Continuous Subcutaneous Recombinant Parathyroid Hormone (1-34) Infusion in the Management of Childhood Hypoparathyroidism Associated with Malabsorption.

BACKGROUND/AIMS: Hypoparathyroidism associated with malabsorption can be particularly challenging to manage due to limited and erratic intestinal absorption of calcium and vitamin D analogues, resulting in episodes of hypo- or hypercalcaemia. We evaluated the role of continuous subcutaneous recombinant parathyroid hormone (rhPTH 1-34) infusion (CSPI) in children with hypoparathyroidism associated with intestinal malabsorption resistant to conventional therapy. METHOD: Four patients (8-13 years of age), with symptomatic hypocalcaemia resistant to conventional therapy, were started on CSPI (follow-up 3-8 years) in two paediatric endocrinology units in Europe. RESULTS: Serum calcium normalized within 48 h of commencing treatment in all 4 patients. An average rhPTH 1-34 dose of 0.4 µg/kg/day resulted in a substantial reduction in symptomatic hypocalcaemia and hypo-/hypercalcaemia-related hospital admissions. An increased alkaline phosphatase activity was noted in the first 6 months on CSPI, indicating an increase in bone turnover. In 2 patients with elevated urinary calcium excretion before CSPI, this normalized in the first year on treatment. No significant side effects were noticed in the short or long term, with patient-reported preference of CSPI over conventional treatment. CONCLUSION: CSPI is a promising and effective treatment option for managing hypocalcaemia and hyperphosphataemia in children with hypoparathyroidism associated with intestinal malabsorption.

Isotope concentrations from 24-h urine and 3-h serum samples can be used to measure intestinal magnesium absorption in postmenopausal women.

Studies suggest a link between magnesium status and osteoporosis. One barrier to more conclusive research on the potential relation is measuring intestinal magnesium absorption (MgA), which requires the use of stable isotopes and a ≥6-d stool or 3-d urine collection. We evaluated alternative methods of measuring MgA. We administered 2 stable magnesium isotopes to 15 postmenopausal women (cohort 1) aged 62 ± 8 y with a dietary magnesium intake of 345 ± 72 mg/d. Participants fasted from 1200 h to 0700 h and then consumed breakfast with ∼23 mg of oral ²6Mg and ∼11 mg of i.v. ²5Mg. We measured magnesium isotope concentrations in 72-h urine, spot urine (36, 48, 60, and 72 h), and spot serum (1, 3, and 5 h) samples collected after isotope dosing. We calculated MgA using the dose-corrected fraction of isotope concentrations from the 72-h urine collection. We validated new methods in 10 postmenopausal women (cohort 2) aged 59 ± 5 y with a dietary magnesium intake of 325 ± 122 mg/d. In cohort 1, MgA based on the 72-h urine collection was 0.28 ± 0.08. The 72-h MgA correlated most highly with 0-24 h urine MgA value alone (ρ = 0.95, P < 0.001) or the mean of the 0-24 h urine and the 3-h (ρ = 0.93, P < 0.001) or 5-h (ρ = 0.96, P < 0.001) serum MgA values. In cohort 2, Bland-Altman bias was lowest (-0.003, P = 0.82) using means of the 0-24 h urine and 3-h serum MgA values. We conclude that means of 0-24 h urine and 3-h serum MgA provide a reasonable estimate of 72-h MgA. However, if researchers seek to identify small changes in MgA, we recommend a 3-d urine or extended stool collection.

Serum vitamin D increases with weight loss in obese subjects 6 months after Roux-en-Y gastric bypass.

