To characterize parathyroid hormone-related protein (PTHrP) in the human placenta, we measured PTHrP-like immunoreactivity (PRP-LI) in the term placenta and studied the elution profiles of placental tissue extracts on Sephadex G-75 chromatography with a specific RIA. We also examined the gene expression of PTHrP mRNA by Northern blot analysis and the localization of PRP-LI in the placenta by immunohistochemistry. The amount of PRP-LI in placental extracts (n = 7) was 20.9 +/- 2.2 pg/g wet tissue (mean +/- SE). Dilution curves of placental tissue ran parallel to those of synthetic PTHrP (1-34) standards. Sephadex G-75 gel chromatography demonstrated two major PRP-LI peaks; the first peak was eluted around the molecular size between 10 kilodaltons (Kda) and 20 Kda and the other around 5 Kda. Northern blot analysis of PTHrP mRNA extracted from placental tissues showed a major hybridization signal around 18S. PTHrP immunohistochemistry showed PRP-LI staining in the cytoplasm of syncytiotrophoblasts and stroma cells (Hofbauer cells) in the term placenta. These results suggest that syncytiotrophoblasts and stroma cells in the term placenta synthesize PTHrP in two major molecular forms, 10 Kda-20 Kda and around 5 Kda.

To elucidate possible negative feedback regulation of circulating PTH-related protein (PTHrP) by serum calcium levels, we measured serum immunoreactive PTHrP (iPTHrP) by a specific RIA for PTHrP-(1-34) in patients with hypocalcemia due to PTH deficiency or resistance. Serum iPTHrP levels were not detectable (< 4 pmol/L) in 9 of 11 patients with postoperative hypocalcemia who presented with transient tetany, in 1 patient with hypocalcemia due to hypomagnesemia induced by cisplatin treatment, in normal subjects (n = 60), or in 1 normocalcemic patient with pseudopseudohypoparathyroidism. In contrast, the other 2 patients with postoperative hypocalcemia who had had hypocalcemic symptoms for longer periods (6 months and 3 yr, respectively) showed increased iPTHrP levels (6.3 and 5.3 pmol/L). All 6 patients with idiopathic hypoparathyroidism showed undetectable or low PTH, but increased iPTHrP, ranging from 6.5-19.5 pmol/L (mean +/- SD, 10.8 +/- 4.8 pmol/L). Elevated serum iPTHrP levels (7.4 and 8.1 pmol/L) were also found in both patients with pseudohypoparathyroidism type I. When chronic and profound hypocalcemia in these patients was normalized by treatment with 1 alpha-hydroxyvitamin D3, the elevated serum iPTHrP levels were normalized (undetectable, < 4 pmol/L) in all 6 patients examined. These results suggest that chronic and profound hypocalcemia and/or vitamin D deficiency can stimulate endogenous PTHrP secretion via a negative feedback mechanism, although elevated iPTHrP does not normalize the decreased serum calcium levels.

A 49-year-old female with multiple endocrine neoplasia (MEN)type 1 associated with malignant lymphoma, lipoma, functioning adenomatous goiter, non-functioning adrenal tumor, polyneuropathy, postoperative primary hyperparathyroidism, and hepatitis B virus was a human T lymphotropic virus type 1 (HTLV-1) carrier. She underwent parathyroidectomy for primary hyperparathyroidism at age 44. At age 49, examinations of the enlarged para-aortic lymph nodes revealed diffuse small non-cleaved B cell lymphoma in stage II, and other various complications were also found. Multiple tumorigenetic factors were considered to be involved in the present case. (Internal Medicine 35: 849-854, 1996)

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SummaryA 32-year-old woman presented with 3days of epigastric pain and was admitted to our hospital (day 3 of disease). We diagnosed acute pancreatitis based on epigastric abdominal pain, hyperamylasemia, and an inflammatory reaction of withdrawn blood, pancreatic enlargement, and so on. Her condition improved with treatment; however, on day 8, she had decreased level of consciousness. Laboratory results led to a diagnosis of fulminant type 1 diabetes mellitus (FT1DM) with concomitant diabetic ketoacidosis. Insulin therapy improved her blood glucose levels as well as her symptoms. Fatty liver with liver dysfunction was observed on day 14, which improved by day 24. Blood levels of free fatty acids (FFAs) increased rapidly from 440μEq/L (normal range: 140–850μEq/L) on day 4 to 2097μEq/L on days 7–8 (onset of FT1DM) and subsequently decreased to 246μEq/L at the onset of fatty liver. The rapid decrease in insulin at the onset of FT1DM likely freed fatty acids derived from triglycerides in peripheral adipocytes into the bloodstream. Insulin therapy rapidly transferred FFAs from the periphery to the liver. In addition, insulin promotes the de novo synthesis of triglycerides in the liver, using newly acquired FFAs as substrates. At the same time, inhibitory effects of insulin on VLDL secretion outside of the liver promote the accumulation of triglycerides in the liver, leading to fatty liver. We describe the process by which liver dysfunction and severe fatty liver occurs after the onset of FT1DM, from the perspective of disturbed fatty acid metabolism.Learning pointsFT1DM is rare but should be considered in patients with pancreatitis and a decreased level of consciousness.Fatty liver should be considered in patients with FT1DM when liver dysfunction is observed.Insulin is involved in mechanisms that promote fatty liver formation.Pathophysiological changes in fatty acid metabolism may provide clues on lipid metabolism in the early phases of FT1DM.