Iron deficiency anaemia in general practice: presentations and investigations.

Twenty-six patients over the age of 50 years with proven iron deficiency anaemia were identified, investigated and followed up in general practice over a five-year period. The anaemia was symptomatic in 50% of patients but only 20% had symptoms related to the gut. Faecal occult blood testing was positive in five patients only and negative tests occurred in three patients with significant disease, including one caecal carcinoma. All patients agreed to oesophagogastroduodenoscopy (OGD) and fibreoptic sigmoidoscopy carried out on the same occasion. In eight patients, significant abnormalities were found on OGD and in two patients on sigmoidoscopy. Four patients declined barium enema examinations, two of whom had significant OGD abnormalities. Barium enema examination of the other 22 patients showed polyposis of the colon and a caecal carcinoma and initially missed one carcinoma of the caecum which was found subsequently. The likelihood of finding significant disease in iron-deficient patients over 50 years of age is high and should be assumed to be due to blood loss into the gut. Investigation by OGD, sigmoidoscopy and barium enema in the first instance seems warranted and is a condition that can be safely managed by the GP.

Sucralfate for the prevention of early rebleeding following injection sclerotherapy for esophageal varices.

One hundred eighty patients with variceal bleeding and treated by long-term sclerotherapy were randomized into a prospective randomized controlled clinical trial to assess the efficacy of sucralfate in reducing the frequency of rebleeding from esophageal ulceration prior to variceal obliteration. Overall, 29 (32%) of the 92 patients treated with the addition of sucralfate rebled, compared to 37 (42%) of 88 patients managed by sclerotherapy alone (p less than 0.10), but when patients with well-compensated liver disease were considered, the respective figures were 14 (24%) and 25 (42%)--a statistically significant difference (p less than 0.05). The frequency (approximately 70%), number (per patient) and extent of sclerotherapy-induced esophageal mucosal ulceration were not different for the two groups, although proven rebleeding from the ulceration occurred less frequently in those receiving sucralfate (10 and 20 occasions, respectively, p less than 0.05). Mortality was not different for the two groups. Thus, use of sucralfate will reduce the frequency of rebleeding during long-term treatment by sclerotherapy, although benefit appears to be restricted to well-compensated patients and without an endoscopic overt effect upon esophageal mucosal ulceration.

Maintenance of remission in autoimmune chronic active hepatitis with azathioprine after corticosteroid withdrawal.

Forty-seven patients with autoimmune chronic active hepatitis in remission on azathioprine and/or prednisolone were entered into a randomized controlled trial to assess the value of azathioprine alone in maintenance of remission. The trial design involved administering azathioprine at a dose of 2 mg per kg to one-half of the patients, in whom prednisolone was then gradually withdrawn, whereas the remaining patients, the "control" group, were maintained on the conventional combination regimen of azathioprine (1 mg per kg) with prednisolone. At 1 year there was no significant difference in respect of standard liver function tests or histological appearances between the two groups. Two patients in the azathioprine group required dosage reduction because of myelosuppression and both subsequently relapsed. Following withdrawal of corticosteroids Cushingoid features were lost with a return of weight and blood pressure to normality. In 75% of the patients, corticosteroid withdrawal was marked by arthralgias and myalgias which lasted for up to 12 months: no other major side effects of corticosteroid withdrawal were noted. Thus in the majority of cases, remissions in autoimmune chronic active hepatitis which are induced by corticosteroids can be maintained with azathioprine alone.

Bone histomorphometry and structure in corticosteroid treated chronic active hepatitis.

Transiliac biopsies from 34 female patients with corticosteroid treated chronic active hepatitis have been examined to determine the contributions made by decreased bone formation and increased bone resorption to bone loss associated with this condition and to determine the structural basis of the bone loss. Mean wall thickness was significantly reduced when compared with control values (p less than 0.001) as was the bone formation rate at tissue (p less than 0.005) and basic multicellular unit (p less than 0.005) level. The osteoid maturation period and the bone formation period were significantly prolonged (p less than 0.02 and 0.05). The total resorption surfaces were significantly increased (p less than 0.02) but the mean interstitial bone thickness was normal. The mean trabecular plate thickness was significantly reduced (p less than 0.005). These findings indicate that decreased bone formation plays a major role in bone loss associated with corticosteroid treated chronic active hepatitis and that the structural basis of bone loss is trabecular thinning.

Low bone turnover state in primary biliary cirrhosis.

