Tag: disease

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Liver fibrosis linked to CV events, survival in NAFLD, chronic kidney disease

After a median follow-up of 10 years, NAFLD correlated with an increased risk for: “Variable A” – Cardiovascular events; HR = 1.39 “Variable B” – All-cause mortality; HR = 1.1

Source:

Hydes T, et al. Abstract OS048. Presented at: International Liver Congress; June 22-26, 2022; London (hybrid meeting).


Disclosures:
Hydes reports no relevant financial disclosures.


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LONDON — Elevated noninvasive markers of liver fibrosis correlated with an increased risk for cardiovascular events, end-stage renal disease and worse survival in patients with chronic kidney disease and nonalcoholic fatty liver disease.

“Multimorbidity is increasing, and it is vital to understand the clinical consequences of having more than one medical condition,” Theresa Hydes, MBBS, BSc, PhD, NIHR clinical lecturer in hepatology at the University of Liverpool, told Healio. “Fatty liver disease, in particular, is independently associated with several non-liver conditions, including heart disease and chronic kidney disease.”


After a median follow-up of 10 years, NAFLD correlated with an increased risk for: “Variable A” – Cardiovascular events; HR = 1.39 “Variable B” – All-cause mortality; HR = 1.1



Seeking to assess the effect of NAFLD and NAFLD fibrosis on adverse clinical outcomes and mortality among patients with chronic kidney disease (CKD), Hydes and colleagues analyzed data from 26,074 patients using the UK Biobank. Participants provided information related to medical history, demographics and lifestyle factors, which was supplemented via electronic linkage to hospital records and death records.

Researchers used Cox regression to estimate hazard ratios associated with NAFLD and advanced liver fibrosis on CV events, progression to end-stage renal disease (ESRD) and all-cause mortality.

At baseline, 54,5% of patients with CKD had NAFLD, with evidence of advanced fibrosis among 7% [NAFLD fibrosis score (NFS) 0.676], 3.2% [elevated fibrosis-4 (FIB-4) > 2.67] and 1.1% [AST to platelet ratio index (APRI) 1].

After a median follow-up of 10 years, NAFLD correlated with an increased risk for CV events (HR = 1.39; 95% CI, 1.29-1.51) and all-cause mortality (HR = 1.1; 95% CI, 1.01-1.19) but not ESRD (HR = 1.22; 95% CI, 0.95-1.56) in a univariate analysis. Following multivariate adjustment for demographics, metabolic factors and baseline renal functions, NAFLD did not associate with an increased risk for primary outcomes.

Advanced liver fibrosis using all scores correlated with an increased risk for all-cause mortality (HR = 2.34-2.9), and NFS and FIB-4 associated with an elevated risk for CV events (HR = 2.49; 95% CI, 2.11-2.93 and HR = 1.94; 95% CI, 1.53-2.45) and ESRD (HR = 6.85; 95% CI, 4.29-10.94 and HR = 2.35; 95% CI, 1.19-4.67). After full adjustment, FIB-4 correlated with an increased incidence of CV events (HR = 1.39; 95% CI, 1.06-1.82), notably heart failure (HR = 1.65; 95% CI, 1.16-2.33).

Both FIB-4 and APRI associated with all-cause mortality (HR = 1.55; 95% CI, 1.21-2 and HR = 2.83; 95% CI, 1.95-4.11) and NFS ( –1.455) associated with progression to ESRD (HR = 1.89; 95% CI, 1.13-3.17).

“These results highlight the importance of enhanced recognition of fatty liver disease with fibrosis in people with chronic kidney disease to inform the need for vigorous cardiometabolic risk factor control in this group,” Hydes said. “It also suggests the need for work to understand the mechanisms linking these conditions to help drive new drug discoveries.”


