Steatorrhea in patients with liver disease

Intestinal function was studied in 26 patients with seven types of acute and chronic liver disease, documented by liver biopsy. Steatorrhea, defined by a stool fat higher than 6 g. per day, was present in 18 of 23 consecutive patients studied, an incidence of 78.3%. Two patients with infectious hepatitis associated with steatorrhea studied previously were added and the 20 cases were analyzed. The malabsorption found was confined to fat and fat-soluble vitamins; stool excretion varied from 6.1 to 22 g. per day in the seven groups studied. No histological abnormality was seen on jejunal biopsy, serum vitamin B₁₂, D-xylose and Schilling tests were normal, and no radiological findings associated with malabsorption were detected in the small bowel. It is concluded that steatorrhea is a common finding in a wide variety of acute and chronic liver diseases and cannot be attributed to a primary defect of the small bowel.     

Oxalate uptake by everted sacs of rat colon. Regional differences and the effects of pH and ricinoleic acid

Hyperoxaluria is a complication of disorders associated with steatorrhea. The colon is the presumed site of enhanced oxalate absorption in patients with steatorrhea. We performed studies of colonic mucosal oxalate uptake in everted sacs of rat colon to determine the kinetics of colonic oxalate transport and to evaluate the effect of both pH and ricinoleic acid, a hydroxy fatty acid, on colonic oxalate uptake. Our study demonstrated that oxalate is transported throughout the colon by passive diffusion. Tissue uptake increased linearly with increasing oxalate concentrations and was unaffected by metabolic inhibitors, oxygen deprivation, or temperature changes. There were pH-dependent regional differences of oxalate uptake both in the presence and absence of ricinoleic acid. In the absence of ricinoleic acid, the highest oxalate uptake occurred at the lower pH values (5.4 and 6.4). In the presence of ricinoleic acid oxalate uptake was enhanced at the higher pH values (7.4 and 8.4); a finding most likely related to decreased solubility of ricinoleic acid at pH 5.4 and 6.4. Intraluminal pH is an important determinant of colonic oxalate uptake in the presence and absence of ricinoleic acid.     

Small intestinal manifestations of diabetes mellitus

Diabetic diarrhea and steatorrhea occur predominantly in young adult males who have juvenile-onset diabetes mellitus complicated by neuropathy. The presentation is often severe, with nocturnal or postprandial watery diarrhea and tenesmus. Massive malabsorption of fat may occur; however, malabsorption of other nutrients and generalized wasting are quite rare. Because the symptoms are relatively refractory to treatment, it is important to rule out other, more easily treatable causes of this presentation. Bacterial overgrowth, exocrine pancreatic insufficiency, and celiac disease are also associated with diabetes mellitus and can mimic this process. Although the mechanism of diabetic diarrhea and steatorrhea remains unclear, neuropathy, gastrointestinal motor abnormalities, bacterial overgrowth, and bile acid abnormalities have been implicated in the pathogenesis.     

The Role of the Upper Gastrointestinal Flora in the Malabsorption Syndrome

Bacterial contamination of the upper gastrointestinal tract by colonic flora appears important in the production of some forms of secondary steatorrhea. Gastric contents have been studied in patients with normal intestinal absorption and with malabsorption syndrome. In secondary steatorrhea there is a significantly increased incidence of gastric contamination by colon organisms, and this is usually associated with absence of free hydrochloric acid. It seems probable that such contamination interferes with intestinal digestion and absorption. The benefit resulting from the oral administration of broad-spectrum antibiotics to a group of patients with secondary steatorrhea supports this concept.     

Hepatic structure and function after modified jejunoileal bypass surgery for obesity.

The most serious adverse effect of standard intestinal bypass for obesity is the high incidence of hepatic dysfunction and death from hepatic failure. We therefore examined the long-term effects of a modified form of jejunoileal bypass (in which a greater continuous length of ileum is retained), on liver function in 120 patients. Substantial weight loss (119-0+/-SD 23-3 kg to 82-3+/-18-8 kg) occurred during the first nine months after surgery, accompanied by a significant rise in serum concentrations of bilirubin, alanine transferase, and alkaline phosphatase, and a significant reduction in albumin concentrations. Biochemical changes were unrelated to weight loss or halothane anaesthesia. After weight stabilisation liver function reverted to normal, and four years after bypass sulphobromophthalein retention and hepatic histology did not differ from those in obese controls. There were two postoperative deaths. Three other patients died during the period of rapid weight loss with severe hepatic steatosis. While transient mild impairment of liver function is common after modified jejunoileal bypass, clinically significant hepatic dysfunction is a rare and unexplained early complication.     

