Medical costs (cost ratio, 0.684; 95% CI, 0.564–0.830) and HCV-related total costs (cost ratio, 0.657; 95% CI, 0.522–0.828) were also significantly lower in treated than in untreated patients with ESLD (Table 5, Figure 2).

In contrast, the estimated difference in total health care costs between treated and untreated patients in the CC group was not statistically significant (cost ratio, 0.760; 95% CI, 0.573–1.008; Figure 2). There was also no statistically significant difference in medical costs between treated and untreated patients (cost ratio, 1.043; 95% CI, 0.716–1.518). However, HCV-related costs were significantly lower among treated vs. untreated patients in this group (cost ratio, 0.539; 95% CI, 0.386–0.753; Figure 2).

Discussion

This was an exploratory analysis to assess whether or not HCV treatment might be associated with lower downstream direct medical costs resulting from prescription medications, physician office visits, emergency department use and hospitalisation for patients with chronic HCV infection. In this analysis, we showed that HCV treatment in the baseline period was associated with significant reductions in subsequent all-cause direct health care costs in the follow-up period. Among patients with NCD, all-cause follow-up costs were 35% lower in treated patients than in untreated patients. The reduction in costs was also evident in patients with ESLD, and the magnitude of the reduction (30%) was similar to that in the NCD group. However, although the mean PPPM all-cause health care cost was 22% lower in treated patients with CC ($1404) compared with untreated patients with CC ($1795), this difference was not statistically significant (P = 0.057). Because it is clinically unlikely that patients with CC would differ from the other groups with respect to costs, we believe that the most likely reason for the lack of a statistically significant difference between treated and untreated patients with CC is the small number of treated patients (261), which reduced the power to detect statistically significant differences between treated and untreated patients.

These results build on previous analyses[25] that showed that all-cause health care costs associated with chronic HCV infection are driven by disease severity. The previous analysis showed that the mean annual all-cause health care costs associated with chronic HCV infection exceeded $24 000 and that the mean annual costs increased in a stepwise fashion and were approximately $17 000, $23 000 and $60 000 for those with NCD, CC and ESLD respectively.[25] A 48-week course of dual peginterferon plus ribavirin would cost approximately $48 000 in US$ 2010, which is approximately $1000 per week, and this would increase by an additional $1100 (US$ 2010) per week if either telaprevir or boceprevir was included in the regimen.[29]

The analysis showed that only 12% of patients with chronic HCV infection received treatment during the baseline period and that altogether approximately 25% of patients received treatment during the baseline or follow-up periods. The nature of a claims database does not allow us to determine how many patients were considered for treatment, how many patients were offered treatment or the specific reasons why treatment was not offered. Regardless, the frequency of treatment was very low, especially given the recognised clinical benefits that can be achieved if treatment is successful.

Comorbidities are common in patients with chronic HCV infection.[30] Indeed, an analysis of data from a cohort of 7411 patients with chronic HCV infection showed that HCV-infected patients had twice the burden of comorbidities compared with uninfected control patients, 99.4% of patients with chronic HCV infection had ≥1 comorbid condition and 52% had 6–15 comorbidities.[31] Many comorbid conditions can complicate or may be contraindications to treatment with peginterferon and ribavirin.[30] Thus, it is not surprising that there were differences in the baseline prevalence of concomitant diseases among those who were and were not treated. It was also not surprising that fewer patients in the NCD group with diagnostic codes for HIV/AIDS, alcohol/substance abuse, diabetes mellitus, cardiovascular disease and COPD received treatment compared with untreated patients. However, the multivariable statistical models were adjusted for the presence of comorbid conditions to ensure that these factors were not driving the differences in costs observed between treated and untreated patients.

It is important to note that the results obtained with t tests and multivariable models were similar (Table 5), which suggests that the covariates in the multivariable model did not account for the differences in total direct medical costs between the treated and untreated groups. However, in an observational study of this type, there are unmeasured confounders.

This study has limitations that are common in observational studies using administrative claims data. The use of ICD-9 codes rather than liver biopsy to assign patients to disease severity groups may have resulted in misclassification of disease severity. The number of patients with claims for anti-HCV therapy can be determined from the database, but it is not possible to determine whether patients took the medication as prescribed, had adjustments in dosage or had a virological response to treatment. It is also not possible to determine why a medication was prescribed or whether a specific medication was HCV treatment related (e.g. a prescription for an antidepressant for a patient who recently started anti-HCV treatment). In conclusion, in this exploratory analysis, anti-HCV therapy during the baseline period was associated with lower all-cause direct medical costs during the follow-up period in patients with NCD and ESLD. These results suggest that increasing the proportion of patients who receive treatment may be beneficial. Further studies are required to confirm these findings and extend them to include regimens that include direct-acting anti-viral agents. The potential availability of more potent and less toxic anti-viral regimens should enable larger numbers of infected individuals to undergo treatment, with the prospect of lower downstream health care costs.

Authorship

Guarantor of the article: Stuart C. Gordon.

Author contributions: Drs Gordon, Pockros and Terrault were involved in the study concept and design; analysis and interpretation of data; drafting of the manuscript; statistical analyses; and critical revision of the manuscript for important intellectual content. Dr Hamzeh, Dr Korner and Mr Hoop were involved in the study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; statistical analysis; obtained funding; technical or material support; and study supervision. Ms Buikema was involved in the study concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content; statistical analysis; and technical support. All authors have reviewed and approved the final version of the manuscript.

