Guidance for the gastrointestinal evaluation and management of iron deficiency in Sub-Saharan Africa.

BACKGROUND: Over 30% of the world's population is anaemic, with a significant proportion of these being iron deficient. As iron deficiency (ID) anaemia in men and post-menopausal women is mostly caused by gastrointestinal blood loss or malabsorption, the initial evaluation of a patient with ID anaemia involves referral to a gastroenterologist. The current drive towards patient blood management in sub-Saharan Africa (SSA)prescribes that we regulate not only the use of blood transfusion but also the management of patients in whom the cause of iron loss or inadequate iron absorption is sought. Recommendations have been developed to: (i) aid clinicians in the evaluation of suspected gastrointestinal iron loss and iron malabsorption, and often a combination of these; (ii) improve clinical outcomes for patients with gastrointestinal causes of ID; (iii) provide current, evidence-based, context-specific recommendations for use in the management of ID; and (iv) conserve resources by ensuring rational utilisation of blood and blood products. METHOD: Development of the guidance document was facilitated by the Gastroenterology Foundation of Sub-Saharan Africa and the South African Gastroenterology Society. The consensus recommendations are based on a rigorous process involving 21 experts in gastroenterology and haematology in SSA. Following discussion of the scope and purpose of the guidance document among the experts, an initial review of the literature and existing guidelines was undertaken. Thereafter, draft recommendation statements were produced to fulfil the outlined purpose of the guidance document. These were reviewed in a round-table discussion and were subjected to two rounds of anonymised consensus voting by the full committee in an electronic Delphi exercise during 2022 using the online platform, Research Electronic Data Capture. Recommendations were modified by considering feedback from the previous round, and those reaching a consensus of over 80% were incorporated into the final document. Finally, 44 statements in the document were read and approved by all members of the working group. CONCLUSION: The recommendations incorporate six areas, namely: general recommendations and practice, Helicobacter pylori, coeliac disease, suspected small bowel bleeding, inflammatory bowel disease, and preoperative care. Implementation of the recommendations is aimed at various levels from individual practitioners to healthcare institutions, departments and regional, district, provincial and national platforms. It is intended that the recommendations spur the development of centre-specific guidelines and that they are integrated with the relevant patient blood management protocols. Integration of the recommendations is intended to promote optimal evaluation and management of patients with ID, regardless of the presence of anaemia.

Kinetic analysis of the rapid intraoperative parathyroid hormone assay in patients during operation for hyperparathyroidism.

BACKGROUND: Rapid intraoperative parathyroid hormone (RI-PTH) assay is used to guide adequacy of resection during operation for hyperparathyroidism. We compared the RI-PTH assay (15 minutes) with a standard PTH assay, determined whether the PTH half-life varied between patients, and constructed a kinetic analysis of the RI-PTH data. METHODS: Forty-five patients with hyperparathyroidism had blood sampled at baseline and at times after parathyroid resection. Intact PTH was determined using RI-PTH and a standard assay. Values were fitted to an exponential decay curve using the baseline and the follow-up time points. PTH half-life and the new postexcision baseline value were calculated from the decay curve. RESULTS: The RI-PTH assay and the standard PTH assay correlated well. Average PTH half-life was 1.68 +/- 0.94 minutes (0.42 to 3.81 minutes). A kinetic analysis yielded a formula for the generation of a PTH decay curve. Using a 50% reduction in RI-PTH at 5 minutes as the criterion for adequate resection, 2 patients were incorrectly classified as not being cured. These patients were correctly classified using the kinetic analysis. CONCLUSIONS: PTH half-life can vary substantially. A kinetic analysis may be more accurate in assessing adequacy of resection. This method allows the surgeon to interpret RI-PTH data independent of the timing of samples.

Intestinal absorption of sodium dodecyl sulfate in the rodent: evidence for paracellular absorption.

