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Fluorescently labeled antibodies were used to identify transferrin receptors and mucosal transferrin in human gastrointestinal biopsy sections. Transferrin receptors were evident in the villous epithelium and the crypt areas of duodenum, ileum, and colon, predominantly in the basal-lateral area. In 7 subjects with low iron stores, the intensity of duodenal villous staining for receptor, on a scale of 0–4, was 2.1 ± 0.3 (mean ± SD). This value was significantly higher than the value in 13 subjects with normal iron stores (1.1 ± 0.4). In 5 patients with hereditary hemochromatosis, duodenal transferrin receptor staining was not significantly different from that in the subjects with normal iron stores. Transferrin staining was found in the apical cytoplasm of epithelial cells in the duodenum, ileum, and colon, but observer assessment was not sufficiently reproducible to make a quantitative analysis. Our results suggest that iron deficiency is accompanied by an increase in transferrin receptors in duodenal absorptive cells, and the genetic lesion in hemochromatosis does not involve an increase in transferrin receptors in the intestinal mucosa compared with subjects with normal iron stores.

The pattern of transmission of the predisposing alleles of idiopathic hemochromatosis was traced in 111 members of 12 pedigrees by typing for the A and B alleles of the HLA complex. The 12 probands were assigned the status of homozygotes. Other family members were grouped according to their HLA typing into one of three categories independent of their iron stores: homozygotes who shared two haplotypes with the proband; heterozygotes who shared one haplotype; and normals who lacked both haplotypes. Clinical manifestations of iron loading were prevalent in male homozygotes and absent in heterozygotes and normals. The results of tests of iron metabolism were compared with age- and sexmatched controls. Abnormalities in 12 probands and 6 discovered homozygotes were characterized by a significant increase in mean serum iron, a decrease in serum transferrin, an increase in both transferrin saturation, and serum ferritin. Similar but less marked abnormalities were found in 25% of 69 heterozygotes with the exception that mean serum ferritin was normal. In 24 normal family members a slight increase in mean serum iron and transferrin saturation was detected, but mean serum ferritin was normal. Radioiron absorption in relation to the respective serum ferritin concentration measured in selected subjects was markedly increased in 1010 homozygotes, moderately increased in 514 heterozygotes and within the control range in 22 normals. In summary, phenotypic expression of hemochromatosis was characterized by increased serum iron, decreased transferrin, increased serum ferritin, and iron absorption relative to serum ferritin in both homozygous males and females, but a major degree or iron loading with clinical features was only prevalent in homozygous males. Partial biochemical expression of the disorder in some heterozygotes was associated with an increase in iron absorption and a minor degree of iron loading in the absence of clinical manifestations.

To determine whether or not hepatic computed tomography density is an alternative to liver biopsy for the diagnosis of body iron overload, hepatic computed tomography density was determined in healthy controls, patients with idiopathic hemochromatosis, and patients with liver disease. Hepatic computed tomography density was obtained from a single computed tomography slice taken through the liver on a General Electric CT/T 8800 scanner. In 69 controls, hepatic computed tomography density ranged from 11 to 36 units (mean = 30). Given an upper limit of normal of 36 computed tomography units, 4 of 6 untreated patients with idiopathic hemochromatosis had elevated hepatic computed tomography density compared with 0 of 8 patients after venesection (X2 = 7.5, p = 0.01). Hepatic computed tomography density correlated directly with serum ferritin (r = 0.72, p = 0.01). In 58 consecutive patients with clinical or biochemical evidence, or both, of liver disease who underwent liver biopsy for diagnostic purposes, 0 of 52 patients with normal hepatic iron had an elevated hepatic computed tomography density as compared with 4 of 6 patients with excess iron (X2 = 35, p less than 0.001). An elevated hepatic computed tomography density associated with an elevated serum ferritin indicates iron overload; however, a normal hepatic computed tomography density does not exclude iron overload. When computerized tomography is applied to patients with an unexplained elevation of the serum ferritin, it provides a noninvasive alternative to liver biopsy for the detection of excess hepatocellular iron.