Acknowledgements

Declaration of personal interests: Dr Gordon has reported that he has received grant/research support and honoraria from, served as a consultant/advisor and member of Data Monitoring Board for Abbvie Pharmaceuticals, Bristol-Myers Squibb, CVS Caremark, Gilead, GlaxoSmithKline, Intercept Pharmaceuticals, Merck, Roche, Tibotec/Janssen and Vertex. Dr Terrault has reported that she has received grant support from, served as a consultant/advisor for Abbott, Bitotest, Bristol Myers Squibb, Eisai, Gilead, Merck, Novartis, Roche/Genentech, Siemens and Vertex. Dr Pockros has reported that he has received grant/research support and honoraria, served as a consultant for, and received unrestricted CME support from Roche/Genentech, Merck and Vertex. Dr Hamzeh, Dr Korner and Mr Hoop are employees of Genentech, Inc. Ms. Buikema is an employee of OptumInsight.

Declaration of funding interests: Third-party writing assistance for this manuscript, furnished by Blair Jarvis, MSc, ELS and Sue Currie, PhD, Health Interactions, all of which was funded by Genentech Inc. and F. Hoffmann-La Roche Ltd.

References

Source

Baby Shroomers and the Heroin Spike: 6 Surprising Trends in Americans’ Drug Use

A new national study found drug use among those aged 50 to 64 has roughly doubled in the last few years, as has the number of people using heroin. Here's why

By Nate Rawlings @naterawlings Sept. 06, 2013

Getty Images

The most comprehensive study of who’s using what in the U.S. came out on Wednesday. Here are six noteworthy stats from the federal government’s annual National Survey on Drug Use and Health of 70,000 Americans.

The methamphetamine epidemic is waning. The number of meth users in 2012 fell to 440,000, down from 731,000 in 2006. The Substance Abuse and Mental Health Administration, which conducted the survey, attributed the drop to states restricting the sale of key ingredients, like pseudoephedrine, which is found in cold medicines such as Sudafed.

(MORE: Thai Dealers Push Candy-Flavored Methamphetamine on Kids Outside Schools)

But heroin use is exploding. Between 2007 and 2012, the number of Americans shooting up nearly doubled, from 373,000 to 669,000. According to Mark Kleiman, professor of public policy at UCLA’s Luskin School of Public Affairs, that estimate may be low. Many heroin users are incarcerated, homeless, or not in a place where surveys can find them.

With cities and states cracking down on “pill mills”—illegal sources for Oxycontin and other prescription opiates—addicts are looking to get their fix elsewhere. “The prescription opioids are an easy path,” Kleiman says. “Then once people are strung out, they’ll do lots of stuff that they wouldn’t have done before.”

Pot is only getting more popular. Marijuana has long been the most commonly used drug in America, but its fan base is reaching new highs. In 2012, 18.9 million people used marijuana–7.3% of the population–up from 14.5 million in 2007. The number of daily users, now 7.6 million Americans, is growing as well.

Some of that rise likely resulted from growing acceptance of the drug—20 states and Washington, D.C. allow medical use, and Colorado and Washington State recently legalized recreational toking. “It’s clear that people are more willing to use legal than illegal drugs,” says Keith Humphreys, a psychologist and behavioral sciences professor at Stanford who served as a policy advisor at the White House Office of National Drug Control Policy.

The spirit of the ‘60s lives on. Here’s one statistic that will probably surprise people but shouldn’t: drug use among older people is way up. Last year, 7.2% of adults age 50 to 64 got high, up from 3.4 percent a decade ago. Among those aged 55 to 59, the drug use rate more than tripled, from 1.9% to 6.6%.

(MORE: Concert Deaths: Four Myths About the Drug Molly)

But those increases are mostly attributable to Baby Boomers getting older. “This cohort, particularly those born after 1950, had much higher rates of illicit drug use as teenagers and young adults than older cohorts,” the survey explains. “This generational shift in drug use is still evident in the most recent data.”

One of your neighbors is probably a binge drinker. Last year, 52.1% of Americans, 135.5 million people, reported drinking alcohol. Nearly one quarter, about 60 million people, were binge drinkers, which the study classified as having five or more drinks in the same occasion on at least one day during the month before being surveyed.

Teens don’t think smoking is cool anymore. 70 million Americans used tobacco last year, but fewer teens are lighting up. Over the last decade, tobacco use among teenagers (12 to 17-year-olds) dropped by nearly half, from 15.2% to 8.6%.

They’re still experimenting with alcohol though. Of the 4.1 million people who reported having their first drink in 2012, more than 80 percent were under the age of 21. You can’t win them all.

Source

Clinical Presentation, Outcome, and Response to Therapy Among Patients With Acute Exacerbation of Chronic Hepatitis C

Clinical Gastroenterology and Hepatology
Volume 11, Issue 9 , Pages 1174-1180.e11, September 2013

Evangelista Sagnelli, Mariantonietta Pisaturo, Maria Stanzione, Vincenzo Messina, Loredana Alessio, Caterina Sagnelli, Mario Starace, Giuseppe Pasquale, Nicola Coppola

published online 15 April 2013.

Abstract

Background & Aims

The slow asymptomatic progression of chronic hepatitis C (CHC) can be interrupted by an acute exacerbation, characterized by increased serum levels of alanine aminotransferase (ALT) and bilirubin and other symptoms of acute hepatitis. We aimed to provide more information about the clinical presentation of acute exacerbation of CHC.