Experiments were performed to define the mechanism of intestinal absorption of dodecyl sulfate (DS), an amphipathic organic anion whose chemical structure resembles that of dodecanoate, a C12 fatty acid anion. With jejunal segments perfused in single-pass fashion in the anesthetized rat, steady-state absorption of DS was concentration dependent, with the apparent permeability constant (P(app)) ranging from 4 to 22 x 10(-5) cm/s. When DS concentration was held constant and net water absorption was induced by decreasing perfusate osmolality, DS absorption increased in direct proportion to water absorption, suggesting absorption by solvent drag via the paracellular route. However, DS absorption continued even when water secretion was induced by a hypertonic perfusate. Consequently, for all experiments, DS absorption could be empirically described as the sum of two terms: 1) absorption in the absence of water absorption (P(app) = 5.6 x 10(-5) cm/s) and 2) absorption induced by water movement [(delta P(app)/delta water absorption) = 0.2 x 10(-5) cm x s(-1) x microl segment(-1) x min(-1)]. In a polarized epithelial monolayer of renal epithelial cells (Madin-Darby canine kidney cells), DS was absorbed predominantly by a paracellular pathway, as the absorption rate increased threefold when paracellular junction pore size was increased by the addition of cytochalasin D. The calculated apparent radius was 2.9 A, indicating that the cross section of the molecule, not its length, determined the rate of absorption. It is concluded that absorption of DS in the intact animal occurs slowly and mostly via the paracellular route, because the fixed negative charge on the molecule retards rapid passive entry into the enterocyte, as occurs with protonated fatty acids. That absorption of DS persisted despite net water secretion suggests a low level of transcellular absorption across the jejunal enterocyte also occurs.

Effect of Pluronic L81, a hydrophobic surfactant, on intestinal mucosal cholesterol homeostasis.

Addition of triglyceride and phospholipid to sodium taurocholate when chylomicron output was blocked by L81 did not increase lymphatic total cholesterol output or mucosal unesterified (UC) content more than with sodium taurocholate alone, but mucosal esterified cholesterol (CE) was increased slightly. In these animals with defective chylomicron formation, excess cholesterol accumulated in the intestinal mucosa mainly as CE. The mucosal cholesterol content of animals with normal chylomicron transport expanded during cholesterol and triglyceride absorption, and the expansion led to increased lymphatic secretion of CE. These animals accumulated significantly less CE in their mucosa than did rats treated with L81, but had about the same amount of mucosal UC. However, the overall uptake of cholesterol from the lumen, as determined by either radioactivity or mass of cholesterol in mucosa and lymph, was significantly less in the L81 rats. Also, more radioactive cholesterol remained in the lumen of the L81-treated rats. Finally, the data on specific activities of free and esterified cholesterol showed that the mucosal cholesterol derived from the lumen does not mix evenly with the free cholesterol pool in the enterocytes and is preferentially esterified for export in lymph as triglyceride-rich lipoprotein.

The effect of monostearoylglycerol on the metabolism of chylomicron-like lipid emulsions injected intravenously in rats.

In rats, remnant particles derived from chylomicron-like emulsions containing 1,3-dioleoyl-2-stearoylglycerol (OSO) are removed from plasma more slowly than remnants derived from triolein emulsions. The effect associated with a saturated acyl chain at the glycerol 2-position could be reproduced by incorporating 2-stearoylglycerol (MS) in a triolein emulsion. When MS solubilized with rat albumin or in plasma was injected before the injection of a triolein emulsion, clearance of the triolein emulsion was unchanged. The metabolic fate of MS, monitored with 14C-labelled MS, was similar whether incorporated in triacylglycerol emulsion or injected independently. More than 95% of MS had disappeared from the circulation by 5 min after the injection and the radioactivity was found in liver, spleen, muscle and adipose tissue. Some MS label appeared in plasma triacylglycerol. Remnants made in vitro by incubating triolein or OSO emulsions with post-heparin plasma showed no differences in their disappearance from plasma. With OSO emulsion, the in vitro remnants were found to contain more MS than remnants made in vivo in hepatectomized rats. Simultaneous injections of mixtures containing OSO and triolein emulsions, or triolein emulsions with and without MS, each labelled with either [3H]cholesteryl oleate or [14C]cholesteryl oleate showed consistently slower remnant removal and decreased liver uptake of the emulsions containing OSO or MS. Affinity columns and immunodiffusion all indicated that there was no difference in the amounts of apolipoprotein E associated with OSO or triolein particles. The protein spectra of in vivo remnants derived from OSO and triolein emulsion were also similar when examined by SDS-PAGE and isoelectric focusing gels. Our results show that the effects due to OSO or MS are mediated by the presence of MS in the emulsion particle surface, while indirect effects expressed in plasma or liver are excluded. The precise mechanism of the effect remains to be established, but it does not correlate with measurable changes in the spectra of apolipoproteins associated with the emulsion remnants.