BACKGROUND: Malabsorptive surgical procedures lead to deficiencies in fat-soluble vitamins. However, results concerning serum vitamin D (25OHD) after gastric bypass (GBP) are controversial. The aim of the study was to assess the influence of GBP on 25OHD and calcium metabolism. METHODS: Parameters of calcium metabolism were evaluated in 202 obese subjects before and 6 months after GBP. Thirty of them were matched for age, gender, weight, skin color, and season with 30 subjects who underwent sleeve gastrectomy (SG). A multivitamin preparation that provides 200 to 500 IU vitamin D3 per day was systematically prescribed after surgery. RESULTS: In the 202 patients after GBP, serum 25OHD significantly increased from 13.4 ± 9.1 to 22.8 ± 11.3 ng/ml (p < 0.0001), whereas parathyroid hormone (PTH) did not change. Despite a decrease in calcium intake (p < 0.0001) and urinary calcium/creatinine ratio (p = 0.015), serum calcium increased after GBP (p < 0.0001). Preoperatively, 91 % of patients had 25OHD insufficiency (< 30 ng/ml), 80% deficiency (< 20 ng/ml), and 19% secondary hyperparathyroidism (> 65 pg/ml) vs. 76, 44, and 17%, respectively, following GBP. Serum 25OHD was negatively correlated with BMI at 6 months after GBP (R = -0.299, p < 0.0001). In the two groups of 30 subjects, serum 25OHD and PTH did not differ at 6 months after GBP or SG. CONCLUSIONS: At 6 months after GBP, serum 25OHD significantly increased in subjects supplemented with multivitamins containing low doses of vitamin D. These data suggest that weight loss at 6 months after surgery has a greater influence on vitamin D status than malabsorption induced by GBP.

Postprandial protein metabolism but not a fecal test reveals protein malabsorption in patients with pancreatic exocrine insufficiency.

BACKGROUND & AIMS: Pancreatic exocrine insufficiency (PEI) impairs fat absorption, but few data are available on protein absorption. We investigated this question in patients with chronic pancreatitis, both in the absence and presence of enzyme therapy, using a stable isotope sensitive method. METHODS: Eleven patients with sustained PEI and regular enzyme substitution were investigated at hospital, after a washout period without enzyme substitution, and later after reintroduction of substitution. The digestibility and postprandial metabolism of dietary protein were characterized after the ingestion of a semi-synthetic single meal containing 20 g (15)N-labeled casein. RESULTS: At baseline, 20 ± 8% of dietary nitrogen was transferred to the metabolic pools vs. 24.5 ± 7% under enzyme treatment (P = 0.04). After treatment, the transfer of dietary nitrogen tended to increase in plasma amino acids, and increased significantly in plasma proteins and the deamination pool. In contrast, the fecal excretion of dietary nitrogen did not demonstrate any treatment effect. In patients not receiving insulin for diabetes, the treatment stimulated insulin secretion. CONCLUSIONS: Protein malabsorption was mostly undetectable using standard fecal tests. The study of the postprandial fate of dietary protein revealed a moderate increase of its transfer to metabolic pools after enzyme substitution.

The effect of restrictive bariatric surgery on urinary stone risk factors.

OBJECTIVES: Malabsorptive bariatric procedures such as Roux-en-Y gastric bypass (RYGB) place patients at risk for developing kidney stones. Stone risk factors after purely restrictive procedures such as gastric banding and sleeve gastrectomy are not well characterized. Therefore, we performed a study to examine urinary risk factors of patients who underwent restrictive gastric surgery for bariatric indications. METHODS: A total of 18 patients were enrolled in the study; 14 underwent gastric banding and 4 underwent sleeve gastrectomy. All subjects collected 24-hour urine specimens; at least 6 months had elapsed between surgery and urine collection. Standard stone risk parameters were assessed, and comparisons were made with a group of normal adult nonstone-formers, routine stone-formers, and RYGB bariatric surgery subjects. RESULTS: Urinary oxalate excretion of the restrictive cohort was significantly less than the RYGB cohort (35.4 vs. 60.7 mg/d; P <.001) and not significantly different from that of the normal subjects (32.9 mg/d; P = .798) and routine stone-formers (37.2 mg/d; P = .997). There were no other significant differences in urinary parameters. CONCLUSIONS: Restrictive bariatric surgery does not appear to be associated with an increased risk for kidney stone disease. In particular, urinary oxalate levels were significantly less than those of RYGB subjects and not significantly different from routine stone-formers and nonstone-forming controls.

Assessment of small intestinal permeability using 1H-NMR spectroscopy.