Methods

We identified 82 consecutive patients, from 2 locations in Italy, who had an acute exacerbation of CHC from January 2005 through June 2010; we followed them up for a median period of 36 months. These cases were hepatitis C virus (HCV) RNA positive, hepatitis B surface antigen-negative, and had not received anti-HCV therapy. They were matched with 82 subjects with hepatitis C without reactivation for age, sex, and HCV genotype (controls). Sixty-nine cases and 73 controls were followed up for at least 2 years. Liver biopsy specimens had been taken from 23 cases and 31 controls—once before enrollment in the study and once during the follow-up period.

Results

HCV genotype 2 was detected in 46.4% of cases, and HCV genotype 1 was detected in 43.9%. Among cases, the mean ALT level was 1063 ± 1038 IU/dL, and the mean total bilirubin level was 15.87 ± 7.15 mg/dL. A higher percentage of cases carried the interleukin-28B CC genotype than controls (40.2% vs 24.4%; P < .05). Among cases, 43.5% had a steady increase in ALT level (>2-fold baseline value); for 56.5% of these patients, ALT levels returned to baseline values before the acute exacerbation of chronic hepatitis. Based on comparisons of biopsy specimens, 18 cases (78.3%) and 11 controls (35.5%) had increasing fibrosis, with Ishak scores increasing by more than 2 (P < .005); 14 cases (60.9%) and 3 controls (9.6%) had increases in necroinflammation of more than 2 points (P < .005). Thirty-two cases (46.4%) and 38 controls (52%) received treatment with pegylated interferon and ribavirin; a sustained virologic response was achieved in 26 cases (81.2%) and 23 controls (60.5%).

Conclusions

Although an acute exacerbation of chronic hepatitis is a serious medical condition, most patients achieve a sustained virologic response after treatment with pegylated interferon and ribavirin.

Keywords: Hepatic Flare , Cirrhosis , Response to Therapy , Complication

Abbreviations used in this paper: ALT, alanine aminotransferase, AST, aspartate aminotransferase, CHC, chronic hepatitis C, HAI, Histologic Activity Index, HAV, hepatitis A virus, HBsAg, hepatitis B surface antigen, HCC, hepatocellular carcinoma, HCV, hepatitis C virus, HDV, hepatitis D virus, HEV, hepatitis E virus, IL, interleukin, LB, liver biopsy, peg-IFN, pegylated interferon, SVR, sustained virologic response

Conflicts of interest The authors disclose no conflicts.

Funding This study was supported by a grant from Progetti di Ricerca di Interesse Nazionale (PRIN) 2008, Ministero dell'Istruzione e dell'Università e della Ricerca Scientifica, Rome, Italy “Ottimizzazione Della Diagnosi Eziologica dell'epatite Acuta C E Studio dei Fattori Viro-Immunologici di Guarigione, di Cronicizzazione E di Risposta Alla Terapia Con Interferone,” and in part by a grant from Regione Campania “Progetti per il miglioramento della qualità dell'assistenza, diagnosi e terapia del paziente affetto da AIDS nei settori: immunologia, coinfezioni, informazione e prevenzione,” 2008.

PII: S1542-3565(13)00466-7

doi:10.1016/j.cgh.2013.03.025

© 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

Source

Bermuda Triangle for the liver: Alcohol, obesity, and viral hepatitis

Journal of Gastroenterology and Hepatology

Special Issue: 7th International Symposium on Alcoholic Liver and Pancreatic Diseases and Cirrhosis. Funding for this conference was made possible (in part) by Grant 5 R13AA20691-02 from the National Institute on Alcohol Abuse and Alcoholism (NIAAA). Guest Editors: Bin Gao and Fu-Sheng Wang

Volume 28, Issue Supplement S1, pages 18–25, August 2013

Review

Samir Zakhari

Article first published online: 15 JUL 2013

DOI: 10.1111/jgh.12207

© 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd

Keywords: Alcohol; viral hepatitis; liver; oxidative stress; free radicals; CYP2E1

Abstract

Despite major progress in understanding and managing liver disease in the past 30 years, it is now among the top 10 most common causes of death globally. Several risk factors, such as genetics, diabetes, obesity, excessive alcohol consumption, viral infection, gender, immune dysfunction, and medications, acting individually or in concert, are known to precipitate liver damage. Viral hepatitis, excessive alcohol consumption, and obesity are the major factors causing liver injury. Estimated numbers of hepatitis B virus (HBV) and hepatitis C virus (HCV)-infected subjects worldwide are staggering (370 and 175 million, respectively), and of the 40 million known human immunodeficiency virus positive subjects, 4 and 5 million are coinfected with HBV and HCV, respectively. Alcohol and HCV are the leading causes of end-stage liver disease worldwide and the most common indication for liver transplantation in the United States and Europe. In addition, the global obesity epidemic that affects up to 40 million Americans, and 396 million worldwide, is accompanied by an alarming incidence of end-stage liver disease, a condition exacerbated by alcohol. This article focuses on the interactions between alcohol, viral hepatitis, and obesity (euphemistically described here as the Bermuda Triangle of liver disease), and discusses common mechanisms and synergy.

