Biomedical subjects
Publications and source records attributed to M S Tanner.
Two fatal cases of invasive pneumococcal disease in the newborn are reported, both acquired from the maternal vagina. The rarity of vaginal carriage of pneumococcus suggests that this organism has a higher invasion to colonisation ratio than group B streptococcus and maternal carriage or neonatal colonisation should be more aggressively treated.
Explore the source record for details and available documents.
Genetic factors have been implicated in the pathogenesis of liver disease in cystic fibrosis. To investigate whether liver disease is associated with particular mutations of the defective gene in cystic fibrosis, we have determined the frequencies of three mutations--delta F508, G551D and R553X--in 111 children and young adults with cystic fibrosis by analysis of genomic DNA segments amplified by the polymerase chain reaction. Twenty-nine patients had severe liver disease with portal hypertension, 19 had clinical and/or biochemical evidence of liver disease but no associated portal hypertension and 63 had no evidence of liver disease. No significant differences in the frequencies of the delta F508, G551D or R553X mutations in the three clinical subgroups were found, and we conclude that the development of liver disease in cystic fibrosis is unlikely to be associated with a specific mutation in the gene. However, because 27% of cystic fibrosis chromosomes do not have a defined mutation, this possibility cannot be ruled out. A familial concordance for clinical liver disease of 20% in this study, compared with a reported prevalence of 4.7%, suggests that genes outside the cystic fibrosis locus and/or environmental factors are involved in the pathogenesis of liver disease in cystic fibrosis.
The possible aggravation of liver injury by impaired cellular antioxidant function was investigated. A vitamin E-deficient diet (0.5 mg/kg alpha-tocopherol; control 100 mg/kg) significantly reduced rat liver alpha-tocopherol concentrations after 4 weeks (1.8 +/- 1.7 micrograms/g; control 34.4 +/- 2.4 micrograms/g, p < 0.001). The effects of copper loading (Cu, 3 g/kg diet); galactosamine (GalN, 0.85 g/kg i.p.); or carbon tetrachloride (CCl4, 10 mmol/kg i.p.) were examined. Serum aspartate transaminase activity was elevated slightly by vitamin E deficiency but not by hepatic copper accumulation. In vitamin E-replete (E+) and vitamin E-deficient (E-) rats, GalN or CCl4 caused a large and comparable elevation in serum AST and OCT activity. This effect on AST was markedly reduced by copper loading in vitamin E replete (E+) rats, but in E(-) rats copper had significantly less protective effect. Copper also diminished the OCT response to GalN in E+, though not E-, rats. A significant rise in total hepatic alpha-tocopherol content followed administration of GalN or CCl4 in both normocupric and copper-laden E(-) rats. Thus alpha-tocopherol deficiency (a) was not hepatotoxic per se; (b) failed to potentiate the toxicity of copper, GalN or CCL4; but (c) partially abolished the protection by copper against toxin-induced liver injury. Retention of hepatic alpha-tocopherol after liver damage may partly explain low serum vitamin E levels seen in clinical liver disease.
Previous studies have led to the hypothesis that the gross hepatic copper storage characteristic of Indian childhood cirrhosis (ICC) is due to the early introduction of animal milk feeds which have been contaminated with copper from brass household utensils. Amongst the families of 100 cases of ICC, the incidence of ICC in children born after dietary advice had been given (1/86) was significantly lower than in older siblings (12/125). This study attempted to document the incidence of ICC and the usage of brass before and after an intervention programme in Pune District advising against this pattern of infant feeding. The study encountered numerous difficulties in data gathering, but documented a fall in ICC prevalence resulting in its virtual disappearance in Pune District. This contrasted with an unchanged incidence in Chandigarh. Although a fall in brass usage was seen in Pune District, this was actually a spontaneous sociological change rather than a result of health education.
There have been striking advances in the management of complications of cirrhosis in the 50 years since biliary cirrhosis was recognised as a feature occurring in a minority of patients with cystic fibrosis. Many questions remain unanswered with regard to its pathogenesis, its effect on other systems, morbidity and mortality and to its optimum management. Factors which may initiate liver disease and/or cause progressive biliary fibrosis leading to biliary cirrhosis in some cystic fibrosis patients are being defined but much is still poorly understood and further research is required. Clinical and pathological studies confirm that cirrhosis is frequently asymptomatic and only slowly progressive, with the prevalence rising with age. In a recent large epidemiological study, however, it was found that the age related prevalence fell in patients over the age of 20 years although deaths from liver disease were rare. Does the presence of liver disease cause premature respiratory death in teenagers? Current treatments control variceal bleeding, the important sequel for most patients with biliary cirrhosis, with less morbidity and mortality than in the past but require reappraisal as newer techniques become available. Endoscopic radiologically controlled methods are emerging as an important adjunct to the surgical control of biliary complications which cause symptoms in up to 4%. Ursodeoxycholic acid improves liver function tests but its effect on hepatic fibrosis and portal hypertension will only be demonstrated by large scale prospective controlled trials. Should liver transplantation have a larger role in management? In this chapter we have attempted to summarise the current state of knowledge and to assess the efficacy of present management.