BACKGROUND: Evaluation of small intestinal permeability (SIP) is based on the estimation of the urinary excretion ratio of a large and a small molecule (lactulose and mannitol, L/M) after oral administration. We evaluated SIP using 1H-NMR spectroscopy. METHODS: In-vitro experiments on known concentration of mannitol and lactulose solutions were performed to measure accuracy and precession of quantification using 1H-NMR spectroscopy. Eighteen patients with malabsorption syndrome (MAS) and 28 healthy subjects (HS) underwent SIP evaluation using L/M excretion ratio over 6-h after oral administration of 15 mL (10g) lactulose and 5 g mannitol using 1H-NMR spectroscopy and trimethyl silyl propionic acid as external reference and for quantification. RESULTS: Median errors of estimation of mannitol and lactulose were 5% (range 1.2 to 5) and 1.3% (range 0.2 to 1.3), respectively in-vitro. Patients with MAS excreted higher quantity of lactulose in urine than HS (median 0.33 mmol vs 0.12, 0 to .676 mmol, p<0.008). There was a trend towards lower urinary excretion of mannitol in patients with MAS than HS (median 3.58, range 0.61 to 15.77 mmol vs. 3.82, 1.34 to 16.42 mmol, p = ns). L/M ratio was higher among patients with MAS as compared to HS (median 0.1172 vs 0.045, p< 0.002). A cut-off value of L/M excretion ratio by receiver-operating characteristic (ROC) curve of 0.049 had a sensitivity and specificity of 72% and 61%, respectively; a cut-off value of 0.078 had a specificity of 90% but low sensitivity (67%). Area under ROC curve was 0.77. CONCLUSION: 1H-NMR spectroscopy is an analytical tool for assessment of SIP with reasonable sensitivity and specificity.

Fat malabsorption induced by gastrointestinal lipase inhibitor leads to an increase in urinary oxalate excretion.

BACKGROUND: Unabsorbed fat and bile acids may react with calcium in the intestinal lumen, limiting the amount of free calcium binding with oxalate and thereby raising intestinal oxalate absorption leading to hyperoxaluria. The aim of the present study was to determine whether orlistat (Xenical), a gastrointestinal lipase inhibitor, might increase urinary oxalate in an experimental rat model. METHODS: Thirty-nine male adult Wistar rats were fed a standard diet alone (controls) or supplemented with either 2% sodium oxalate (NaOx) or 3.2 mL of soy oil, or with both (NaOx + soy oil) for 4 weeks (diet period). Orlistat (16 mg/day) was added to the diet from the 5th to the 8th week (diet + orlistat period). Urinary oxalate (uOx), calcium (uCa), magnesium (uMg), and citrate (uCit) were determined and the ion-activity product of calcium oxalate [AP (CaOx) index(rat)] was estimated. RESULTS: Compared to baseline uOx significantly increased after diet + orlistat in controls (0.64 +/- 0.1 mg/24 hours vs. 0.56 +/-0.1 mg/24 hours), soy oil (0.80 +/- 0.3 mg/24 hours vs. 0.49 +/-0.2 mg/24 hours), and NaOx (2.48 +/- 0.8 mg/24 hours vs. 0.57 +/- 0.2 mg/24 hours), but the most marked increase occurred in NaOx + soy oil (3.87 +/- 0.7 mg/24 hours vs. 0.47 +/- 0.1 mg/24 hours). All groups except controls presented a significant reduction in uCa and uMg. Orlistat induced a significant increase in AP (CaOx) index(rat) compared, respectively, to baseline and to the diet period in NaOx (4.52 +/- 2.34 mg/24 hours vs. 0.94 +/- 0.86 and 1.53 +/- 0.93 mg/24 hours) and NaOx + soy oil (6.49 +/- 4.03 mg/24 hours vs. 0.54 +/- 0.17 and 1.76 +/- 1.32 mg/24 hours). CONCLUSION: These data suggest that the use of lipase inhibitors, especially under a diet rich in oxalate alone or associated with fat, leads to a significant and marked increase in urinary oxalate and a slight reduction in uCa and uMg that, taken together, resulted in an increase in AP (CaOx) index(rat), elevating the risk of stone formation.

1H NMR spectroscopic method for diagnosis of malabsorption syndrome: a pilot study.