The global burden

Liver cirrhosis and hepatocellular carcinoma (HCC) represent end-stage liver disease (ESLD) and thus are associated with mortality. Globally, the incidence and prevalence of liver cirrhosis vary markedly based largely on the causative factors. In the developed world, alcohol, hepatitis C virus (HCV), and nonalcoholic steatohepatitis are the leading causes of cirrhosis, whereas viral hepatitis (especially hepatitis B virus [HBV]) is considered the leading cause in developing countries. Data from 2001 indicate that in developed countries, cirrhosis was the sixth most common cause of death among adults, and in developing countries, it claimed 320 000 lives, ranking as the ninth most common cause of death. In the European Union alone, approximately 29 million individuals suffer from chronic liver disease of whom 170 000 and 47 000 die annually from cirrhosis and liver cancer, respectively.[1] In the United States, approximately 46 700 individuals died from liver cirrhosis and cancer in 2002.[2] HBV and HCV infection are major causes of morbidity and mortality. According to World Health Organization, an estimated 2 billion people have been infected with HBV, and more than 240 million have chronic liver infections worldwide. About 600 000 people die every year from the acute or chronic consequences of HBV infection, which is endemic in China and other parts of Asia, where most people become infected during childhood; 8–10% of the adult population is chronically infected. HBV-induced liver cancer is among the top three causes of death from cancer in men, and a major cause of cancer in women in this region. Globally, cirrhosis attributable to HBV or HCV accounted for 30% and 27%, respectively, and HCC was attributable to HBV (53%) or HCV (25%). Applied to 2002 worldwide mortality estimates, chronic HBV and HCV infections represent 929 000, including 446 000 cirrhosis deaths (HBV: 235 000; HCV: 211 000) and 483 000 liver cancer deaths (HBV: 328 000; HCV: 155 000).[3]

Nonalcoholic fatty liver disease (NAFLD) comprises a wide spectrum of liver damage including steatosis, steatohepatitis, fibrosis, and cirrhosis in patients who do not consume large amount of alcohol.[4] NAFLD is a significant factor for serious liver disease because of its rising prevalence in the general population,[5] and the potential to progress to ESLD and HCC.[6] NAFLD commonly occurs in patients with obesity, diabetes, and hyperlipidemia. In the past two decades, obesity in North America has more than doubled and continues to rise worldwide. In 2005, 8% of men and 12% of women were obese. By 2030, the number of obese adults globally is projected to be 573 million individuals.[7]

The combination of chronic heavy alcohol consumption, viral hepatitis infection, and obesity represent a major assault on liver's health worldwide.

Alcoholic liver disease (ALD)

Chronic alcohol consumption results in liver disease which varies extensively between individuals in severity and progression for comparable levels of alcohol consumption. This variability could be attributed to variations in the expression and activity of individual isoforms of the alcohol-metabolizing enzymes: alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), but is also influenced by variations in patterns of alcohol intake (binge vs chronic drinking), nutritional status, gender, smoking, or abuse of other drugs. In addition, the onset and severity of ALD is strongly influenced by other comorbid conditions such as obesity or HCV infection. This increase in susceptibility to ALD is not due solely to intrahepatic factors, but may also involve alcohol-induced changes in other tissues, such as adipose tissue, central nervous system, the gut, and the immune system. Factors contributing to alcohol-induced liver disease are thus complex and systemic.[8] The spectrum of ALD includes:

1. Fatty liver (hepatic steatosis), characterized histologically by lipid droplets in hepatocytes. This condition is usually reversible upon cessation of alcohol consumption, and thus is thought to be a relatively innocuous side effect of heavy drinking. However, hepatic steatosis often develops in obesity, metabolic syndrome, and type 2 diabetes, clinical conditions that involve significant metabolic defects. Thus, fatty liver by itself reflects a condition of metabolic stress that is a risk factor for the development of more severe forms of liver disease.
2. Alcoholic hepatitis, an inflammatory condition characterized by significantly increased serum levels of liver enzymes (alanine aminotranferease and aspartate aminotransferase) and moderate to severe tissue damage, including necrotic foci with neutrophil infiltration. Acute alcoholic hepatitis is a potentially fatal disease that develops in a significant fraction (30–40%) of chronic heavy drinkers.
3. Liver fibrosis/cirrhosis, about 10–15% of chronic heavy drinkers proceed to develop fibrosis and cirrhosis.
4. HCCs occur in about 2% of cirrhotic patients.

Although factors that facilitate the development of hepatitis and cirrhosis are not well characterized, impairment in the cellular stress defense mechanisms, (e.g. oxidative stress),[9] or derailment of the balance of autocrine or paracrine mediators that are critical in maintaining normal homeostatic conditions are documented. In addition, chronic alcohol consumption interferes with liver regeneration, which under normal conditions is a highly effective repair mechanism that avoids scar tissue formation.

Mechanisms of ALD

Various mechanisms have been identified for ALD (Fig. 1) which are involved at various stages of progression.

Figure 1. Known mechanisms of alcoholic liver damage. CB, cannabinoid receptor; ER, endoplasmic reticulum; Fe, Ferrous molecule; HCC, hepatocellular carcinoma; HNE, 4-hydroxynonenal; HSC, hepatic stellate cell; KC, Kupffer cells; LPS, lipopolysaccharide; MAA, malondialdehyde-acetaldehyde adduct; MDA, malondialdehyde; Mt GSH, mitochondrial glutathione; NAD, nicotinamide adenine dinucleotide; NADH, reduced NAD; ROS, reactive oxygen species; TGF, transforming growth factor.