Under normal conditions, vitamin D absorbed from the diet or synthesized in the skin is transported to the liver where it undergoes hydroxylation. The purpose of this study was to determine whether excess hepatic iron affects this process and the subsequent production of 1,25-dihydroxyvitamin D (1,25-[OH]2D) in the kidney. Mean serum 25-hydroxyvitamin D (25-OHD) concentrations in untreated hereditary hemochromatosis were 13 +/- 6 (SD) in 9 patients with cirrhosis, 13 +/- 6 in 5 patients with hepatic fibrosis, and 22 +/- 6 in 10 patients with normal hepatic architecture aside from siderosis and were significantly lower than the levels found in 24 controls matched for age, sex, and season, p less than 0.05. The mean serum 25-OHD levels in the two groups with hemochromatosis and hepatic damage were significantly lower than the value in the group with normal hepatic architecture, p less than 0.05. Serum 25-OHD levels in individual patients were inversely related to the size of body iron stores as measured by exchangeable body iron, r = -0.64, or serum ferritin, r = -0.47, p less than 0.05. In 15 patients removal of excess body iron by venesection therapy produced a significant increase in the mean serum 25-OHD from 20 ng/ml to 30 ng/ml, p less than 0.05. In contrast, mean serum 1,25-[OH]2D levels were similar in iron-loaded and control subjects, indicating that the regulation of this metabolite was intact in patients with hemochromatosis. The results reveal that the low serum 25-OHD concentration in patients with hemochromatosis is directly related to the extent of iron loading and it is improved by venesection therapy.

In mice fed a low iron diet, the addition of low levels of cadmium chloride (10 μm) to the drinking water impaired growth and accentuated the development of anemia. Cadmium had no effect on mice given a similar diet supplemented with iron. Iron deficiency increased the concentration of cadmium in the duodenal mucosa, the transfer of cadmium to the body from the intestinal tract, and the deposition of absorbed cadmium in the kidneys. In human subjects, the average absorption of 25 μg of cadmium, labeled with 115m Cd, from a test meal was 8.9 ± 2.0% (mean ± se) in 10 people with low body iron stores (serum ferritin 23 ng per ml). The biological half-time of the radiocadmium in 3 of the subjects ranged from 93 to 202 days. Thus, the intestinal adaptive response to iron deficiency in both experimental animals and human subjects leads to the increased absorption of cadmium, a potentially toxic element.

We studied a patient with Whipple’s disease to determine whether an immunological defect might accompany or predispose to this rare disorder. The humoral immune system was evaluated by immunolglobulin studies and by measuring the antibody response to antigenic stimulation. Plasma immunoglobulin levels were elevated before treatment, but after successful antibiotic therapy, IgG and IgA fell towards normal and IgM declined to a subnormal level. Intestinal secretions contained both IgA and free secretory component, and all three major classes of immunocytes were present in histological sections of the jejunal mucosa. Antibody synthesis to diphtheria antigen was normal and although the patient could not synthesize antibody to tetanus toxoid during the active phase of the disease he was able to do so after antibiotic therapy. Cell-mediated immunity was assessed by skin tests, ability to reject homografts, and lymphocyte transformation studies. Initial cutaneous anergy to histoplasmin and Candida albicans remitted with therapy; anergy £ tuberculin, trichophyton, and mumps antigen persisted despite clinical remission. In addition, skin homografts from unrelated donors were only slowly rejected both during the active phase of the disease and during remission. Moreover, the patient's lymphocytes in vitro demonstrated impaired incorporation of both 3H-thymidine and 3H-uridine in response to phytohemagglutinin. The defect was partially reversed by the addition of normal serum in vitro, whereas the patient’s serum blocked the response of normal lymphocytes. This abnormal response to phytohemagglutinin also persisted despite successful treatment of the disease. Our patient thus had relatively minor abnormalities of the humoral immune system which largely regressed on antibiotic therapy. In contrast, evidence of impaired cell-mediated immunity persisted during clinical remission of the disease. Whether selective immunological abnormalities predispose to the development of Whipple's disease or the disorder secondarily causes irreversible immune defects remains unclear.