The effect of added monoacylglycerols on the removal from plasma of chylomicron-like emulsions injected intravenously in rats.

Lipid emulsions were prepared with compositions similar to the triacylglycerol-rich plasma lipoproteins, but also incorporating added small amounts of monoacylglycerols. Control emulsions without monoacylglycerol were metabolized similarly to natural chylomicrons or very-low-density lipoproteins when injected intravenously in rats. The emulsion triacylglycerols and cholesteryl esters were both removed rapidly from the bloodstream, with the removal rates of triacylglycerols faster than those of cholesteryl esters. Much of the removed cholesteryl ester was found in the liver, but only a small fraction of the triacylglycerol, consistent with hepatic uptake of the triacylglycerol-depleted remnants of the injected emulsion. Emulsions incorporating added monooleoylglycerol or stearic acid were metabolized similarly. Added 1- or 2-monostearoylglycerol had no effect on triacylglycerol removal from plasma, but the removal rate of cholesteryl esters was decreased and less cholesteryl ester was found in the liver. These effects are similar to those recently described when emulsions and chylomicrons contained triacylglycerols with a saturated acyl chain at the glycerol 2-position, suggesting that saturated monoacylglycerol produced by the action of lipoprotein lipase may cause triacylglycerol-depleted remnant particles to remain in the plasma instead of being rapidly taken up by the liver.

Glutathione and enzymes related to free radical metabolism in liver of rats fed a choline-devoid low-methionine diet.

Fischer F-344 male rats, fed a choline-devoid diet that leads to a highly reproducible sequence of biochemical and biological changes with an ultimate development of hepatocellular carcinoma, show elevated levels of glutathione in the liver at 3, 6 and 8 days. Several enzymes related to the metabolism of free radicals, including superoxide dismutase, catalase, glutathione peroxidase, glutathione S-transferase and DT-diaphorase show neither increased nor decreased activity as measured between 12 h and 8 days on the diet. Thus, of several known cellular components related to the possible scavenger of free radicals in the liver, only glutathione responded to the feeding of the CD diet. It is tentatively concluded that a decrease in the levels of possible scavengers for free radicals is not a major basis for the nuclear and mitochondrial lipid peroxidation seen early in rats fed a choline-devoid diet.

Regulation of the metabolism of lipid emulsion model lipoproteins by a saturated acyl chain at the 2-position of triacylglycerol.

Lipid emulsion particles were prepared by sonicating four different lipid mixtures (triacylglycerol (TAG), 70%; phospholipid, 25%; cholesteryl oleate (CO), 3%; and free cholesterol, 2%), then purified by density gradient ultracentrifugation. For three test mixtures, the TAG contained 50, 75, or 100% 1,3-dioleyl-2-stearylglycerol (OSO) with the remainder being triolein (OOO); 100% triolein in the lipid mixture was used as the control. After intravenous injection of the lipid particles into unanesthetized rats, removal of radioactive TAG fatty acid and CO from plasma was measured for 30 min, then liver and spleen uptakes were measured. When emulsions contained 75% or 100% OSO as TAG, the plasma removal rates of CO were, respectively, 60% or 30% of the rate when the TAG was 100% triolein; smaller recoveries of CO were found in the liver. The clearances of TAG fatty acid did not differ significantly and the recoveries of TAG fatty acid in the organs were not affected by the type of emulsion injected. Remnant particles were derived from donor rats in which uptake was blocked by exclusion of liver and other viscera from the circulation before injection of 100% OOO and 100% OSO emulsions. When injected into recipient intact rats, the removal of remnants from plasma was slower for remnants derived 15 min after injection of 100% OSO emulsions than from 100% OOO emulsions, showing that the slower removal of emulsion CO was due to slower remnant uptake from the plasma with OSO emulsions.(ABSTRACT TRUNCATED AT 250 WORDS)

Homeostasis of mucosal cholesterol in the small intestine of the rat.