Fatty liver

Both intrahepatic and extrahepatic mechanisms are involved in hepatic steatosis:

a) Intrahepatic factors

Hepatic steatosis due to heavy alcohol consumption has been attributed to a metabolic stress imposed by the fact that the liver is the predominant site of ethanol metabolism. Possible mechanisms include: (i) suppression of mitochondrial fatty acid β-oxidation; (ii) a limitation in the permeability of the outer mitochondrial membrane pore protein voltage-dependent anion-selective channel;[10] (iii) enhancement of hepatic uptake of free fatty acids from the circulation; (iv) increase in de novo synthesis of fatty acids and triglycerides; and (v) derailment of lipoprotein synthesis and secretion.

Chronic alcohol consumption induces a marked increase in cytochrome P450 2E1 (CYP2E1) activity, with a resultant increased demand for nicotinamide adenine dinucleotide phosphate (NADPH), an increased rate of formation of reactive oxygen species (ROS), and a decrease in oxidative stress defense capacity. At the same time, impairment of mitochondrial respiratory capacity caused by defects in the electron transport and ATP synthase complexes results in further increase in ROS formation at the mitochondrial level.[11] The ethanol-induced stress is further exacerbated by defects in the methionine cycle, resulting in a decrease in glutathione (GSH) synthesis, which contributes to the decline in oxidative stress defenses. Importantly, these conditions also reflect an increase in endoplasmic reticulum (ER) stress, a common response do the accumulation of defective proteins.[12] The resulting accumulation of stress conditions in hepatocytes causes an increased susceptibility to cell death signals. Accompanying the structural and functional changes in subcellular organelles, chronic ethanol treatment results in significant changes in the profile of transcription factors that regulate lipid homeostasis in the liver. Ethanol consumption elicits a decrease in peroxisome proliferator-activated receptor (PPAR)-α activity, thereby suppressing the catabolic lipid metabolic pathways, including peroxisomal and mitochondrial fatty acid oxidation. At the same time, ethanol increases the activity of sterol regulatory element-binding protein (SREBP)-1c and SREBP-2, which enhances lipid synthetic pathways. In addition, there has been some evidence that the adenosine monophosphate (AMP)-activated protein kinase (AMPK) is inhibited by ethanol. However, it is difficult to distinguish direct and indirect effects of ethanol. For instance, AMPK activity in the liver is regulated not only by the availability of AMP in the cell, but also responds to extracellular signals, including the adipose tissue derived cytokine adiponectin.

A related regulatory pathway affected by ethanol may involve the deacetylase silent information regulator-1 (SIRT-1), which requires activation by nicotinamide adenine dinucleotide (NAD⁺). Thus, the change in NAD redox state in the liver during ethanol oxidation may facilitate inhibition of SIRT-1. It has been reported that SIRT-1 activity in the liver of mice is decreased after ethanol treatment.[13] Among the targets of SIRT-1 are several key regulators of lipid metabolism, including the transcriptional coregulators peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Its deacetylation by SIRT-1 allows it to stimulate gene expression through its interactions with PPAR-α. Furthermore, SREBP-1c is a target for SIRT-1 and its acetylation state may affect its transcriptional activity.

b) Extrahepatic factors

Lipid metabolism in the liver is integrated with a variety of signals, including circulating hormones, cytokines, nutrition, and other factors that impinge on the intrahepatic processes leading to steatosis. While some of these factors are intrahepatic (e.g. cytokines released from Kupffer cells, endothelial cells, or stellate cells), others are dispatched by remote tissues. Of particular relevance are hormones (e.g. insulin), adiponectin and leptin (secreted from adipose tissue), and stress hormones and satiety factors that act through the hypothalamus or other brain structures to regulate food intake. Chronic ethanol consumption has a notable impact on the synthesis and secretion of several of these factors, in addition to affecting their capacity to impact lipid metabolic pathways in the liver.

Adiponectin, one of the adipokines secreted by adipose tissue to regulate lipid homeostasis, acts on multiple tissues including the liver to sensitize the response to insulin and enhance fatty acid oxidation. In animal experiments, ethanol feeding tends to suppress adiponectin secretion from adipose tissue. However, the effects of ethanol on adiponectin levels may depend on dietary factors such as the content of saturated and unsaturated fat.[14] Whether circulating adiponectin levels are similarly correlated with liver damage in human alcoholics remains unclear.[15]

Insulin plays a dominant role in integrating fatty acid and carbohydrate metabolism in the liver with the energetic needs of other tissues. Nonalcoholic hepatic steatosis that occurs in the metabolic syndrome and type II diabetes is commonly associated with insulin resistance, that is, a decreased capacity to respond to changes in circulating insulin, in multiple tissues including liver and muscle. There is strong evidence that stress responses mediated by free fatty acid accumulation or ER stress result in activation of stress response protein kinases, including protein kinase C and Jun-N-terminal kinase, which affect the intracellular signaling pathways through which insulin exerts its effects.

Alcoholic hepatitis

As described earlier, hepatic steatosis represents a severe condition of increased oxidative stress, ER, and metabolic stress. However, the mechanisms by which such stress conditions can lead to a more severe inflammatory condition remain only partly understood. Increased cell death (by necrosis or apoptosis) sets in motion further pro-inflammatory responses in the liver by producing cytokines and chemokines that help mobilize neutrophils and other inflammatory cells that further enhance liver damage. Also, it appears that overproduction of ROS by the damaged mitochondria could play a salient role. Factors that may be involved in the precipitation of alcoholic hepatitis are briefly discussed later.