Lafora disease is a rare inborn error of metabolism resulting in storage of a polyglucosan in tissues including the brain, skin and liver. Four children are described with progressive myoclonus epilepsy and intellectual deterioration in whom this diagnosis was made. In two the diagnosis was confirmed by the presence of periodic acid schiff (PAS) positive, diastase resistant, colloidal iron staining inclusion material in the liver when they were referred to a paediatric gastroenterologist with abnormal liver function tests. In one, the diagnosis was made from cerebellar biopsy, although on retrospective review the liver biopsy performed at this time was abnormal. In a fourth child, whose sibling was affected, histological diagnosis was confirmed by skin biopsy, although clinical and EEG findings had been highly suggestive for several years. The disease has autosomal recessive inheritance, is progressive and the prognosis is poor. Paediatricians should be aware of this diagnosis, which is often delayed, as early histological diagnosis allows prognostic and genetic counselling and optimal treatment. Although the diagnosis was made by liver or brain biopsy in three cases, skin biopsy offers a reliable, less invasive means of diagnosis.
Explore the source record for details and available documents.
To assess the prevalence, demography, and clinical features of liver disease among patients with cystic fibrosis the case notes of 524 patients of all ages who were attending the cystic fibrosis clinic were studied. Computer databases were used to establish the condition of the liver in a further 576 such patients. The overall prevalence of overt liver disease indicated by the presence of an enlarged liver or spleen (or both) was 4.2%. The age related prevalence rose to a peak in adolescence, and then fell in patients over 20 years old. The implied increase in mortality among those with liver disease was not explained by deaths from liver disease, which were rare. Male patients were significantly more affected than female, the ratio being 3:1 among adolescents. Increasing prevalence of liver disease in patients with cystic fibrosis is, therefore, not just a result of longevity.
A positive family history of autoimmune disease is common among patients with autoimmune chronic active hepatitis, but usually autoimmunity is directed at organs other than the liver. We document for the first time the multiple occurrence of autoimmune chronic active hepatitis in a family. Out of a sibship of seven, three sisters developed this, one sister developed coeliac and autoimmune thyroid disease, one sister showed serological signs of autoimmunity, while the two brothers were well with no signs of autoimmunity. HLA typing showed that in association with the female sex DR3 seems to be more important than B8 in conferring susceptibility to autoimmune chronic active hepatitis, at least in this family.
Explore the source record for details and available documents.
Elevated urine mercury levels in two Asian brothers with the nephrotic syndrome led to the discovery of very high mercury concentrations in 7 out of 10 other family members. Mercury contamination was caused by gold refining in a garage at the home. Although childhood nephrotic syndrome is usually idiopathic, the proteinuria and the mercury inhalation were probably causally related in this family.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
1. It has been suggested that low levels of serum caeruloplasmin in Wilson's disease result from the failure to switch from a fetal to an adult mode of caeruloplasmin gene expression. To investigate postnatal expression of the caeruloplasmin gene, steady-state levels of caeruloplasmin messenger RNA in adult and neonatal rat liver were measured. 2. Copper parameters observed in neonatal rats were similar to those seen in Wilson's disease: hepatic copper concentration was significantly elevated (neonatal 164 +/- 35 micrograms/g, adults 50 +/- 8 micrograms/g, P less than .001) and serum copper and caeruloplasmin levels were low (neonatal 0.5 +/- 0.1 microgram/ml, adults 1.3 +/- 0.2 microgram/ml, P less than .001; neonatal 0.20 +/- 0.04 arbitrary units, adults 0.69 +/- 0.16 arbitrary units, P less than .001), respectively. 3. Caeruloplasmin messenger RNA levels were analysed by Northern and dot blotting using a 32P-labelled caeruloplasmin complementary DNA probe. A caeruloplasmin messenger RNA of approximately 4.4 kilobases was detected in both adult and neonatal rat liver, with no significant difference observed in steady-state levels. 4. A step subsequent to caeruloplasmin gene transcription must therefore be impaired in neonatal rats.
To mimic the infant feeding practice associated with Indian childhood cirrhosis (ICC), bovine milk was stored for 6 h in indigenous brass vessels. The milk copper concentration rose from 27 +/- 4 to 621 +/- 65 micrograms/dl, whereas zinc concentration was not significantly changed. Copper in bovine milk was associated with casein (67%), whey proteins (7%), less than 10 kDa molecules (11%), and fat (7%). Addition of copper sulphate to a concentration of 600 micrograms/dl produced a 102-fold rise in copper content of the casein fraction, a 47-fold increase for whey, and 15-fold for the less than 10 kDa fraction. Analysis by sepharose gel chromatography confirmed that casein was the major copper-binding fraction in control and copper-loaded milk. To mimic intragastric conditions, the pH of copper-loaded milk was lowered to 4.5 to precipitate casein, resulting in a rise in less than 10 kDa bound copper (10.7 +/- 4.0 to 104.3 +/- 7.5 micrograms Cu/100 ml) and whey-bound copper (53.1 +/- 4.5 to 118.4 +/- 19.1 micrograms Cu/100 ml). Copper/casein complex (3 micrograms Cu/mg protein, pH 6.6) was dialysed against low-MW metal chelating agents, including picolinate and citrate, which are present in the duodenum. Picolinate 1 mM and citrate 1 mM were able to remove 84% and 29% of copper, respectively. Thus, copper, though not zinc, is avidly taken up from brass and bound largely to casein, from which it is partly liberated by acid precipitation and almost completely removed by picolinate chelation. Milk is an effective carrier of copper from brass utensil to infant enterocyte.
Explore the source record for details and available documents.
Cellobiose and mannitol absorption were studied in patients with suspected abnormal function of the small bowel mucosa. The urinary cellobiose:mannitol ratio was increased in subtotal villous atrophy, iron deficiency anaemia, and small intestinal Crohn's disease. The test seems a sensitive indicator of the integrity of small bowel mucosa.