Increased iron absorption has been a frequent finding in portal cirrhosis and liver disease has been implicated as a common cause of raised iron absorption. In most studies iron stores have not been adequately assessed and iron deficiency has not been excluded as a cause of the increased iron absorption. The present investigation was designed primarily to assess the importance of iron deficiency and the rate of erythropoiesis in the production of increased iron absorption in cirrhosis. Iron stores were assessed by both bone marrow aspiration and liver biopsy. The absorption of a test dose of inorganic iron in 9 patients with portal cirrhosis and 6 with alcoholic fatty liver associated with normal iron stores was similar to the absorption in 12 control subjects with comparable iron stores. An appropriate increase in iron absorption was found in 8 patients with cirrhosis associated with depleted iron stores and an appropriate decrease was present in a patient with cirrhosis and increased iron stores due to blood transfusions. In contrast an inappropriate increase in absorption was detected in 2 patients with portal cirrhosis complicated by iron overload and in 2 patients with cirrhosis in whom it was not clear whether the liver disease or the iron overload was the primary event. No relationship was found between the level of iron absorption and the rate of erythropoiesis, the concentration of either serum folate or serum vitamin B12, the severity of the liver disease, or the presence or absence of a portacaval shunt. The results indicate that increased iron absorption in portal cirrhosis is usually the result of decreased iron stores which in some patients is only evident upon examination of the bone marrow. In a small number of cirrhotic patients with normal or increased iron stores the normal system for excluding unwanted iron breaks down and an inappropriate increase in iron absorption occurs, but the cause of this remains obscure.

Summary Two women, who were previously in good health, developed severe diarrhea and circulatory failure during the administration of antibiotics. Typical gross and microscopic features of pseudomembranous colitis were found in the rectum and later throughout the colon of both patients. No pathogenic organisms were found in the stool or in the rectal biopsy. Initially, dehydration occurred but, later, fluid retention and marked edema predominated. Severe hypoproteinemia appeared to play an important role in the development of edema, reduction in effective plasma volume, and the rapid progression of shock. The 1st patient died of shock despite intensive therapy with parenteral fluids, plasma, and albumin, whereas the 2nd patient survived with a combination of intensive medical therapy and ileostomy with subtotal colectomy to correct the hypoproteinemia. The survival of this patient provided a unique opportunity to study the progress of the disease in the rectum. The pseudomembrane and edema of the mucosa rapidly resolved and there was a gradual diminution in the hypersecretion of the goblet cells and the inflammatory response. At the time of restoration of the continuity of the bowel, the rectal mucosa was still friable and mild inflammation persisted.

In 12 normal control subjects given four oral doses of 20 μmoles of radioactive ferrous chloride or an equimolar amount of radioactive cobaltous chloride followed by an unabsorbable marker, the average excretion of radioactivity in the feces prior to disappearance of the marker was 64 and 54%, respectively. An average of 9% of the iron and 2% of the cobalt was lost in the feces after the marker was passed. The average absorption of iron, 27%, was significantly less than the absorption of cobalt, 44%. The results suggest that the intestinal mucosal uptake of cobalt is slightly greater than that of iron, and cobalt, unlike iron, is not sequestered in the mucosa and subsequently lost with desquamation of the intestinal epithelium. In 6 patients with iron deficiency, the average absorption of iron and cobalt, 60 and 71%, respectively, was significantly increased. A direct correlation was observed between the absorption of iron and cobalt in the control and iron-deficient subjects. In 5 patients with exogenous iron overload, the average percentage absorption of iron, 10%, was markedly reduced whereas the absorption of cobalt was within the range observed in control subjects. The average absorption of both iron and cobalt was increased in 2 patients with cirrhosis associated with iron overload and in 4 patients with idiopathic hemochromatosis. The results demonstrate that cobalt absorption is responsive to the physiological mechanisms that enhance iron absorption but not to those that inhibit it.