To determine whether bone loss in patients with chronic cholestatic liver disease is the consequence of a high or low bone turnover state, 30 female patients with biopsy-proven primary biliary cirrhosis underwent iliac crest biopsy following double tetracycline labeling. The mean trabecular bone volume was decreased as a result of trabecular plate thinning in both the premenopausal (p less than 0.02) and postmenopausal (p less than 0.05) patients, compared to age- and sex-matched controls. Indications that osteoblastic function was impaired included a significantly lower mean wall thickness (p less than 0.01) and mean osteoid seam width (p less than 0.05), and this in association with a decreased mineral appositional rate and prolonged mineralization lag time was suggestive of a defect in matrix synthesis. Further evidence of impaired osteoblastic activity was the significantly lower bone formation rate at both tissue (p less than 0.001) and basic multicellular unit levels (p less than 0.05) in the postmenopausal patients. Total resorption surfaces and fasting urinary calcium/creatinine ratios were significantly increased (p less than 0.005 and 0.05, respectively) in the premenopausal patients and mean interstitial bone thickness reduced in both pre- and postmenopausal patients, suggesting that increased resorption may also contribute to bone loss in primary biliary cirrhosis.

Influence of aetiology, clinical and histological features on survival in chronic active hepatitis: an analysis of 204 patients.

To determine which clinical and laboratory features may influence survival in patients with chronic active hepatitis, we undertook a retrospective study of 204 patients seen on this unit over a 15-year period and applied logistic regression analysis. One hundred and six patients had autoimmune chronic active hepatitis, 69 'cryptogenic' chronic active hepatitis (no autoimmune markers or other aetiological factors identified), and 29 were HBsAg-seropositive. Variceal haemorrhage, encephalopathy and ascites were common presenting features in the cryptogenic group while the presence of jaundice and other immunopathic diseases did not differ between the groups. Cirrhosis was more common at presentation in the cryptogenic group. Remission was induced with corticosteroids and azathioprine in 82 per cent of patients with autoimmune chronic active hepatis and in 77 per cent of patients with cryptogenic chronic active hepatitis and the annual relapse rate was similar in the autoimmune and cryptogenic groups. Five-year survival was 87 per cent in the autoimmune group, 65 per cent in the cryptogenic group, and 80 per cent in those with HBsAg-positive disease, and on logistic regression analysis, the presence of cirrhosis at presentation was the only independent factor which adversely affected survival. Overall survival in the cirrhotic patients at five and 12 years was 63 and 48 per cent respectively compared with 95 and 92 per cent in those without cirrhosis.

Increased incidence of menstrual abnormalities and hysterectomy preceding primary biliary cirrhosis.

A study was performed to assess the incidence of previous hysterectomy and dilatation and curettage among women with primary biliary cirrhosis. In 87 patients with primary biliary cirrhosis hysterectomy or dilatation and curettage had been performed significantly more often than among 100 age matched normal controls and 80 age matched patients with chronic active hepatitis or alcoholic liver disease. Among the 47 patients with primary biliary cirrhosis who had undergone hysterectomy or dilatation and curettage operations had been performed at a mean of 10.7 years and 13.2 years, respectively, before the onset of disease. The main indication for hysterectomy among patients with primary biliary cirrhosis and controls was menorrhagia. These menstrual disorders may be a consequence of high concentrations of oestrogens in patients with primary biliary cirrhosis.

Use of propranolol to reduce the rebleeding rate during injection sclerotherapy prior to variceal obliteration.

In a prospective, randomized controlled trial, 53 patients with variceal hemorrhage from portal hypertension, including 44 with cirrhosis, were allocated, after initial control of the bleeding, to treatment by sclerotherapy alone, or by this together with oral propranolol in a dose sufficient to reduce resting pulse rate by 25% during the period up to the time when varices were obliterated. Eight of the 27 patients undergoing sclerotherapy alone rebled during this period as compared to 7 of the 26 patients in the additional propranolol group (p greater than 0.80), two patients from each group dying from uncontrollable variceal hemorrhage. Propranolol precipitated encephalopathy in one patient and complicated resuscitation following bleeding in a second, and as there was no evidence in this study that use of the drug reduced the frequency or severity of the variceal bleeding, its administration cannot be recommended during the period prior to obliteration of varices by sclerotherapy.

Inter-observer and intra-observer variation in bone histomorphometry.

Inter-observer variation has been examined for a number of histomorphometric indices in 20 normal human iliac crest biopsies. Quantitation was performed using an eye-piece graticule and eye-piece micrometer. The same sections were examined by two observers and the methodology was identical. Intra-observer variation was also assessed. Significant inter-observer differences were found for the measurement of total trabecular bone volume, osteoid volume and surface, double plus single and double tetracycline labeled surfaces, and the mean osteoid seam width. The percentage variance due to inter-observer variation was highest for osteoid surface and volume, total resorption surface, and mean osteoid seam width. Intra-observer variation in both observers was small. We conclude that a large inter-observer variation may occur in the measurement of a number of histomorphometric indices, even when section preparation and methodology are identical. Caution should be used in basing the diagnosis of metabolic bone disease on strictly defined control data from other observers, particularly when this has been obtained from centers where the effects of inter-observer variation may be magnified by differences in methodology.

