Liver Fat, Hepatic Enzymes, Alkaline Phosphatase and the Risk of Incident Type 2 Diabetes: A Prospective Study of 132,377 Adults

Liver Fat, Hepatic Enzymes, Alkaline Phosphatase and the Risk of Incident Type 2 Diabetes: A Prospective Study of 132,377 Adults

Sean Chun-Chang Chen, Shan Pou Tsai, Jing-Yun Jhao, Wun-Kai Jiang, Chwen Keng Tsao & Ly-Yun Chang

Received:08 December 2016

Accepted:18 May 2017

Published online:05 July 2017

Scientific Reports 7, Article number: 4649 (2017)

doi:10.1038/s41598-017-04631-7

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Introduction
The prevalence and incidence of type 2 diabetes (diabetes hereafter) are rising rapidly worldwide, especially in Asia1. Diabetes has been linked to a shorter life expectancy mainly because of its complications, including heart disease, strokes, eye disease, kidney failure and bone disease2. Lifestyle changes and medications are shown to reduce the incidence of diabetes3. Therefore, identification and evaluation of risk factors for diabetes is crucial for early intervention and treatment.

The relationships between hepatic enzymes including alanine transaminase (ALT), aspartate transaminase (AST) and gamma-glutamyltransferase (GGT) and incident diabetes have been examined, but the results are inconsistent. Several prospective studies have reported that ALT was assocaited with incident diabetes4,5,6,7,8,9, but this association was not significant in a study of 4,201 French men and women10. Hanley et al.5, Fraser et al.4, and Schneider et al.11 found that AST independently predicted incident diabetes in 906 non-Hispanic Americans, 3,041 British women, and 9,337 Americans (7,495 white and 1,842 black), respectively. However, others showed that AST did not predict incident diabetes7, 8, 10. In a recent review of literature, Kunutsor and colleagues12 suggested that AST was associated with the risk of incident diabetes after controlling for potential confounding factors. In addition, while most of the studies showed that elevated GGT level was a strong indicator for the onset of diabetes independent of common diabetes risk factors9, 10, a study in Pima Indians found GGT not a predictor8. Several recent studies used the Mendelian randomization to estimate the causal effects of liver enzymes on incident diabetes. ALT was shown to increase the risk of diabetes13 whereas the causal role of GGT in the development of diabetes remained controversial13,14,15.

Non-alcoholic fatty liver disease (NAFLD), the accumulation of excess fat in liver cells that is not caused by alcohol, has been found to be associated with several features of insulin resistance16 and incident diabetes4, 17. Ultrasonography-diagnosed NAFLD is an independent risk factor for diabetes18,19,20,21,22,23,24. Notably, most of them were conducted in Japanese or Korean populations. Notwithstanding the interesting findings, there were concerns about these studies. First, only one of them controlled for ALT and GGT23, both of which have been associated with liver fat accumulation25 Second, most of them used a small sample size and/or a few incident cases, whereas those with a large sample size comprised primarily men22, 23.

Alkaline phosphatase (ALP), an enzyme presented primarily in bone and liver, has been found to elevate in diabetes patients compared with non-diabetes control group26. However, other studies found no significant association between ALP and incident diabetes5, 8, 27, 28.

The aims of the study were: (1) to examine whether baseline NAFLD status and ALT, AST, GGT, and ALP levels are independent risk factors for incident diabetes, and (2) to determine whether these associations vary by gender group. The study population comprised 132,377 non-type 2 nor type 1 diabetic individuals (64,875 men and 67,502 women) aged 35–79 years. They had first physical examination on 1 January 1996 or later and had one or more follow-up examinations on or before 31 December 2014. To our knowledge, this is the largest and the first prospective study that includes five liver-related factors and evaluates their individual effects on incident diabetes, adjusting for a cluster of classical risk factors.

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HIV, Tuberculosis, Hepatitis C: EP proposals for tackling communicable diseases

HIV, Tuberculosis, Hepatitis C: EP proposals for tackling communicable diseases

make HIV tests free of charge to speed up diagnosis
address growing antimicrobial resistance of tuberculosis
develop a consistent approach to fight viral hepatitis across the EU

MEPs urged the Commission on Wednesday to address the increase in HIV/AIDS, tuberculosis and viral hepatitis cases in the EU and to develop long-term programmes.

A harmonised infection surveillance programme is needed to immediately detect outbreaks of these contagious diseases, assess trends in prevalence, provide disease burden estimates and effectively track in real time how diagnosis, treatment and care are managed.  As HIV remains the communicable disease bearing the greatest social stigma, Commission and Member States should facilitate access to innovative treatments, also for the most vulnerable groups, and combat social stigma.