This study was undertaken to investigate the capacity of the intestinal mucosa to maintain a constant cholesterol content under conditions where mucosal uptake or cholesterol transport into the lymph were manipulated. Two series of bile-diverted unanaesthetised rats were infused intraduodenally with saline, triolein emulsified with Pluronic F68, or taurocholate with or without added tomatine. Pluronic F68 is a nontoxic detergent which promotes mucosal uptake of polar lipids but not cholesterol. Tomatine is a cholesterol-binding saponin. One series of rats was used for measuring mucosal cholesterol content, DNA and protein after the test infusions. A second series of rats had the thoracic lymph duct cannulated but otherwise remained the same as the first series. The second series was used for measuring the effect of the different infusions on mass cholesterol output into lymph. Mucosal cholesterol content of rats that were not fed decreased with bile-diversion and was restored with taurocholate infusion. This suggested a contribution of luminal cholesterol to the mucosal cholesterol pool. However, evidence for a contribution from the lumen was provided by only one of two groups of rats given infusions which did not promote mucosal uptake of cholesterol. First, addition of tomatine to the taurocholate infusate prevented both the increase in lymph output of cholesterol and the increased mucosal cholesterol content shown in rats given taurocholate alone. Second, in another group of rats in which mucosal uptake of cholesterol was prevented, i.e. in rats given Pluronic F68-triolein emulsions, the increased fat absorption was accompanied by a marked increase in cholesterol output into lymph without a concomitant decrease in mucosal cholesterol content.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of four taurine-conjugated bile acids on mucosal uptake and lymphatic absorption of cholesterol in the rat.

The importance of the bile acid structure on mucosal uptake and lymphatic absorption of cholesterol was investigated using four different taurine-conjugated bile acids. Pure synthetic conjugates of a trihydroxy bile acid, taurocholate, and three dihydroxy bile acids, tauroursodeoxycholate, taurochenodeoxycholate, and taurodeoxycholate were used to completely solubilize [14C]cholesterol and polar lipids for steady rate intraduodenal infusion for 8 hr in bile fistula rats. Lymph output and esterification of [14C]cholesterol and endogenous cholesterol were measured in hourly samples. A second group of bile fistula rats was given the same bile acids as the first group but without added cholesterol or other lipid, i.e., fasting lymph fistula group. Mucosal uptake of [14C]cholesterol was studied using recovery of [14C]cholesterol from lumen and mucosa after 1-hr infusions in conscious bile fistula rats. Lymph output of [14C]cholesterol was promoted more rapidly with taurocholate than with the dihydroxy conjugates and [14C]cholesterol output differed for the three groups given dihydroxy bile acids. The mass of cholesterol in lymph, measured chemically, varied in parallel with [14C]cholesterol absorption. For fasting lymph, infusion of dihydroxy bile acids failed to produce a significant change in endogenous cholesterol output when compared with rats given saline only. Taurocholate infusion markedly increased endogenous cholesterol in lymph of fasted rats. Under all conditions where cholesterol output was stimulated, the increase could be accounted for mainly as esterified cholesterol. Mucosal uptake of [14C]cholesterol during 1-hr infusions in conscious bile fistula rats was slower with the dihydroxy bile acids than with taurocholate. The results indicate the marked effect of the number and configuration of the hydroxyl groups on the solubilizing bile acid for cholesterol absorption.

The effect of pancreatic diversion on lymphatic absorption and esterification of cholesterol in the rat.

Lymph fistula rats with either biliary fistula or pancreaticobiliary fistula were used to measure coenzyme A-independent mucosal cholesterol esterifying activity in the presence and absence of pancreatic exocrine secretion. Efficiency of pancreatic diversion was verified to minimize contamination of mucosal homogenates with adherent luminal enzyme. The synthetic activity of cholesteryl ester hydrolase (E.C. 3.1.1.13) was measured directly in mucosal homogenates. Indirect evidence for mucosal esterifying activity was obtained from hourly cholesteryl ester output into lymph when other factors known to affect cholesterol absorption were controlled. Rats infused intraduodenally at a constant rate with different concentrations of bile salts, polar lipid, and [3H]cholesterol showed that the infused [3H]cholesterol was absorbed and esterified with equal efficiency in the presence and absence of pancreatic flow. Total lymph output of free and esterified endogenous cholesterol was slightly less efficient in the pancreaticobiliary fistula group (85% of bile fistula values) but percent esterification was the same for both groups. Infusion of lipid-free micellar bile salts separately from other bile components produced a highly significant increase in absorption and esterification of lymph cholesterol for both groups. No correlation was found between cholesterol esterifying activity in a) the lumen or b) the mucosa, and cholesteryl ester output into lymph. The present study suggests an alternative enzyme dependent directly or indirectly on the presence of micellar bile salts in the lumen to explain intestinal cholesterol esterifying activity during absorption.