Lack of osteomalacia in chronic cholestatic liver disease.

Assessment of osteomalacia using rigorous histologic definition was carried out in 36 unselected patients with chronic cholestatic liver disease, 33 with primary biliary cirrhosis, and 3 with primary sclerosing cholangitis. Disease duration varied from 1 to 11 years. The mean values for total trabecular bone volume, osteoid volume, osteoid surface, and mineralization appositional rate were all decreased when compared to age-matched and sex-matched controls. There was a highly significant decrease in the mean osteoid seam width in both females (P = 0.001) and males (P = 0.02), and a significant prolongation of the mineralization lag time was found in females (P = 0.05), but failed to reach significance in males. These results excluded osteomalacia but were more indicative of osteoporosis. Biochemical evidence of osteomalacia was also absent, with serum calcium, serum phosphorus, and mean 25-hydroxyvitamin D levels not significantly different from control values, although there was a nonsignificant decrease in the mean value of 25-hydroxyvitamin D in patients with elevated serum bilirubin levels, and all patients with levels below 20 nmol/L had avoided sunlight exposure. The present results suggest that osteoporosis is the major type of metabolic bone disease in patients with chronic cholestatic liver disease.

Osteoporosis in chronic cholestatic liver disease.

Assessment for both trabecular and cortical osteoporosis was carried out in 36 unselected patients with chronic cholestatic liver disease of whom a number had received corticosteroids during the course of their illness. Symptoms suggestive of osteoporosis were present in 42 per cent of patients of whom 11 per cent had evidence of one or more wedged or collapsed vertebrae. There was a highly significant decrease in the cortical area (total area ratio of the second metacarpal (p = 0.05), bone mineral content at the metaphyseal site of the radius (p = 0.01) and the total trabecular bone volume of the iliac crest biopsies (p = 0.005) in the 31 female patients when compared with age and sex-matched healthy controls). There was a nonsignificant decrease in total trabecular bone volume of the iliac crest and bone mineral content of the radial metaphysis in the males compared with age and sex-matched controls but the cortical plate thickness of the iliac crest (p = 0.005) and bone mineral content of the radial diaphysis (p = 0.02) were significantly higher. In total, 42 per cent of patients had evidence of either excessive cortical (28 per cent) and/or trabecular (36 per cent) bone loss as judged by radiological and histological criteria. Only the total trabecular bone volume of the iliac crest, of all the parameters measured was significantly (p = 0.02) lower in patients with backache compared with those without back pain. Significantly greater bone loss was demonstrated at all sites measured in those patients that were receiving or had received corticosteroids in the past.

Bone loss in autoimmune chronic active hepatitis on maintenance corticosteroid therapy.

To determine the frequency of osteoporosis in patients with autoimmune chronic active hepatitis who are maintained on corticosteroids, both cortical and trabecular bone loss were studied in a group of 36 patients. A significant decrease in both the total trabecular bone volume (p = 0.005) and cortical plate thickness (p = 0.01) of iliac crest biopsy specimens was found in the patients with chronic active hepatitis. Bone mineral content of the radial metaphysis, a site composed of both cortical and trabecular bone, was found to be significantly decreased (p = 0.05). However, no statistical reduction in cortical bone mass of the radial diaphysis and second metacarpal was detected. Altogether, 47% of patients had evidence of either excessive trabecular or cortical bone loss, or both, as judged by histologic and radiologic criteria. The presence of cirrhosis at the time of diagnosis or subsequently did not appear to lead to greater loss of bone mass. However, a weak inverse correlation was found between the product of mean dose and duration of corticosteroid therapy and both the trabecular bone volume and the cortical plate thickness of the iliac crest biopsy specimens. Based on these results, patients with autoimmune chronic active hepatitis on low doses of prednisolone therapy may need to be treated with calcium and vitamin D at an early stage of their disease.

Randomised controlled trial of azathioprine withdrawal in autoimmune chronic active hepatitis.

To assess the value of azathioprine in the maintenance therapy of autoimmune chronic active hepatitis a controlled trial of azathioprine withdrawal was carried out in 50 patients who had been maintained in remission on a combination of azathioprine and prednisolone. The patients were randomly allocated to remain on combination therapy (23) or to discontinue azathioprine (27). These 2 groups were comparable at the start of the study. Over a follow-up period of up to 3 years, biochemical and histological relapse occurred in 8 patients in the azathioprine-withdrawal group but in only 1 patient in the combination-therapy group. Cumulative probability of relapse was 32% among the patients in the withdrawal group, compared with 6.0% for those in the combination group.