They encourage Member States to make HIV tests available free of charge, to ensure early detection.

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Tuberculosis (TB), which is the biggest killer of people living with HIV, has become a serious cross-border threat in a globalised world in which population mobility is increasing, MEPs stress. The number of people affected by TB in the world rose in 2014 for the third year in a row.

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MEPs emphasise the importance of tackling growing anti-microbial resistance and call on EU leaders to establish cross-border prevention measures and initiate joint action.

Against Hepatitis C, where 90% of patients show no symptoms of contracting the disease, there is no standard protocol for screening in the Member States. The number of people affected might be underestimated, say MEPs.. The Commission should launch a plan to standardise screening, testing and treatment protocols to eradicate hepatitis C in the EU by 2030.

The resolution was adopted by show of hands.

Quick Facts

• In 2015, almost 30 000 new HIV infections were reported by the 31 EU/EEA countries.
• An estimated 120 000 people in Europe developed Multi-Drug Resistant TB.
• Viral hepatitis (HCV) is considered one of the most serious public health threats globally.
• According to the European Center for Disease Control (ECDC), one out of seven people living with HIV are not aware that they are HIV positive.
• The estimated average time between HIV infection and diagnosis is four years
• By 2050, out of an estimated 10 million annual deaths in the EU due to drug resistance , one quarter will be caused by drug resistant strains of TB

http://www.europarl.europa.eu/news/en/press-room/20170629IPR78636/hiv-tuberculosis-hepatitis-c-ep-proposals-for-tackling-communicable-diseases

Changes in renal function indices in cirrhotic chronic hepatitis C patients treated with sofosbuvir-containing regimens

Changes in renal function indices in cirrhotic chronic hepatitis C patients treated with sofosbuvir-containing regimens

Jianhong Chen1, Xiaxia Zhang1, Hao Luo1, Chihong Wu1, Min Yu1, Dan Liu1, Hongli Xi1, Yihang Zhou1, Yaoyu An1 and Xiaoyuan Xu1

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doi: 10.18632/oncotarget.18701

Received: March 26, 2017

Accepted: June 04, 2017

Published: June 28, 2017

INTRODUCTION
Hepatitis C virus (HCV) is an important pathogen affecting approximately 130–150 million people worldwide [1, 2]. Chronic hepatitis C (CHC) patients have enhanced risk of cirrhosis and hepatocellular carcinoma [3, 4]. The emergence of direct-acting antivirals (DAAs) has revolutionized the treatment of HCV with shorter treatment durations, higher sustained virological response (SVR) rates, fewer adverse events (AEs) and fewer contraindications than those of traditional peginterferon and ribavirin (PegIFN/RBV, PR) treatment regimens [5–8].

With the wide application of DAAs, challenging issues regarding the efficacy and safety of new DAAs regimens have arisen, e.g., resistance-associated variants, drug-drug interactions (DDIs), HBV (hepatitis B virus) reactivation, hepatotoxicity and nephrotoxicity [9–20]. In October 2016, the United States Food and Drug Administration issued a black box warning regarding the risk for HBV activation with 9 DAAs, citing 24 cases that included 3 reports of acute liver failure (https://www.fda.gov/).

The Institute for Safe Medicine Practices followed up with a review of Adverse Event Reporting System data covering a 12-month span. The review uncovered 524 cases of liver failure associated with DAAs and that 31.5% of the patients had died at the time of the review (http://www.ismp.org/default.asp).

Traditional PR treatment regimens and first-generation protease inhibitors are considered nephrotoxic [21, 22]. Although all-oral DAAs regimens were well tolerated in clinical trials, recent real-world studies demonstrated some cases with nephrotoxicity that were treated with sofosbuvir (SOF)-containing regimens [18–20]. Some cases with hepatotoxicity and nephrotoxicity associated with DDIs were reported in CHC patients with concomitant diseases, HBV or HIV co-infections, and liver transplantations [11, 14, 16, 17].

Considering the increasing occurrence of cases with hepatotoxicity, nephrotoxicity, and DDIs, this study aimed to explore the changes of hepatic and renal function indices in CHC patients treated with DAAs.

