The edition · Gastroenterology & Hepatology
Misfolded protein in routine gut biopsies predicted dementia seven years out
Archival biopsies from unexplained GI symptoms read for neurodegenerative proteinopathy, bile acid patterns across 5,056 IBD patients, the FDA's own view of drug-induced liver injury, and every segment of the gut in scleroderma.
The edition in brief
Two FDA hepatology specialists set out eight areas where the agency's approach to drug-induced liver injury in trials needs revisiting, driven by biologics whose hepatotoxicity does not behave like small molecules, small underpowered rare-disease trials, and drugs being developed for people who already have liver disease. In 196 archival gastrointestinal biopsies from people investigated for unexplained GI symptoms and followed 13 to 15 years, misfolded TDP-43, tau or alpha-synuclein was found in 60%; those with gut proteinopathy were substantially more likely to develop non-Alzheimer's dementia or an alpha-synucleinopathy, with over 80% sensitivity but low specificity, and the changes preceded neurological symptoms by an average of 6.9 years. Two or more markers went with progressively worse survival. A meta-analysis of 28 metabolomics studies covering 5,056 patients with inflammatory bowel disease found consistently lower secondary bile acids in IBD than controls, in ulcerative colitis compared with Crohn's disease, and in active compared with quiescent disease, with deoxycholic acid and its conjugates the most reliably reduced. The practice-changer is a review of gastrointestinal involvement in systemic sclerosis, which affects the oesophagus in about 90% of patients and produces disease in every segment from dysphagia and reflux to gastric antral vascular ectasia, small intestinal bacterial overgrowth, pseudo-obstruction and faecal incontinence — with symptoms correlating poorly with the underlying pathology, and almost all treatment evidence borrowed from patients without scleroderma.
The FDA's own hepatologists on what drug-induced liver injury assessment is missing
Read hepatotoxicity signals with the population in mind — the monitoring rules in use were built for small molecules in people with healthy livers.
Neurodegenerative proteins found in gut biopsies, years before the brain declared itself
Nothing to do in clinic — but archived gut biopsies may become how prevention trials find people seven years before symptoms.
Secondary bile acids fall consistently in inflammatory bowel disease
Nothing to order — but the consistent fall in bacterially produced bile acids is real, and it tracks disease activity.
Read the drug chart before you scope the chronic diarrhoea
Before investigating chronic diarrhoea, read the drug chart for metformin, magnesium, proton pump inhibitors and olmesartan — and stop the suspect first.
In scleroderma, assume every segment of the gut is involved
Screen the whole tract on your own initiative in systemic sclerosis — ask about incontinence, chase iron deficiency to the stomach, and do not let mild symptoms reassure you.
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