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International Liver Congress

International Liver Congress

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Corticosteroid exposure associated with hospitalization for severe pain event among patients with sickle cell disease

Corticosteroid exposure associated with hospitalization for severe pain event among patients with sickle cell disease

People with sickle cell disease (SCD) who were recently prescribed a corticosteroid – a medicine frequently used to treat asthma or inflammation – were found to be significantly more likely to be hospitalized for a severe pain event, according to a paper published today in the journal Blood. The research also found that older adults, women, and people who were not taking the drug hydroxyurea to manage their underlying SCD symptoms were the most likely to be hospitalized.

SCD is the most common inherited red blood cell disorder in the United States, affecting an estimated 100,000 people. According to the Centers for Disease Control and Prevention (CDC), SCD affects one out of every 365 Black or African American births and one out of every 16,300 Hispanic American births. Pain events, also known as vaso-occlusive episodes (VOE), are the most common complications of SCD and can result in intense pain and potentially irreversible organ damage.

Apart from case reports, researchers say this is the first study to systematically evaluate the association between corticosteroid exposure and hospitalization for VOE.

Individuals living with SCD often suffer crippling episodes of pain, which can greatly impair their quality of life. Based on our data, corticosteroids are commonly prescribed for conditions unrelated to their underlying SCD. Vaso-occlusive events and related hospitalization appear to follow corticosteroid prescription fairly quickly. This evidence suggests corticosteroids may be contributing to the events and should be avoided as much as possible in these patients.”


Ondine Walter, MD, Study Author, Toulouse University Hospital in France

Notably, the median time between filling a prescription for a corticosteroid and hospitalization was just five days. Also striking was the fact that nearly half (46%) of patients with SCD had been prescribed at least one systemic corticosteroid during the study period. Dr. Walter said the results underscore the need for widespread education of clinicians and patients alike about the potential risks of using corticosteroids, especially when there isn’t a clear indication to use them.

“Corticosteroids are mostly easy to avoid, and in circumstances when they are necessary, it’s important to start them in collaboration with an SCD expert and to take all appropriate precautionary measures to administer them safely,” said Dr. Walter.

The study used data from a total of 5,151 patients with SCD drawn from the French National Health Insurance Database between 2010 and 2018. Patients had to have at least one hospitalization for VOE to be included, and corticosteroid exposure was identified using outpatient prescribing records.

The study found that those who had exposure to a corticosteroid – defined in the month leading up to the event – were significantly more likely to be hospitalized for VOE. People who were also taking hydroxyurea seem to have less risk of hospitalization compared with those not taking the drug, which may signal a potential protective effect of hydroxyurea on the occurrence of VOE, Dr. Walter explained. Hydroxyurea is often prescribed to reduce the number of pain events caused by SCD as well as the need for blood transfusions. The risk of admission was also lower in men compared to women and in children compared to adults.

“Some factors such as hydroxyurea use, male gender, and younger age were associated with a lower risk of hospitalization for VOE after corticosteroid exposure in our study. Still, based on these results, we still need to think twice about using corticosteroids when treating patients with SCD,” said Dr. Walter.

This study is limited in that it can only show an association between corticosteroids and VOE-related hospitalizations and not prove causation. Because corticosteroid exposure was based on dispensing data, it is also not possible to confirm that patients took the medicine, only that the prescription was filled.

With future research, investigators aim to understand how corticosteroids may prompt VOE. Studies have shown that the cessation of corticosteroids, in particular, has been associated with rebound pain. ASH’s Clinical Practice Guidelines on SCD recommend against using corticosteroids for acute pain management in patients with SCD. This study adds important data about the association of corticosteroid use with subsequent VOE to a growing body of evidence that suggests corticosteroids should be used only when needed, and under the guidance of an SCD expert.

Source:

American Society of Hematology

Journal reference:

Walter, O., et al. (2022) Risk of vaso-occlusive episode after exposure to corticosteroids in patients with sickle cell disease. Blood. doi.org/10.1182/blood.2021014473.

