Inorganic pyrophosphate (PPi) levels were estimated by radiometric assay in urine and in synovial fluid (SF) from asymptomatic, nonarthritic knees of patients with untreated metabolic disease and normal controls. SF PPi was significantly elevated in patients with hyperparathyroidism (mean +/- SEM 19 +/- 3 microM; n = 9), hemochromatosis (23 +/- 5 microM; n = 6), and hypomagnesemia (27 +/- 0.1 microM; n = 2) compared with normal subjects (10 +/- 0.5 microM, n = 50), and was low in patients with hypothyroidism (4.2 +/- 2.3 microM; n = 11) (P less than 0.05 all comparisons). Urinary PPi was elevated only in those with hypophosphatasia. Local elevation of ionic PPi may be relevant to the mechanism of crystal formation in metabolic diseases predisposing to calcium pyrophosphate dihydrate (CPPD) crystal deposition. The finding of low SF PPi levels in patients with hypothyroidism further questions the association between this condition and CPPD.