Increased Calcium Absorption in Nephrolithiasis Explained by Uptake Studies in Ileal Brush Border Membrane Vesicles

We previously showed that recurrent calcium renal stone formers have enhanced urinary excretions of calcium and oxalate resulting from malabsorption of citrate. In the present investigation, the mechanism of the citrate-induced increased calcium uptake was studied using guinea pig ileal brush border membrane vesicles. In this model, calcium is absorbed in a concentration dependent, single mechanism uptake with a K_m of 275 ± 30 umol/liter (SD) and a V_max of 4.0 ± 0.5 nmol/min · mg protein. Under conditions of maximal calcium uptake, both citrate and phosphate inhibited calcium absorption into brush border membrane vesicles (BBMVs). In contrast, when phosphate and citrate were added together, calcium absorption normalized. Citrate inhibition of calcium absorption appeared to be due to free citrate ions, and phosphate ions overcame this inhibition. Phosphate inhibition was mostly due to decreased concentrations of ionized calcium and partly to precipitation of insoluble calcium phosphate. These studies confirm that the effects of citrate in humans in enhancing calcium absorption occur in the lumen of the gut and are not related to further biochemical conversions of citrate by the gut cells, to effects of citrate on calcium-related hormones, or to the renal handling of calcium. Also, the effects of citrate on increasing calcium absorption should be increased or attenuated in patients who malabsorb citrate, and this explains the increased urinary calcium and oxalate excretions reported for recurrent calcium stone formers.     

Hydroxyproline metabolism in mouse models of primary hyperoxaluria

Primary hyperoxaluria type 1 (PH1) and type 2 (PH2) are rare genetic diseases that result from deficiencies in glyoxylate metabolism. The increased oxalate synthesis that occurs can lead to kidney stone formation, deposition of calcium oxalate in the kidney and other tissues, and renal failure. Hydroxyproline (Hyp) catabolism, which occurs mainly in the liver and kidney, is a prominent source of glyoxylate and could account for a significant portion of the oxalate produced in PH. To determine the sensitivity of mouse models of PH1 and PH2 to Hyp-derived oxalate, animals were fed diets containing 1% Hyp. Urinary excretions of glycolate and oxalate were used to monitor Hyp catabolism and the kidneys were examined to assess pathological changes. Both strains of knockout (KO) mice excreted more oxalate than wild-type (WT) animals with Hyp feeding. After 4 wk of Hyp feeding, all mice deficient in glyoxylate reductase/hydroxypyruvate reductase (GRHPR KO) developed severe nephrocalcinosis in contrast to animals deficient in alanine-glyoxylate aminotransferase (AGXT KO) where nephrocalcinosis was milder and with a lower frequency. Plasma cystatin C measurements over 4-wk Hyp feeding indicated no significant loss of renal function in WT and AGXT KO animals, and significant and severe loss of renal function in GRHPR KO animals after 2 and 4 wk, respectively. These data suggest that GRHPR activity may be vital in the kidney for limiting the conversion of Hyp-derived glyoxylate to oxalate. As Hyp catabolism may make a major contribution to the oxalate produced in PH patients, Hyp feeding in these mouse models should be useful in understanding the mechanisms associated with calcium oxalate deposition in the kidney.     

Reduction in urinary oxalate excretion in mouse models of Primary Hyperoxaluria by RNA interference inhibition of liver lactate dehydrogenase activity

The Primary Hyperoxaluria's (PH) are rare autosomal recessive disorders characterized by elevated oxalate production. PH patients suffer recurrent calcium oxalate kidney stone disease, and in severe cases end stage renal disease. Recent evidence has shown that RNA interference may be a suitable approach to reduce oxalate production in PH patients by knocking down key enzymes involved in hepatic oxalate synthesis. In the current study, wild type mice and mouse models of PH1 (AGT KO) and PH2 (GR KO) were treated with siRNA that targets hepatic LDHA. Although siRNA treatment substantially reduced urinary oxalate excretion [75%] in AGT KO animals, there was a relatively modest reduction [32%] in GR KO animals. Plasma and liver pyruvate levels significantly increased with siRNA treatment and liver organic acid analysis indicated significant changes in a number of glycolytic and TCA cycle metabolites, consistent with the known role of LDHA in metabolism. However, siRNA dosing data suggest that it may be possible to identify a dose that limits changes in liver organic acid levels, while maintaining a desired effect of reducing glyoxylate to oxalate synthesis. These results suggest that RNAi mediated reduction of hepatic LDHA may be an effective strategy to reduce oxalate synthesis in PH, and further analysis of its metabolic effects should be explored. Additional studies should also clarify in GR KO animals whether there are alternate enzymatic pathways in the liver to create oxalate and whether tissues other than liver contribute significantly to oxalate production.     