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Lancet - Prevalence and risk factors for HIV, hepatitis B, and hepatitis C in people with severe mental illness: a total population study of Sweden

The Lancet Psychiatry
Prevalence and risk factors for HIV, hepatitis B, and hepatitis C in people with severe mental illness: a total population study of Sweden
Clarissa Bauer-Staeb, MSc, Lena Jörgensen, PhL, Prof Glyn Lewis, PhD, Prof Christina Dalman, PhD, Prof David P J Osborn, PhD, Dr Joseph F Hayes, MB ChB

Published: 04 July 2017

Introduction

Severe mental illness is commonly defined as a mental disorder that is persistent and disabling in nature, such as schizophrenia, schizoaffective disorder, bipolar disorder, and other psychoses.¹ Increased mortality rates of 2–3 times the general population are well documented among people with severe mental illness, and translate into a reduction in life expectancy of up to 20 years.² Approximately 60% of this excess in mortality has been attributed to poor physical health.² Although much attention has been focused on addressing cardiovascular, respiratory, and cancer health inequalities, infectious diseases have been largely neglected in mental health research and policy.³ This situation is problematic as meta-analytic evidence suggests blood-borne virus (BBV) prevalence is elevated amongst individuals with severe mental illness.³ In North America, the pooled prevalence of BBVs in populations with severe mental illness is estimated to be as high as 6% for HIV, 2·2% for hepatitis B virus (HBV), and 17·4% for hepatitis C virus (HCV).³ Therefore, HIV and HCV are ten times, and HBV around five times, more common in people with severe mental illness than in the general population.⁴ Although lower, similar patterns are evident in people with severe mental illness in European countries (Germany, Belgium, Spain, Greece, Italy), with combined prevalence estimates of 1·9% for HIV, 2·7% for HBV, and 4·9% for HCV.³ However, the true scale of the problem is unclear, because previous studies have used small, unrepresentative convenience samples recruited from treatment settings.³ As far as we are aware, no population-based studies have been done of BBV prevalence in severe mental illness, and no studies have examined prevalence in northern European countries.³ Additionally, literature on risk factors for BBV in individuals with severe mental illness is limited, but high prevalence of substance misuse has been identified as a particular concern in this group.⁵

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New At Healio - Nexavar beneficial in liver cancer regardless of prognostic factors

Nexavar beneficial in liver cancer regardless of prognostic factors

Nexavar treatment consistently showed benefit in hepatocellular carcinoma regardless of prognostic factors, according to results of a recently published study.

“Although analyses of potential predictive factors for sorafenib benefit have been attempted with data from single-arm, observational studies, the lack of a placebo arm in these trials has prevented proper differentiation between prognostic and predictive markers,” Jordi Bruix, MD, from the BLCL Hospital Clinic Barcelona, Spain, and colleagues wrote. “Our analysis showed a consistent OS benefit with sorafenib treatment compared with placebo irrespective of patient baseline characteristics, subgroup or prognostic factors for survival.”

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Healio Hepatology - Top HCV reports for June 2017 focus on guides, screening

Top HCV reports for June 2017 focus on guides, screening
July 5, 2017

In the direct-acting antiviral era, researchers and medical professionals are continuing their efforts to eliminate hepatitis C by defining the most instrumental guides for screening, treatment and management.

Healio.com/Hepatology presents some of the highlights in HCV research data and formal reports for June 2017. The reports include EASL’s response to a controversial review of DAA studies, recommendations for the elimination of HCV from Georgetown University, the utility of electronic screening for HCV among the baby boomer generation, and a survey that identified gaps in current HCV and hepatitis B testing guides in Europe.

The European Association for the Study of the Liver responded with serious concern to a systematic review published by the Cochrane Group Review....

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Behind The Headlines - Heartburn drugs linked to premature death

Behind The Headlines: Analysis by Bazian edited by NHS Choices

What is Behind the Headlines?
Each day the NHS Choices team selects health stories that are making headlines. These, along with the scientific articles behind the stories, are sent to Bazian, a leading provider of evidence-based healthcare information. Bazian's clinicians and scientists analyse the research and produce impartial evidence-based assessments, which are edited and published by NHS Choices.

Heartburn drugs linked to premature death
"Millions of people taking common heartburn and indigestion medications could be at an increased risk of death," The Guardian reports after a US study found people taking proton pump inhibitors (PPIs) had a slightly higher risk of death than the control group.

PPIs reduce the amount of acid in the stomach. As well as being used to treat heartburn, they're often given to people as a protective measure if they're thought to be at risk of a stomach ulcer – for example, people who take daily low-dose aspirin, which is known to irritate the lining of the stomach.

This headline is based on research in 350,000 predominantly male US veterans who were prescribed PPIs or H2 blocker drugs to either treat heartburn or protect the stomach. PPIs and H2 blockers both work by reducing stomach acid.