Oxidative alcohol metabolism in the liver

Only about 2–10% of the absorbed alcohol is eliminated via the lungs and kidneys; the remaining 90% is metabolized mainly by oxidative pathways in the liver and by nonoxidative pathways in extrahepatic tissues. Oxidative metabolism in the liver results in extensive displacement of the liver's normal metabolic substrates, the production of acetaldehyde and ROS, and an increase in the NADH/NAD⁺ ratio (Fig. 2).

Figure 2. Hepatitis C virus (HCV), alcohol metabolism, and liver damage. ALD, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase; GSH, glutathione; HCC, hepatocellular carcinoma; IFN, interferon; NAD, nicotinamide adenine dinucleotide; NADH, reduced NAD; NADP, nicotinamide adenine dinucleotide phosphate; RNS, reactive nitrogen species; ROS, reactive oxygen species.

The major pathway of oxidative metabolism of ethanol in the liver involves multiple isoforms of cytosolic ADH, which results in the production of acetaldehyde. Accumulation of this highly reactive and toxic molecule contributes to liver damage. The oxidation of ethanol is accompanied by the reduction of NAD⁺ to NADH and, thereby, generates a highly reduced cytosolic environment in hepatocytes. The cytochrome P450 isozymes, including CYP2E1, 1A2, and 3A4, which are predominantly localized to the ER, also contribute to ethanol's oxidation to acetaldehyde in the liver. CYP2E1 is induced by chronic ethanol consumption and assumes an important role in metabolizing ethanol to acetaldehyde at elevated alcohol concentration. It also produces ROS, including hydroxyethyl, superoxide anion, and hydroxyl radicals.

Acetaldehyde, produced by ethanol oxidation, is rapidly metabolized mainly by mitochondrial ALDH2 to form acetate and NADH. Mitochondrial NADH is reoxidized by the electron transport chain (ETC). Most of the acetate resulting from ethanol metabolism escapes the liver to the blood and is eventually metabolized to CO₂ by way of the tricarboxylic acid cycle in tissues such as heart, skeletal muscle, and brain, where mitochondria are capable of converting acetate to the intermediate acetyl coenzyme A.

Consequences of alcohol metabolism by oxidative pathways

a) Acetaldehyde generation/adduct formation: if accumulated to high concentrations, acetaldehyde can form adducts with DNA and RNA, and decrease DNA repair. It also has the capacity to react with lysine residues on proteins including enzymes, microsomal proteins, microtubules, and affect their function. Formation of protein adducts in hepatocytes may contribute to impaired protein secretion, resulting in hepatomegaly. In addition, acetaldehyde and malondialdehyde (a by-product of lipid peroxidation) can combine and react with lysine residues on proteins, giving rise to stable malondialdehyde-acetaldehyde-protein adducts that are immunogenic and, thus, can contribute to immune-mediated liver damage.

b) Change in hepatocyte redox state (increase in NADH/NAD⁺ ratio): both acute and chronic alcohol consumption shift the redox state of the liver to a more reduced level, similar to but more pronounced than the shift observed in diabetes and during starvation. Alcohol metabolism produces a significant increase in the hepatic NADH/NAD⁺ ratio in both the cytosol and the mitochondria, as evidenced by an increase in the lactate/pyruvate and β-hydroxybutyrate/acetoacetate ratios, respectively, and vastly increases the availability of oxidizable NADH to the ETC in the mitochondria. The liver responds to ethanol exposure in part by increasing the rate of oxygen uptake, which may lead to periods of hypoxia, particularly in the downstream (pericentral) parts of the liver lobule.

c) Formation of ROS, reactive nitrogen species (RNS), and oxidative stress: Hepatic mitochondria produce ROS through the activity of the ETC as a by-product of oxidative phosphorylation. Normally, a small fraction of electrons entering the ETC can prematurely escape from complexes I and III and directly react with 1–3% of respiratory oxygen molecules to generate the superoxide anion radical, which is then dismutated by the mitochondrial manganese superoxide dismutase into hydrogen peroxide (H₂O₂). Mitochondrial glutathione peroxidase (GPx) then converts H₂O₂ into water by using reduced glutathione (GSH) as a cofactor. Thus, most of the ROS generated by the ETC in the normal state are detoxified by the mitochondrial antioxidant defenses. The nondetoxified portion of ROS diffuses out of mitochondria, and affects signal transduction pathways and gene expression, triggering cytokines, hormones, and growth factors, which if excessive may lead to hepatic inflammation, necrosis, and/or apoptosis. In addition, metals (e.g. iron and copper) can further react with H₂O₂ to produce hydroxyl radicals via the Fenton reaction (Fig. ).

Figure 3. Alcohol, reactive oxygen species (ROS), and mitochondrial dysfunction. CYP2E1, cytochrome P450 2E1; GSH, glutathione; GSSG, oxidized glutathione; H2O2, hydrogen peroxide; MnSOD, manganese superoxide dismutase; NO●, nitric oxide; O₂●^–, speroxide; ●OH, hydroxyl radical; ONOO^–, peroxinitrite.

Nitric oxide (NO), an RNS critical for hepatocyte biology, can interact with peroxides to generate peroxynitrite, which could be detrimental to the liver depending on the amount and duration. NO is produced by inducible nitric oxide synthase which is expressed in all liver cells (i.e. hepatocytes, stellate cells, Kupffer cells, and vascular endothelial cells) and its expression is induced by interleukin (IL)-1β alone or in combination with tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and/or lipopolysaccharide (LPS).