Despite its well-documented limitations, colorimetry has been commonly used for the d-xylose test in the diagnosis of malabsorption syndrome (MAS). With a possibility of overcoming its limitations, the use of (1)H NMR spectroscopy for D-xylose test is explored herein. Urine samples from 35 adults with suspected MAS were obtained before and after oral ingestion of D-xylose. The diagnosis of MAS was based on fecal fat (72 h excretion using Van de Kamer's technique, normal < 7 g/24 h and/or Sudan III stain of spot stool specimen, normalor=1 g/5 g/5 h). In vitro experiments on the standard specimens of D-xylose were also performed independently using both methods. Colorimetry showed a lower value for the quantity of D-xylose excreted in urine than NMR [median 0.73 (0.17-1.89 g) vs 1.37 (0.17-3.23 g), respectively; p<0.0001, Wilcoxon's signed ranks test]. Colorimetry and NMR correctly diagnosed 11/12 and 10/12 (p=N.S.) patients with MAS and 14/23 and 20/23 (p<0.05) without MAS, respectively. Sensitivity and specificity of colorimetry and NMR were 91.6 and 60.7% vs 83.3 and 86.9%, respectively. In in vitro experiments, the values obtained for standard xylose using NMR showed a maximum error of 7%, whereas the colorimetric method showed 20%. The NMR method is simple and may be more accurate for the D-xylose absorption test. Colorimetry was found to be inferior as compared with NMR due to its low specificity.

Biokinetics and radiation dosimetry for patients undergoing a glycerol tri[1-14C]oleate fat malabsorption breath test.

The glycerol tri[1-14C]olein test for fat malabsorption was carried out in two male volunteers and measurements of the loss of 14C in expired air, urine and faeces and the retention of 14C in biopsy samples of abdominal fat were made using accelerator mass spectrometry. Exhalation accounted for 73% and 55% of the administered activity and could be described by three-component exponential functions with halftimes of about 1h, 2 days and 150 days, respectively. Urinary excretion accounted for 24% of the administered activity, almost all during the first 24h after administration; about 2% was excreted in the faeces in 48h. The halftime of retention of 14C in fat ranged from 137 to 620 days. Absorbed dose calculations indicate that for a normal adult the largest dose, 1.5-7.0mGy/MBq is received by the adipose tissue, and that the effective dose is 0.3-0.5mSv/MBq. It is concluded that no restrictions need to be placed on radiation safety grounds on the administration of 0.05-0.1MBq 14C-triolein for the triolein breath test.

Urinary patterns of patients with renal stones associated with chronic inflammatory bowel disease.

OBJECTIVE: The aim of this study was to analyze the frequency of renal stone patients with chronic inflammatory bowel disease and their urinary patterns. METHODS: During a 20-year period, 1941 consecutive patients with renal stone disease underwent routine laboratory procedures including a fasting blood sample for chemistry profile and a 24-hour urine collection for analyses of electrolytes. Thorough histories including chronic inflammatory disease or ileal resection were obtained. Patients with inflammatory bowel disease together with a control group comprising 47 idiopathic renal calcium stone formers were submitted to a xylose absorption test for evaluation of intestinal absorption. RESULTS: We observed 10 patients with Crohn's disease, 12 with ulcerative colitis and one patient with ileal bypass for obesity. Six patients underwent ileal resection and 10 patients total colectomy. Urinary oxalate excretion was significantly higher and urinary citrate lower in stone patients with ileal disease (Ox 60 +/- 23, Cit 113 + 7-118 mg/day) than in idiopathic stone formers (Ox 28.2 +/- 11.5, Cit 381 +/- 205) and stone patients with ulcerative colitis (Ox 20.3 +/- 14.8, Cit 369 +/- 247). Urinary volume was significantly lower in patients with ulcerative colitis. A significant inverse correlation (-0.38, p < 0.01) between oxalate urinary excretion and blood xylose level was found 2 hours after ingestion of xylose. No significant reduction of xylose absorption was demonstrated in both normoxaluric and hyperoxaluric idiopathic stone patients. CONCLUSIONS: Crohn's disease and ulcerative colitis are characterized by recurrent inflammatory involvement of different intestinal segments involving distinctive urinary patterns. Malabosorption associated with ileal disease causes increased oxalate absorption by increasing oxalate solubility in the intestinal lumen and permeability of the colonic mucosa; a reduced citrate excretion is associated in relation to mild acidosis due to the loss of bicarbonate in the liquid stool. In ulcerative colitis, especially if an ileostomy is present, urine are scanty and concentrated, and urine pH falls, leading to uric acid or mixed stones. Mild hyperoxaluria of idiopathic renal stone formers is not related to subtle intestinal malabsorption.