Applications of electromyography in the study of changes in intestinal motility following surgery on the small intestine]

Changes in the intestinal motility were studied in dogs after different surgical operations performed on the small bowel. Electrodes were implanted on the intestine and the electrical activity of the bowel was recorded after transection of the bowel and after jejunoileal shunt. The results showed that the transection of the bowel provoked a slowing of the propagation of the intestinal contractions. This phenomenon was particularly important at the level of the ileum. The jejunoileal shunt was followed by a strong increase of the level of the motor activity, probably related with an increase of the intraluminal content at the level of the ileum. These results gave an explanation for the slowing of the intestinal transit which is observed after some operations which involve a transection of the small bowel.     

The influence of lactose intolerance and other gastro-intestinal tract disorders on L-thyroxine absorption

The preferred treatment for hypothyroidism is oral levothyroxine (LT4) ingestion, in doses that ensure a sustained state of hormonal balance. Many different factors may significantly influence the absorption of LT4, including: interval between the ingestion of the drug and the last meal, eating habits, and different functional and organic pathologies of the gastro-intestinal tract. The main purpose of this paper is to review and systematise the available literature on the subject of the influence of different malabsorption syndromes on the effectiveness of LT4 preparations. The need to use high LT4 doses in the substitutional treatment of hypothyroidism is often the very first sign of one of the pathologies that are connected with malabsorption syndrome, which might have been asymptomatic and undiagnosed previously. Patients who require more than 2 μg/kg body weight of LT4 per day, with constantly increased thyrotropin level, should be diagnosed with the suspicion of pseudomalabsorption or real absorption disorder. An LT4 absorption test, using high doses of LT4, may be useful in the diagnosis of pseudomalabsorption. After excluding non-compliance, the differential diagnosis should include such disorders as lactose intolerance, coeliac disease, atrophic gastritis, Helicobacter pylori infection, bowel resection, inflammatory bowel disease, and parasite infection. Where there is a diagnosis of lactose intolerance, both a low lactose diet and a lactose-free LT4 preparation should be administered to restore euthyroidism or make it possible to decrease the dose of the LT4 preparation. In coeliac disease, a gluten-free diet usually allows a normalisation of the need for LT4, as do eradication of the H. pylori infection or parasite colonisation. In cases of atrophic gastritis or inflammatory bowel disease, treating the underlying diseases and regaining the state of remission may improve the absorption of LT4. In patients after gastro-intestinal tract surgery, a dose of LT4 higher than that typically used is needed to restore euthyroidism.     

Gluten-sensitive enteropathy in a cynomolgus monkey

A malabsorption syndrome was observed in a cynomolgus macaque. Clinical signs included weight loss despite increased appetite, and diarrhea, characterized by an increased volume of soft, tan, malodorous feces. Clinicopathologic findings included hypoalbuminemia, generalized dilation of bowel loops with a prolonged transit time, steatorrhea and markedly diminished absorption of D-xylose. Biopsies of the duodenum and jejunum had total villous atrophy, crypt hyperplasia and a plasmacytic-lymphocytic infiltrate of the lamina propria. The monkey's diet was changed to a semi-synthetic diet containing no grain products. Subsequently, stool characteristics, body weight and intestinal villous morphology returned to normal. This response to removal of grain products from the diet suggests a syndrome similar to gluten-sensitivity enteropathy in human beings.     