Ethanol-induced oxidative stress has been attributed to a decrease in the NAD⁺ : NADH ratio, acetaldehyde formation, CYP2E1 induction, hypoxia, cytokine signaling, mitochondrial damage, LPS activation of Kupffer cells, reduction in antioxidants particularly mitochondrial and cytosolic GSH, one electron oxidation of ethanol to 1-hydroxy ethyl radical, and the conversion of xanthine dehydrogenase to xanthine oxidase.

Fibrosis and cirrhosis

Fibrosis is a common response of the liver to a chronic inflammatory condition, where hepatic stellate cells (HSC) play a critical (though not exclusive) role.[19] HSCs exist in a quiescent state in the normal liver, but can be activated directly or indirectly in response to apoptotic or necrotic cell death. Cytokines released in the tissue as a result of injury further contribute to HSC activation, resulting in the expression of a myofibroblast phenotype and stimulating the expression of extracellular matrix (ECM) proteins, in particular collagen type 1, which are not normally expressed in the liver. Under conditions of an acute tissue injury, the deposition of collagen fibers is a transient wound-healing response and is followed by fibrinolysis mediated by metalloproteases that are activated as damaged tissue is replaced by newly generated liver cells by the regenerative response. Continuous tissue damage and repair after chronic inflammation, and an imbalance in the normal liver repair mechanisms results in excessive deposition of collagen fibers.[19]

Chronic ethanol consumption can influence this process at multiple levels: (i) enhancement of the pro-inflammatory environment in the liver by stimulating the release of pro-inflammatory cytokines from macrophages and decreasing the activity of protective cell types, including natural killer cells;[20] (ii) enhancement of hepatocyte apoptosis and necrosis in response to oxidative stress and shifting in stress defense signaling pathways; (iii) activation of HSCs and collagen formation (studies on isolated HSCs have demonstrated that ethanol alters their response to transforming growth factor (TGF-β) and IFN-γ through effects on intracellular signaling pathways); and (iv) suppression of the regenerative response to tissue damage that is an essential component of the liver's repair mechanism and thereby facilitates the deposition of scar tissue, which is the hallmark of fibrosis. This is probably accompanied by a suppression of metalloproteases (e.g. by the activation of inhibitor proteins, such as plasminogen activator inhibitor-1 [PAI-1]), which normally would maintain the balance of ECM deposition and resolution to facilitate tissue repair.[21]

Common factors involved in alcohol, obesity, and viral infection

Chronic heavy alcohol consumption, obesity, and viral infection have some common features/mechanisms that may contribute to exacerbation of liver damage when these conditions coexist. Several common mechanisms between two or more of these conditions have been advocated, including oxidative stress, CYP2E1 induction, increased fat synthesis and mobilization, selected gut bacteria, free fatty acids, ER stress, immune response, among others.[22-25] Because of page limitations, only the first two mechanisms (oxidative stress and CYP2E1 induction) will be discussed. Oxidative stress due to alcohol has been discussed earlier.

Obesity and oxidative stress

Obesity involves the accumulation of body fat and is a major risk factor for metabolic syndrome, which is characterized by hyperglycemia, dyslipidemia, and hypertension.[26] Increased oxidative stress in accumulated fat has been reported as a pathogenic mechanism of obesity-associated metabolic syndrome. In nondiabetic humans, systemic oxidative stress correlated positively with fat accumulation and negatively with plasma adiponectin levels. In obese mice, ROS production was selectively increased in adipose tissue, and was accompanied by enhanced expression of NADPH oxidase and decreased expression of anti-oxidative enzymes such as superoxide dismutase in white adipose tissue and GPx in liver.[27] In cultured adipocytes, mitochondrial and peroxisomal oxidation of fatty acids activates NADPH oxidase resulting in increased oxidative stress, which caused increase in messenger RNA (mRNA) expression of inflammatory (PAI-1, TNF-α, IL-6, and monocyte chemotactic protein-1), and suppression of mRNA and secretion of anti-inflammatory (adiponectin, leptin) adipocytokines. Conversely, in obese KKAy mice, treatment with apocynin, an NADPH oxidase inhibitor, reduced ROS production in adipose tissue, increased plasma adiponectin levels, and improved hyperlipidemia and hepatic steatosis. Because oxidative stress underlies the pathophysiology of hepatic steatosis,[28] these results suggest that increased oxidative stress in obese individuals could be further exacerbated by oxidative stress due to chronic heavy alcohol consumption.

Viral infection and oxidative stress

Infection with HCV, in most cases, develops into chronic disease which is manifested by steatosis and fibrosis, as well as HCC. HCV replication induces oxidative stress (Figure 2), which contributes to insulin and interferon resistance, as well as disorders of iron metabolism. Specifically, virus core and nonstructural NS5A proteins increase ROS levels through alteration of calcium homeostasis[29] via a primary effect on the uniporter,[30] and the induction of NADPH oxidase 4.[31] In addition, E1 and E2 and the transmembrane protein NS4B increase ROS generation via ER stress and unfolded protein response,[32, 33] and activates the antioxidant defense regulated by NF-E2-related factor 2.[34] Furthermore, HCV causes mitochondrial damage and induction of double-stranded DNA breaks mediated by NO and ROS, which is abolished by NO and ROS inhibitors.[35] HCV-induced ROS causes hepatic iron accumulation in mice by reducing hepcidin transcription, further magnifying ROS production,[36] and regulating TGF-β1.[37]