[The absence of metabolic disorders 8 years after detubulized Z entero-cystoplasty]. / Absence de trouble métabolique 8 ans après entéro-cystoplastie en Z détubulée.

Intestinal resection can lead to decreased gastrointestinal absorption of various metabolic substances. The use of these intestinal segments as materials for urinary tract reconstruction can also induce metabolic disorders. The authors studied the long-term metabolic consequences of replacement enterocystoplasty after radical cystectomy for bladder cancer.

Accuracy of measurement of dual-isotope Schilling test urine samples: a multicenter study [corrected].

UNLABELLED: As a component of our quality assurance program, this multicenter study was performed to characterize the magnitude and types of error present in measurement of typical dual-isotope Schilling test (DIST) urine samples. METHODS: A panel of three simulated DIST urine samples was formulated corresponding to diagnoses of normal excretion, malabsorption and pernicious anemia and was distributed to eight hospitals in our regional area (three novice and five experienced users). Count-rate data and urine volume measurements from each site were analyzed for accuracy against the predicted values and a carefully measured gold standard and were correlated with the methodology and equipment used. RESULTS: Three of 24 results were uninterpretable due to an overly low ratio of intrinsic factor bound to free vitamin B12 excretion (B/F ratio), inconsistent with possible diagnoses. In 20 of 21 interpretable samples, results corresponded to the appropriate diagnoses, with typical values noted in 18 of the cases and slightly atypical yet diagnostic values seen in the remaining two cases. In only one sample did values correspond to an erroneous diagnosis (low normal or partial malabsorption rather than pernicious anemia). The four major discrepancies (test failure or misdiagnosis) were largely attributable to blunders and were limited to two of the three novice sites and to a single experienced site which had grossly inaccurate raw data (background greater than sample counts). CONCLUSION: Quantitation of vitamin B12 excretion in DIST urine samples is a reliable method of evaluation when performed by reasonably experienced and competent clinical laboratories. Improved accuracy may be obtained by increasing the stochastic certainty of the count data and by more careful measurement of the sample and urine volumes.

Histidinuria: defective transport of histidine.

A-7-year-old boy was found to have histidinuria without histidinemia. Low concentrations of histidine in plasma were consistent with impaired intestinal and renal tubular absorption of histidine. The patient was developmentally delayed and had some minor anomalies. Only 4 other patients in 3 families have been reported. Each had abnormality of the central nervous system. All were male.

Intestinal permeability to intact lactose in newborns and adults.

Small amounts of lactose have been shown to be absorbed intact across the intestine and excreted unchanged in the urine of newborns and adults. We designed a study to quantitate the intestinal uptake and urinary excretion of this disaccharide in these age groups. Similar amounts of lactose were given orally to 17 term newborns (age: 24.8 +/- 3.0 h) as a standard infant formula, and to 15 adult lactose absorbers (age: 28.1 +/- 2.6 years) and 11 adult lactose malabsorbers (age: 24.7 +/- 2.9 years) as a 20% water solution. Following lactose ingestion, breath was collected every 30 or 60 min for 3 h and analyzed for hydrogen concentration. Urine was also collected, and lactose and creatinine concentrations were determined. Peak hydrogen concentration was less than 20 ppm above baseline in newborns and adult lactose absorbers and 85 +/- 14 ppm in adult lactose malabsorbers. Urinary lactose excretion, expressed as a function of body weight (mg/ml/kg b.w.), was substantially greater in newborns (4.2 +/- 0.82) than in adult lactose absorbers (0.29 +/- 0.07; p less than 0.001) and adult lactose malabsorbers (0.55 +/- 0.04; p less than 0.01). Similarly, urinary lactose excretion expressed as a ratio of urinary lactose to urinary creatinine (mg/mg) was increased (p less than 0.001) in newborns (2.05 +/- 0.26) when compared to adult lactose absorbers (0.11 +/- 0.02) and adult lactose malabsorbers (0.20 +/- 0.02). Our data demonstrate that the intestinal uptake and urinary excretion of intact lactose is significantly increased in newborns compared to adult subjects.