The researchers found people who took PPIs had a greater risk of death from any cause compared with those who took H2 blockers or nothing at all.

But there was no proof that the increased risk of death was directly caused by the PPI drugs. The researchers tried to adjust for underlying health factors, such as cardiovascular disease, which is often treated with daily aspirin, but it's possible the effects of these or other factors could still have influenced the results.

If you've been prescribed PPIs, you shouldn't stop taking them without first consulting your GP. The risk of not taking them (such as a stomach bleed) may be greater than any risk associated with taking them.

Where did the story come from?
The study was carried out by researchers from VA Saint Louis Health Care System, Washington University School of Medicine, and Saint Louis University in the US.

No information on funding was provided, but the data the researchers analysed came from the US Department of Veterans Affairs.

The study was published in the peer-reviewed journal BMJ Open and is open access, so it's free to read on the BMJ website.

The UK media's coverage of the story was generally accurate, but the headlines failed to reflect the inherent limitations of the study – including the fact that the conditions people were taking PPIs for in the first place may also have been one of the main causes of death.

What kind of research was this?
This large cohort study of US veterans aimed to look at whether PPIs or H2 blockers were associated with risk of death.

H2 blockers are drugs like ranitidine (Zantac) that reduce stomach acid, and are commonly used to treat acid reflux or heartburn.

PPIs such as omeprazole work in a slightly different way, but are also used to protect the stomach, often in people who have ulcers or those at risk because they take anti-inflammatories or aspirin long term.

Both types of drugs are available on prescription, and some can be purchased over the counter in pharmacies.

As this was a cohort study, it can't prove that taking one drug directly causes death – it can only show there's an association. It might be the case that other health, sociodemographic or lifestyle factors, such as high body mass index (BMI), contributed to the higher risk of death.

A randomised controlled trial (RCT) would give more reliable evidence on the direct effect of either taking the different drugs or doing nothing (control group) while controlling for other factors.
But RCTs can be expensive and time consuming to carry out. Cohort studies can be useful to assess potential adverse effects, as they're able to follow an extensive number of people (in this case 349,312) over a long period of time.

What did the research involve?
Researchers used the US Department of Veterans Affairs national databases to identify 349,312 people (average age 61, 94% male) who'd been prescribed acid suppression therapy (PPIs or H2 blockers) between 2006 and 2008. They looked at their likelihood of death by any cause over 5.71 years on average.

Information on deaths is routinely gathered by the Veterans Benefit Administration for all US veterans.

The 275,977 participants whose first acid reflux drug was a PPI were placed in the PPI group, while the 73,335 participants who received H2 blockers first were the reference group.
In the H2 blocker group, 33,136 participants were later prescribed a PPI and were placed in the PPI group from the point they started taking PPI drugs.

The main outcome of interest was drug use in relation to death.  The researchers also looked at how long the drugs were prescribed for.

They adjusted their data to take into account a number of things that could have influenced the results, including:

• age
• race
• gender
• kidney function
• number of hospitalisations

They also took into account a range of chronic illnesses, including:

• diabetes
• hypertension
• cardiovascular disease
• peripheral artery disease
• stroke
• chronic lung disease
• hepatitis C
• HIV
• dementia
• cancer
• a range of gastrointestinal illnesses

What were the basic results?
Overall, 23.3% of the entire cohort died over the 5.71-year follow-up. The rate was 12.3% in those using H2 blockers at the start of the study, 24.4% in those using PPIs at the start of the study, and 23.4% in those who'd ever used PPIs.
The researchers found:

• PPI use was associated with increased risk of death compared with H2 blocker use (hazard ratio [HR] 1.25, 95% confidence interval [CI] 1.23 to 1.28)
• PPI use versus no known exposure to acid suppression therapy (PPIs or H2 blockers) was also linked with a similar increased risk of death (HR 1.23, 95% CI 1.22 to 1.24)

Risks were similar when only looking at participants with no known gastrointestinal problems:

• PPI versus H2 blocker use (HR 1.24, 95% CI 1.21 to 1.27)
• PPI versus no known acid suppression therapy (HR 1.22, 95% CI 1.21 to 1.23)

Compared with participants taking PPIs for 30 days or less, risk of death gradually increased with the length of time they were taking them:

• 31-90 days (HR 1.05, 95% CI 1.02 to 1.08)
• 91-180 days (HR 1.17, 95% CI 1.13 to 1.20)
• 181-360 days (HR 1.31, 95% CI 1.29 to 1.34)
• 361-720 days (HR 1.51, 95% CI 1.47 to 1.56)

How did the researchers interpret the results?
The researchers concluded that, "The results suggest excess risk of death among PPI users; risk is also increased among those without gastrointestinal conditions and with prolonged duration of use. Limiting PPI use and duration to instances where it is medically indicated may be warranted."