Cholestyramine and medium-chain triglyceride in prolonged management of patients subjected to ileal resection or bypass

The pathophysiology of cholerrheic enteropathy is described and a series of patients reviewed. Of 11 patients with chronic disabling diarrhea and steatorrhea after ileal resection or bypass, two had recurrent ileitis, three had lactose intolerance and six of those operated on five years or more previously had vitamin B₁₂ deficiency. Cholestyramine was given alone or with medium-chain triglyceride (MCT) or Portagen (MCT and lactose). The maximal response occurred when cholestyramine was given with Portagen — significantly reduced stool frequency and weight in all patients and stool fat in five. Restudy of five patients four to 11 months later showed the same pattern of response: cholestyramine with 70% MCT abolished symptoms in four patients (ileectomy) and 100% MCT alone greatly improved the condition of the fifth (extensive small bowel resection).     

Puberty in chronically diseased patients

Delayed onset of puberty and a reduced pubertal growth spurt are often reported in patients suffering from chronic diseases. The basis of abnormal puberty in these patients is multifactorial. Nutritional deficiency may contribute to growth disorders and delayed puberty. Insufficient food supply and/or eating disorders and/or malabsorption of nutrients can be observed in these patients. Moreover, increased energy supplies are often needed in patients with chronic lung disease, infection or inflammation. More specific factors due to the disease itself may be involved in growth and puberty disorders. Abnormalities of the growth hormone (GH)-insulin-like growth factor (IGF)1 axis and gonadotrophin secretion have been described in patients with chronic renal failure, cystic fibrosis and Crohn's disease. More recently, it has been shown that cytokines produced during chronic diseases such as juvenile idiopathic arthritis may affect the GH-IGF1 axis. Finally, concomitant medication, namely corticosteroids, which are often given to these patients, may contribute to delayed puberty and poor pubertal growth.     

Cystic fibrosis and calcium oxalate nephrolithiasis.

During the past six years, we have treated eight patients with cystic fibrosis (CF) for nephrolithiasis. In seven patients, the stones were comprised of calcium oxalate. Another six patients had calcium oxalate crystalluria. In our CF population of 140 patients, this represents a cumulative incidence of calcium oxalate nephrolithiasis of 5.7 percent and an additional 4.2 percent incidence of crystalluria. Experience with these patients is reviewed. Pancreatic insufficiency was universally associated with nephrolithiasis or crystalluria. Diabetes and cirrhosis were also common. Predisposing factors and potential mechanisms of stone disease in pancreatic insufficient CF patients are discussed, focusing on the relationship between fat malabsorption in CF to oxalate metabolism.     

Dissociation of absorptions of calcium and phosphate after successful cadaveric renal transplantation.

Calcium and phosphate absorptions were studied by radiotracer techniques in 30 patients after successful cadaveric renal transplantation, and results were compared with those in a group of normal subjects and in groups of patients with chronic renal failure (CRF). Both calcium and phosphate absorptions were impared in patients with CRF, including those receiving haemodialysis. Abnormalities of calcium absorption, however, seemed to occur earlier in the course of advanced renal failure than abnormalities in phosphate absorption. Calcium absorption improved dramatically after successful renal transplantation, while phosphate absorption remained the same. A dissociation between calcium and phosphate absorptions is not often seen clinically, and the mechanisms for it are unknown. Phosphate malabsorption may be a further contributing factor in the development of persistent hypophosphataemia after transplantation.     

Symposium on diarrhea. 1. Definition and mechanisms of diarrhea.

Diarrhea, an increase in frequency of evacuation and in water content of the stool, is the result of three categories of mechanism--solute malabsorption, secretion of fluid and motility disturbance. Before diarrhea is considered an abnormal condition, any alteration in stool frequency and content must be related to an individual person''s normal bowel habit and to norms for the population, but more than three bowel movements or the passage of liquid stools exceeding 300 g daily should, in general, be considered abnormal. A useful way of understanding the mechanism of diarrhea is to become familiar with the normal functions of the bowel in regard to water and electrolyte absorption and motility, and then to relate these functions to solute malabsorption, fluid secretion and motility disturbance.     

Clinical application of breath hydrogen measurements

Breath hydrogen (H2) measurements are applied in clinical medicine for the detection of carbohydrate malabsorption. H2 in expired air results when dietary sugars escape absorption in the small intestine, thereby becoming available for bacterial fermentation. H2 produced by bacterial metabolism of the carbohydrate is absorbed into the portal circulation and excreted in breath. Relatively simple collection, storage, and analysis methodologies have been developed in recent years. They permit convenient and noninvasive testing of patients in most age groups for common clinical disorders of digestion and absorption, including lactase deficiency and other disorders of di- and mono-saccharide malabsorption, starch malabsorption, and small bowel bacterial overgrowth. Limitations of breath hydrogen testing are few. Developmental considerations constrain the ease of interpretation of breath H2 measurements in early infancy, and factors affecting intraluminal H2 production by the intestinal flora may occasionally affect the H2 signal. Despite these factors, breath H2 testing has repeatedly been demonstrated to be the most accurate indirect indicator of lactase deficiency, and breath H2 measurements have been widely applied in studying digestion of the entire spectrum of dietary carbohydrates.     