Role of biliary phosphatidylcholine in the absorption and transport of dietary triolein in the rat.

This study was undertaken to determine the role of luminal phosphatidylcholine in the intestinal absorption and transport of glycerol trioleate in the rat. Rats with bile and thoracic duct lymph fistulas were infused with a bile salt-stabilized emulsion of glycerol trioleate only or with either dioleoyl or dipalmitoyl phosphatidylcholine added. Uptake of infused lipid was greater than 95% in all groups. The presence of supplemental phosphatidylcholine in the infusate greatly enhanced the lymphatic triglyceride and phosphatidylcholine outputs in the bile-diverted rats as compared with rats without phosphatidylcholine supplementation. There was no difference in lipid outputs between the dioleoyl or dipalmitoyl phosphatidylcholine-supplemented rats. The fatty acid pattern of the lymph phosphatidylcholine of the two groups of phosphatidylcholine-supplemented rats reflected that of the added phosphatidylcholine. In the absence of luminal phosphatidylcholine there was increased accumulation of mucosal triglyceride and evidence suggesting increased portal transport of absorbed fatty acid. Therefore, this study demonstrated that the presence of luminal phosphatidylcholine is important for the normal lymphatic transport of the absorbed digestion products of triglyceride, the major dietary fat.

The importance of the lysophosphatidylcholine and choline moiety of bile phosphatidylcholine in lymphatic transport of fat.

A luminal supply of biliary phosphatidylcholine is important in the translocation of absorbed fat into lymph and in the amount and composition of phosphatidylcholine concurrently synthesized. This study was undertaken to determine whether the effect was due to absorbed lysophosphatidylcholine, to a specific (1-palmitoyl) biliary lysophosphatidylcholine or to extra choline supplied by lysophosphatidylcholine. Rats with bile fistulae and thoracic duct lymph fistulae were given test meals of oleic acid and monoolein (molar ratio 2 : 1) infused duodenally for 8 h. Addition of choline chloride to the test meal increased lymphatic output of triglyceride and phospholipid but not to values found previously in rats with supplements of bile phosphatidylcholine or with bile ducts intact. Addition of dioleoyl phosphatidylcholine increased triglyceride and phospholipid output to values found in rats with intact bile ducts. Since dioleoyl phosphatidylcholine was as efficient as biliary phosphatidylcholine it was concluded that a luminal supply of 1-palmitoyl lysophosphatidylcholine was not essential. It seemed likely from the smaller effect of supplemented choline and from the fatty acid composition of lymph phosphatidylcholine that the essential requirement was a supply of absorbed lysophosphatidylcholine for rapid reacylation to phosphatidylcholine.

Role of biliary lecithin in lymphatic transport of fat.

This study was undertaken to asses the role of luminal lecithin in the lymphatic transportation of fat as chylomicrons. Two doses of fat, the low and high dose, were fed to two different groups of rats, control and bile fistula. At low dose, infusing at 35 mumoles of total fatty acid per hr of a mixture of oleic acid and monoolein, molar ratio 2:1, solubilized in 55 mumoles of sodium taurocholate, there was no difference in the lymphatic output of absorbed fat during steady state (7th and 8th hour) absorption. Infusing at a high dose, 173 mumoles of total fatty acid per hr of a mixture of oleic acid and monoolein, molar ratio 2:1, solubilized in 55 mumoles of sodium taurocholate, the bile fistula rats had lower triglyceride and phospholipid output, with a higher proportion of oleic acid in lymph lecithin than did control rats. These alterations in bile fistula rats returned to normal by addding 10 mumoles per hr of biliary lecithin to the infusate. We conclude that intraluminal biliary lecithin plays a significant role in the translocation of high doses of absorbed fat into lymph and in the amount and type of lecithin synthesized.

Importance of luminal lecithin in intestinal absorption and transport of lipid in the rat.

Feeding a gastric test meal, the absorption and transport of fat was studied in control and bile fistula rats with bile salts replaced but with and without egg lecithin supplemented. No evidence was found that luminal lecithin played an important role in the transport of absorbed fat as chylomicrons.