Ionized calcium and cyclic AMP in plasma and urine. Biochemical evaluation in calcium metabolic disease.

Measurement of ionized calcium and cAMP in plasma and urine are used as sensitive parameters for the evaluation of calcium disorders. Ionized calcium is accepted as the biologically active form of calcium in the extracellular fluid, while urine cAMP provides an in vivo receptor assay for the biologically active parathyroid hormone. When urine is included as part of the calcium metabolic investigation it usually requires 24 h urine collection with a variety of different laboratory tests. Ionized calcium and cAMP are described in the literature in terms of several derived quantities, nomenclatures, and units which are rather unsystematic. The author developed reliable techniques and proposed systematic names and symbols and reference values for these quantities. Due to the lack of guidelines for the collection of urines in calcium metabolic evaluation, the author presented a simplified protocol (4 h standardized urine collection). In clinical investigation plasma and urine cAMP have been used to differentiate idiopathic hypoparathyroidism from pseudohypoparathyroidism (PsHP) based on the results of i.v. injection of parathyroid hormone (PTH). Nephrogenous cAMP has also been used for the detection of primary and secondary hyperparathyroidism with a high nosographic sensitivity (90%) (Broadus). The author showed that measurement of cAMP after i.v. PTH was a reliable and sensitive test to establish the diagnosis of PsHP, and that the urinary cAMP was useful for the diagnosis of secondary hyperparathyroidism in patients with jejunoileal bypass, but could not confirm the high nosographic sensitivity for the diagnosis of primary hyperparathyroidism. Further data are needed for proper conclusion. Although pursued vigorously the research into idiopathic stone formation using different protocols has not prevented stone recurrence nor indicated where further progress might be made. For the evaluation of recurrent calcium disease, the author proposed a simplified 4 h standardized urine collection with plasma albumin, urinary pH, standardized excretion rate of calcium, plasma phosphate glomerular filtration rate, and nephrogenous cAMP as the most important parameters. In this way the author obtained a sensitivity of 93% and specificity of 95.6% for the diagnosis of recurrent stone former. The test may therefore be of value for predicting the risk of recurrent stone formation in the single stone former.

Laboratory diagnosis of malassimilation.

In many instances, the cause for malassimilation can be determined with ease, but finding the cause sometimes can be elusive and require the use of sophisticated laboratory techniques not available to the general veterinary practitioner. In either case, the clinician, whether generalist or specialist, must make an informed decision based on the results of many different testing modalities, and not only on the results of the laboratory tests described here. A flow chart is provided to assist the diagnostician in selecting and applying the more clinically oriented laboratory tests useful in dealing with a patient with chronic diarrhea and weight loss.

Heterogeneity of pepsinogens in the urine of children.

The existence of a significant linear relationship between the concentration of chlorides and the activity of pepsinogen (PG) in the urine was ascertained in the case of full-term infants 3 days to 6 weeks of age. At the age of 4-6 weeks, a significant relationship was found between the urinary pepsinogen activity and the urinary creatinine concentration, and between the urinary pepsinogen activity in the urine and the urine osmolality. Immediately after birth, the Pg7 fraction of PG II in the urine was found in all cases and, at the age of 4-6 weeks, in 11% of cases. In regard to the time factor, the conspicuous drop in the occurrence of the Pg7 fraction corresponds to the new qualitative relationship between the pepsinogen activity in the urine and the creatinine concentration in the urine and between the former and the urine osmolality. In premature infants, the Pg7 fraction disappears more slowly. The spectrum of pepsinogens in the urine was examined in children suffering from various diseases. In a girl with lymphoma, we found the Pg7 fraction, but this finding was temporary only.