CYP2E1, alcohol, and oxidative stress

As mentioned earlier, alcohol-induced oxidative stress is a major mechanism by which ethanol causes liver injury. Of the many suggested pathways by which ethanol induces a state of oxidative stress, induction of CYP2E1 is a central one. Levels of CYP2E1 are increased after acute and chronic alcohol treatment. CYP2E1 generates ROS such as the superoxide anion radical and hydrogen peroxide and, in the presence of iron catalysts, produces the hydroxyl radical, a powerful oxidant (Figure 3). The role of CYP2E1 in chronic ethanol-induced liver injury was studied in wild-type (WT) mice, CYP2E1 knockout (KO) mice and humanized CYP2E1 knockin (KI) mice. Alcohol produced oxidant stress and steatosis in WT mice, but these effects were blunted in the KO mice and restored in the KI mice. These studies show that CYP2E1 contributes to ethanol-induced oxidant stress and liver injury.[38] For a discussion of the biochemical and toxicological properties of CYP2E1 and possible therapeutic implications for treatment of ALD by CYP2E1 inhibitors, the reader is referred to the review article by Lu and Cederbaum.[39]

CYP2E1, obesity, and oxidative stress

As discussed earlier, CYP2E1 is an important factor in liver disease. Several studies suggest that hepatic CYP2E1 activity is increased in patients with nonalcoholic steatohepatitis, chronic alcoholism, or morbid obesity. To study the correlation between obesity and CYP2E1, Emery et al.[40] assessed hepatic CYP2E1 activity—by determining the clearance of chlorzoxazone (CLZ), a CYP2E1-selective probe—in morbidly obese subjects with varying degrees of hepatic steatosis, and normal-weight controls. Obese subjects were evaluated at baseline and 1 year after gastroplasty, a procedure that leads to weight loss. Compared with controls, oral CLZ clearance was elevated approximately threefold in morbidly obese subjects, and was significantly higher among subjects with steatosis involving > 50% of hepatocytes. One year after gastroplasty, the median body mass index decreased by 33%, and total oral CLZ clearance declined by 46%. Thus, hepatic CYP2E1 activity is upregulated in morbidly obese subjects, and the positive association between the degree of steatosis and CYP2E1 activity preoperatively suggests that CYP2E1 induction is related to morbid obesity.[40] Similar results were obtained in genetically obese Zucker rats fed a normal diet (OB) when compared with normal Zucker rats fed a high-fat diet (HF). CYP2E1 induction was greater in both liver and fat of OB rats than in those of HF rats. The induction of CYP2E1 in liver and fat of obese patients may potentially alter the pharmacokinetics of lipophilic drugs metabolized by CYP2E1.[41]

In a recent study, Cederbaum reported that CYP2E1 induction potentiated liver injury in obese mice, and the elevated oxidative stress could be blunted by CYP2E1 inhibitors.[38] In addition, S-Adenosyl-L-methionine decreased oxidative stress, steatosis, liver injury, and mitochondrial dysfunction in the pyrazole-treated obese mice, an important finding with therapeutic implications in obesity-induced metabolic complications.

CYP2E1, HCV, and oxidative stress

CYP2E1 expression in the liver of patients with chronic hepatitis C correlated with the progression of hepatic disease (both lobular inflammation and fibrosis indices), and observed variations were consistent with the preferential distribution of CYP2E1 in the lobular zone.[42] The effect of alcohol metabolism on HCV replication and the antiviral action of IFN was studied in Huh-7 cells that harbor HCV replication and metabolize ethanol via the introduced expression of CYP2E1. Alcohol (up to 100 mmol/L) significantly increased HCV replication, which was dependent on CYP2E1 expression and alcohol-induced oxidative stress, and attenuated the anti-HCV action of IFN.[43] In chronic hepatitis C patients, cross-reactivity between CYP2E1 and specific sequences in HCV-NS5b protein can promote the development of auto-antibodies targeting conformational epitopes on the CYP2E1 surface that might contribute to hepatic injury.[44]

Alcohol's elevation of HCV titer in patients and increase of HCV RNA in replicon cells suggest that HCV replication is increased in the presence and absence of the complete viral replication cycle. Seronello et al.[45] used Huh7 human hepatoma cells that naturally express comparable levels of CYP2E1 as human liver to demonstrate that ethanol, at physiologically relevant concentrations, enhances complete HCV replication. Acetaldehyde, the first metabolite of ethanol, also enhanced HCV replication. They reported that elevated NADH/NAD⁺ is required for the potentiation of HCV replication by ethanol, and inhibiting CYP2E1 or ALDH suppressed replication. Thus, alteration of cellular NADH/NAD ratio is likely to play a critical role in the potentiation of HCV replication by ethanol (Fig. 4).

Figure 4. Summary of alcohol and HCV interactions. HCV, hepatitis C virus; IFN, interferon; ROS, reactive oxygen species.

Concluding remarks

Chronic heavy alcohol consumption in the presence of obesity and viral hepatitis could be damaging for the liver. While moderate alcohol consumption was associated with decreased prevalence of steatohepatitis in patients with NAFLD,[46] heavy alcohol consumption is discouraged whether an individual has NAFLD or not. The presence of common mechanisms for liver damage due to viruses, obesity, or chronic heavy alcohol consumption is relevant and may exacerbate damage to the liver when these three conditions exist. Further research is needed to clarify the interaction, if any, between moderate drinking, NAFLD, and viral hepatitis.

Conflict of interests

The author does not have any conflicting interests to declare.

References

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