Thirteen women aged 21 to 47 years were encountered with intermittent attacks of typical biliary type pain associated with vomiting and tenderness in the right upper abdomen, but the gallbladder filled normally during cholecystography and no stones were identified. Jaundice was not a feature and both liver function tests and serum amylase levels were normal. The pain was reproduced in each of the patients under carefully controlled conditions by the administration of cholecystokinin. In 12 who underwent cholecystectomy, no gross abnormality was found in the biliary tract or pancreas and no consistent pathological abnormality was detected in either the gallbladder or cystic duct to explain the pain. The patients, followed for 3 to 44 months, were relieved of their pain after operation. Although biliary pain is usually due to gallstones, the pain in these patients appeared to arise from the gallbladder and/or cystic duct in the absence of apparent obstruction. Nine of them also had a functional disturbance of the gastrointestinal tract. Six of these had emotional problems and the biliary tract disorder appeared to be part of a generalized disturbance in gastrointestinal function associated with emotional tension. However, in 4 patients, the gastrointestinal disorder was limited to vomiting which occurred only in association with pain and no emotional disorder was present. The etiology of the biliary pain in these patients is unknown.

In mice fed a low iron diet, the addition of low levels of cadmium chloride (10 micrometer) to the drinking water impaired growth and accentuated the development of anemia. Cadmium had no effect on mice given a similar diet supplemented with iron. Iron deficiency increased the concentration of cadmium in the duodenal mucosa, the transfer of cadmium to the body from the intestinal tract, and the deposition of absorbed cadmium in the kidneys. In human subjects, the average absorption of 25 microgram of cadmium, labeled with 115mCd, from a test meal was 8.9 +/- 2.0% (mean +/- SE) in 10 people with low body iron stores (serum ferritin less than 20 ng per ml) and 2.3 +/- 0.3% in 12 subjects with normal iron stores (serum ferritin greater than 23 ng per ml). The biological half-time of the radiocadmium in 3 of the subjects ranged from 90 to 202 days. Thus, the intestinal adaptive response to iron deficiency in both experimental animals and human subjects leads to the increased absorption of cadmium, a potentially toxic element.

To determine whether or not hepatic computed tomography density is an alternative to liver biopsy for the diagnosis of body iron overload, hepatic computed tomography density was determined in healthy controls, patients with idiopathic hemochromatosis, and patients with liver disease. Hepatic computed tomography density was obtained from a single computed tomography slice taken through the liver on a General Electric CT/T 8800 scanner. In 69 controls, hepatic computed tomography density ranged from 11 to 36 units (mean = 30). Given an upper limit of normal of 36 computed tomography units, 4 of 6 untreated patients with idiopathic hemochromatosis had elevated hepatic computed tomography density compared with 0 of 8 patients after venesection (X2 = 7.5, p = 0.01). Hepatic computed tomography density correlated directly with serum ferritin (r = 0.72, p = 0.01). In 58 consecutive patients with clinical or biochemical evidence, or both, of liver disease who underwent liver biopsy for diagnostic purposes, 0 of 52 patients with normal hepatic iron had an elevated hepatic computed tomography density as compared with 4 of 6 patients with excess iron (X2 = 35, p less than 0.001). An elevated hepatic computed tomography density associated with an elevated serum ferritin indicates iron overload; however, a normal hepatic computed tomography density does not exclude iron overload. When computerized tomography is applied to patients with an unexplained elevation of the serum ferritin, it provides a noninvasive alternative to liver biopsy for the detection of excess hepatocellular iron.

Fluorescently labeled antibodies were used to identify transferrin receptors and mucosal transferrin in human gastrointestinal biopsy sections. Transferrin receptors were evident in the villous epithelium and the crypt areas of duodenum, ileum, and colon, predominantly in the basal-lateral area. In 7 subjects with low iron stores, the intensity of duodenal villous staining for receptor, on a scale of 0-4, was 2.1 +/- 0.3 (mean +/- SD). This value was significantly higher than the value in 13 subjects with normal iron stores (1.1 +/- 0.4). In 5 patients with hereditary hemochromatosis, duodenal transferrin receptor staining was not significantly different from that in the subjects with normal iron stores. Transferrin staining was found in the apical cytoplasm of epithelial cells in the duodenum, ileum, and colon, but observer assessment was not sufficiently reproducible to make a quantitative analysis. Our results suggest that iron deficiency is accompanied by an increase in transferrin receptors in duodenal absorptive cells, and the genetic lesion in hemochromatosis does not involve an increase in transferrin receptors in the intestinal mucosa compared with subjects with normal iron stores.