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Cell stress-related biochemical events may be partly driving Parkinson’s disease

Cell stress-related biochemical events may be partly driving Parkinson's disease

Parkinson’s disease may be driven in part by cell stress-related biochemical events that disrupt a key cellular cleanup system, leading to the spread of harmful protein aggregates in the brain, according to a new study from scientists at Scripps Research.

The discovery, published in The Journal of Neuroscience in February 2022, offers a clear and testable hypothesis about the progression of Parkinson’s disease, and may lead to treatments capable of significantly slowing or even stopping it.

We think our findings about this apparent disease-driving process are important for developing compounds that can specifically inhibit the process of disease spread in the brain.”


Stuart Lipton, MD, PhD, study senior author, Step Family Endowed Chair, founding co-director of the Neurodegeneration New Medicines Center, and professor in the Department of Molecular Medicine at Scripps Research

Parkinson’s disease affects roughly one million people in the United States. Its precise trigger is unknown, but it entails the deaths of neurons in a characteristic sequence through key brain regions. The killing of one small set of dopamine-producing neurons in the midbrain leads to the classic Parkinsonian tremor and other movement impairments. Harm to other brain regions results in various other disease signs including dementia in late stages of Parkinson’s. A closely related syndrome in which dementia occurs early in the disease course is called Lewy Body Dementia (LBD), and affects about 1.4 million people in the U.S.

In both diseases, affected neurons contain abnormal protein aggregations, known as Lewy bodies, whose predominant ingredient is a protein called alpha-synuclein. Prior studies have shown that alpha-synuclein aggregates can spread from neuron to neuron in Parkinson’s and LBD, apparently transmitting the disease process through the brain. But precisely how alpha-synuclein aggregates build up and spread in this way has been unclear.

One clue, uncovered by Lipton’s lab and others in prior research, is that the Parkinson’s/LBD disease process generates highly reactive nitrogen-containing molecules including nitric oxide. In principle, these reactive nitrogen molecules could disrupt important cellular systems, including “housekeeping” systems that normally keep protein aggregates under control.

In the new study, the Scripps Research team demonstrated the validity of this idea by showing that a type of nitrogen-molecule reaction called S-nitrosylation can affect an important cellular protein called p62, triggering the buildup and spread of alpha-synuclein aggregates.

The p62 protein normally assists in autophagy, a waste-management system that helps cells get rid of potentially harmful protein aggregates. The researchers found evidence that in cell and animal models of Parkinson’s, p62 is S-nitrosylated at abnormally high levels in affected neurons. This alteration of p62 inhibits autophagy, causing a buildup of alpha-synuclein aggregates. The buildup of aggregates, in turn, leads to the secretion of the aggregates by affected neurons, and some of these aggregates are taken up by nearby neurons.

“The process we observed seems very similar to what is seen in Parkinson’s and LBD brains,” says study first author Chang-Ki Oh, PhD, a staff scientist in the Lipton laboratory.

The researchers also tested postmortem brains of LBD patients, and again found that levels of S-nitrosylated p62 were abnormally high in affected brain areas-;supporting the idea that this process occurs in humans.

Lipton and Oh say that S-nitrosylation of proteins becomes more likely in many situations of cellular stress, including the presence of protein aggregates. Thus, this chemical modification of p62 could be a key factor in a self-reinforcing process that not only stresses brain cells beyond their limits, but also spreads the source of stress to other brain cells.

The team is now working to develop drug-like compounds that specifically inhibit the S-nitrosylation of p62. Although it would take years to develop such compounds as potential commercial drugs, they could, in principle, slow the Parkinson’s/LBD disease process or prevent its further spread in the brain after it begins, Lipton says.

Source:

Scripps Research Institute

Journal reference:

Oh, C., et al. (2022) S-Nitrosylation of p62 Inhibits Autophagic Flux to Promote α-Synuclein Secretion and Spread in Parkinson’s Disease and Lewy Body Dementia. Journal of Neuroscience. doi.org/10.1523/JNEUROSCI.1508-21.2022.