Osteoporosis & fractures
5×
lower calcium-carbonate absorption when achlorhydric (4.2% vs 22.5%)
Nutrient malabsorptionHypergastrinemia
Three mechanisms converge: acid-dependent calcium dissolution, B12-related osteoblast impairment, and gastrin-driven parathyroid stimulation. PPI meta-analyses show hip-fracture risk of 1.26 to 1.30; FDA fracture warning issued 2010. Bone-density data show no clear decline, an unresolved paradox.
Recker, NEJM 1985 · Yu, Am J Med 2011
Acne rosacea
10×
more SIBO than controls
Acid barrier
Epstein (1931) found 75 percent of rosacea patients had subnormal or absent acid. Treating SIBO with rifaximin cleared skin in 71 percent, with clearance lasting at three years. A 2023 Korean cohort linked prolonged acid suppression to rosacea (OR 1.55, dose-response).
Parodi, Clin Gastroenterol Hepatol 2008 · Kim, JKMS 2023
Chronic urticaria
84%
had reduced acid in a 1951 series (unreplicated)
Acid barrier
Rawls and Ancona found 31 percent achlorhydria and 53 percent hypochlorhydria across 77 patients; 65 percent of those with low acid improved on HCl therapy. Striking, but a single older study without modern replication.
Rawls & Ancona, Rev Gastroenterol 1951
Childhood asthma
80%
of asthmatic children had below-normal acid (Bray 1931)
Acid barrier
The proposed route runs through food allergy: poor protein digestion yields allergenic peptides. Prenatal PPI-exposure meta-analyses show pooled effects of 1.30 to 1.57 for childhood asthma. Modern controlled studies of primary hypochlorhydria are needed.
Bray, QJM 1931 · Madej, 2023
Depression
OR 2.08
for major depression at high cumulative PPI dose
Nutrient malabsorptionAcid barrier
Converging pathways: B12-dependent methylation for monoamine synthesis, reduced tryptophan for serotonin, and a gut-brain route through SIBO and inflammation. A 2025 Mendelian randomization study found no strong genetic link between serum B12 and psychiatric disease at population level.
Huang, Psychother Psychosom 2018
Rheumatoid arthritis
22–36%
of RA patients have hypo- or achlorhydria, NSAID-independent
Autoimmune
Documented since 1912. NSAIDs damage the mucosa, the damaged mucosa makes less acid, and lower acid worsens the autoimmune environment. RA appeared in 8.75 percent of a major autoimmune atrophic gastritis cohort.
Henriksson, Ann Rheum Dis 1986
Sjogren's syndrome
~30%
atrophic gastritis in Sjogren's with GI involvement
Autoimmune
Sjogren's destroys exocrine glands, and the gastric mucosal glands are exocrine targets.
Pokorny, Ann Rheum Dis 1991
Alopecia areata
8.3%
prevalence in autoimmune atrophic gastritis cohorts
Autoimmune
Shared CD8+ T-cell organ-specific destruction; part of polyglandular syndrome type IIIc. Iron and B12 deficiency may worsen hair loss.
Lenti, 2022
Graves' disease
44%
of pernicious anemia patients have anti-thyroid autoimmunity
Autoimmune
Shares the thyrogastric relationship with Hashimoto's; part of polyglandular syndrome types II and III.
Doniach, BMJ 1963
Allergic rhinitis
2.2–11×
risk ratios in infants prescribed PPIs
Acid barrier
Supported through the broader acid-suppression to allergy pathway.
Jordakieva, Nat Commun 2019
Histamine intolerance
DAO low
SIBO lowers diamine oxidase; entity contested
Acid barrier
Bacterial overgrowth includes histamine-producing species while reducing diamine oxidase activity. The biochemistry is well-established; the diagnostic entity itself remains debated.
Maintz & Novak, AJCN 2007
Gallstones & cholecystitis
79%
showed reduced gallbladder ejection on omeprazole (n=19)
Other
Delayed gastric emptying and reduced CCK release decrease gallbladder contraction, promoting bile stasis and stone formation.
Cahan, Surg Endosc 2006
Spontaneous bacterial peritonitis
2.2–3.2×
for SBP with PPIs in cirrhosis
Acid barrier
In cirrhosis, acid-barrier loss drives SIBO, bacterial translocation, and peritoneal infection, with a dose-response relationship.
Terg, Clin Gastroenterol Hepatol 2012
Irritable bowel syndrome
26%
of PPI-treated patients had positive SIBO breath tests at 6 months
Acid barrier
The connection runs through the SIBO pathway; 19 percent met Rome III criteria for IBS after six months of PPI therapy.
Lombardo, Clin Gastroenterol Hepatol 2010
Restless legs syndrome
OR 1.3–1.4
restless legs with acid suppression (two cohorts)
Nutrient malabsorption
Iron deficiency lowers brain iron, producing the dopaminergic dysfunction behind the syndrome.
Earley, Sleep 2021
Migraine
OR 0.20
80% lower migraine odds in the highest B12 quartile
Nutrient malabsorption
The pathway runs through B12 deficiency; levels are significantly lower in migraineurs.
Aminianfar, Headache 2019
Parkinson's disease
57.5%
SIBO prevalence in atrophic gastritis
Acid barrier
Significance is mainly as a complicating factor: H. pylori gastritis impairs levodopa absorption and raises SIBO prevalence.
Fasano, Lancet Neurol 2015
Primary biliary cholangitis
47.8%
of anti-parietal-cell-positive autoimmune liver disease was PBC (2025)
Autoimmune
Anti-parietal-cell antibodies appeared in 22.1 percent of autoimmune liver disease, with PBC disproportionately represented. Part of polyglandular syndrome 3B.
Massironi, Front Immunol 2025
Celiac disease
~2%
co-occurrence — paradoxically inverse
Nutrient malabsorption
Both conditions independently cause iron malabsorption at different sites, making them important to consider together in unexplained IDA.
Conti, Dig Liver Dis 2023
Other nutrient deficiencies
Mg·C·Zn·Ca
acid-dependent absorption beyond B12 and iron
Nutrient malabsorption
PPI-induced low magnesium is FDA-warned (hemodialysis OR 2.70). Omeprazole lowers plasma vitamin C, and scurvy is reported in severe atrophic gastritis. Acid solubilizes zinc and dissolves calcium carbonate; calcium citrate does not require acid.
Cavalcoli, WJG 2017 · Vavallo, IJMS 2024