Conclusion
This larger set of observational data finds that PPI drugs are associated with an increase in the risk of early death compared with either H2 blockers or no acid suppression drugs. This was the case for participants both with and without gastrointestinal problems.
It also appears as though the longer the PPIs drugs are taken, the greater the risk of death.
Considering that these drugs are widely used in the UK, these findings may cause concern. But the research has a number of important limitations:

• The study was conducted in a population of mostly white, older US male veterans, which might limit the ability to generalise the results to the whole UK population.
• Deaths can't be linked directly to the use of PPIs. The researchers have tried to adjust for many health and other characteristics that could be linked with both PPI use and higher risk of death, such as cardiovascular diseases, but we still can't be certain the influence of the disease has been fully taken into account.
• Many of the deaths occurred in the first year, so could well be linked to underlying causes. There was also no information on cause of death.
• The follow-up period only lasted around five years. Longer term death outcomes weren't examined – it may be that PPIs are associated with better outcomes for participants in the long term, but we can't say for sure either way.
• The length of follow-up in the PPI group was more than two years longer than in the H2 blocker group, so it's unsurprising there was a greater risk of death given the extra two years of data collection.
• The drugs were all prescribed in outpatient settings. Some brands of these drugs are available over the counter in the UK. There might be a difference between the groups of people who have their drugs prescribed and those who buy them over the counter, both in terms of risk and in the dose of the drugs.
• This study can't attribute risk to any individual PPI drug. If there is a direct mortality risk from PPIs, it may differ according to which drug it is – but this study isn't able to tell us this.

Overall, this large study of good-quality data raises a clear link that needs further examination.
But people who have been prescribed PPIs shouldn't stop taking them – the risk of not doing so may be much greater than any risk the drugs pose. For example, a bleeding stomach ulcer can be very serious and potentially life threatening.
If you're concerned about your medication, you should discuss your treatment options with your GP or the doctor in charge of your care.

Analysis by Bazian

Edited by NHS Choices

Links to the headlines
People taking heartburn drugs could have higher risk of death, study claims.

The Guardian, July 4 2017

Heartburn drugs taken by millions may increase risk of early death, study suggests.

The Daily Telegraph, July 3 2017

Indigestion pills 'may increase the risk of an early death': People who use one type of treatment for heartburn are 25% more likely to die within six years.

Daily Mail, July 4 2017

Acid reflux drugs linked to heightened risk of premature death in new study.

The Independent, July 4 2017

Links to the science
Xie Y, Bowe B, Li T, et al. Risk of death among users of Proton Pump Inhibitors: a longitudinal observational cohort study of United States veterans. BMJ Open. Published online July 4 2017

Sofosbuvir, Velpatasvir and Voxilaprevir combination for the treatment of hepatitis C- Review Article

Expert Rev Gastroenterol Hepatol. 2017 Jul 4. doi: 10.1080/17474124.2017.1351295.
[Epub ahead of print]

Sofosbuvir, Velpatasvir and Voxilaprevir combination for the treatment of hepatitis C
Rebecca Voaklander & Ira M Jacobson

Received 19 Apr 2017, Accepted 03 Jul 2017, Accepted author version posted online: 04 Jul 2017

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Abstract

Introduction

The advent of direct-acting antiviral (DAA) treatments for chronic hepatitis C virus (HCV) infection has dramatically increased rates of cure. However, there remain difficult-to-treat populations, including patients with genotype 3 infection and cirrhosis, and limited salvage treatment options for those that have failed first-line DAA therapy.

Areas covered

This is a review of the preclinical and clinical development of sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX), an interferon-free, oral, once daily, pangenotypic treatment for chronic HCV infection. All relevant literature from 2015 through June of 2017 is included.

Expert commentary

Voxilaprevir, a second-generation HCV protease inhibitor, in combination with the already approved combination of sofosbuvir and velpatasvir, was evaluated in the POLARIS trials and found to be a safe and effective regimen. Patients with prior DAA treatment failure, genotype 3, cirrhosis and/or unfavorable resistance profiles all achieved cure rates of 96% or greater. The most distinctive role for this potent regimen may prove to be as a salvage regimen for patients who have failed previous DAA therapy.

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