Electrolyte transport in rat colon: comparative effects of intestinal resections and bypass

In the present study the influence of different types of intestinal resection (50% distal and 50% proximal small bowel resection) and bypass (50% jejunoileal bypass) upon water and electrolyte (Na and K) colonic transport was examined. Four weeks after resections and bypasses no significant changes in wet and dry tissue weights, serum sodium and potassium values were found in comparison to sham-operated controls. In vivo net absorption of sodium, measured in micromoles of 22Na+ which disappeared from the medium during a determined period (15, 30, 45 and 60 min), in sham-operated animals, showed a gradual increase with the increase in the perfusion time, rising from 144 +/- 20 mumol at 15 min of perfusion to 425 +/- 28 mumol at 60 min. One month after the resection, Na absorption, expressed as total absorption and as micromoles per square centimeter, was not significantly modified in animals distally and proximally resected, but did significantly increase in bypassed rats with respect to sham-operated animals. When the results were calculated taking into account the tissue wet weight, the values of the resected rats continued to show no modifications; however, there was a compensation in the bypassed rats. These data demonstrate that the increase in the absorptive capacity of the colon in bypassed rats is due to morphological changes, which could originate from the trophic influence of enteroglucagon or from the effect of the secretions which flowed directly into the colon from the blind loop, an action which does not occur in resected rats. The effects of resection and bypass upon K+ colonic secretion showed no significant differences among the groups studied.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serum lipid concentrations and blood pressure in obese women.

In 70 obese women no correlation was found between body weight and serum cholesterol or triglyceride concentrations, but there was a significant correlation between weight and blood pressure. Weight reduction by diet or jejunoileal shunt was not accompanied by any significant change in serum lipid concentrations other than the decrease in serum cholesterol expected after intestinal bypass. Twelve months after bypass surgery was carried out on 14 patients, however, both systolic and diastolic blood pressures were significantly reduced and at levels appropriate to the patients'' new weights. These results suggest that obesity in women cannot be taken to indicate the presence of hyperlipidaemia and that sustained weight loss may lower blood pressure.     

Predictors of Osteodystrophy in Patients with Chronic Nonalcoholic Pancreatitis with or without Diabetes

ObjectiveTo study bone mineral content (BMC), bone mineral density (BMD), vitamin D status, and bone mineral variables in patients with chronic nonalcoholic pancreatitis and to determine the relationship between pancreatic dysfunction and these variables.MethodsThirty-one eligible nonalcoholic men with proven chronic pancreatitis and 35 male control subjects were studied. Biochemical data, variables of malabsorption, and BMD of the lumbar spine were evaluated.ResultsIn patients with chronic pancreatitis, the mean body mass index (BMI) was 18.46 kg/m² and the median 25-hydroxyvitamin D value was 15.5 (range, 5.0 to 52.0) ng/mL. A T-score of less than -2.5 was found in a higher proportion of study patients (9 of 31, 29%) than of control subjects (3 of 35, 9%). BMI correlated significantly with BMC (r = 0.426; P = .017). There was an inverse correlation between stool fat and BMC (r = -0.47; P = .03) in patients with chronic pancreatitis and steatorrhea. There was no significant correlation between serum 25-hydroxyvitamin D or biochemical variables and BMD. Patients with steatorrhea had a significantly lower BMC than did those without steatorrhea, and this difference could not be accounted for by differences in BMI, presence of diabetes, or hypovitaminosis D.ConclusionPancreatic osteodystrophy is a novel entity consisting of osteopenia, osteoporosis, and osteomalacia in patients with chronic pancreatitis. The inverse correlation between stool fat and BMC in patients with chronic pancreatitis, the strong positive correlation between BMI and BMC, and the lack of difference in BMC between subjects with vitamin D sufficiency and those with vitamin D deficiency suggest that long-standing malabsorption with attendant chronic undernutrition is the major factor contributing to the changes in BMC. (Endocr Pract. 2011;17:897-905)