1600

PATIENT DETAILS

long periods, as well as after recovery from a non-thyroidal illness, then observation, not treatment, is the best option. Queen

Mary’s Hospital, Sidcup, Kent DA14 6LT, UK

D. A. BLACK

Livingston EH, Hershman JM, Sawin CT, Yokikawa TT. Prevalence of thyroid disease and abnormal thyroid tests m older hospitalized and ambulatory person. J Am Geriatr Soc 1987; 35: 109-14. 2. Cooper DS, Halpem R, Wood LC, Levin AA, Ridgewell EC. L-thyroxine therapy in subclinical hypothyroidism. Ann Intern Med 1984; 101: 18-24. 3. Tunbridge WMG, Brewis M, French JM, et al. Natural history of autoimmune thyroiditis. Br Med J 1981; 282: 258-62. 4. Rosenthal MJ, Hunt WC, Gary PJ, Goodwin JS. Thyroid failure in the elderly. JAMA 1987; 258: 209-13. 1.

Failure of Phyllanthus amarus to eradicate hepatitis B surface antigen from symptomless carriers

*Free T4

by’Amerlex-M’ radioimmunoassay (RIA) (normal 8-24 pmol/I) tThyrotropin immunoradiometnc assay (detection Iimit008 mU/I) (normal 2-5 5 mUll #Cortisol RIA by gamma-BCT (IDS, Tyne and Wear, UK) ITT = Insulin tolerance test, ND=not done; +ve=positive;

CT=computed

tomographic.

hypothyroidismand laboratories using thyrotropin alone as the initial test of a strategic approach to thyroid function testing will miss those with unsuspected pituitary/hypothalamic disease.3 Departments of Medicine and Chemical Pathology, Milton Keynes General Hospital, Milton Keynes MK6 5LD, UK

R. C. PATON T. R. GAMLEN

1. Belchetz PE. Idiopathic hypopituitarism in the elderly. Br Med J 1985; 291: 247-48. 2. Beck-Peccoz P, Amr S, Menezes-Ferreira M, Faglia G, Weintraub BD. Decreased receptor binding of biologically inactive thyrotrophin in central hypothyroidism. N Engl J Med 1985; 312: 1085-90. 3. Mardell RJ, Gamlen TR. Thyroid function tests in clinical practice. Bristol: John Wright, 1985: 63.

SIR,-Your June 2 editorial is right to question the treatment of non-specific symptoms associated with mildly raised thyroid stimulating hormone (TSH). This is especially important in old age since such TSH concentrations are commonly seen on routine thyroid function testing. 40 consecutive elderly patients (mean age 79 years) were 1

identified with documented raised TSH (mean 7-9 mU/1, normal below 5-0 mU/1) and normal T4 (over 55 nmol/1). Follow-up data and thyroid function tests were then obtained for up to 45 years, after 13 patients with known thyroid disease were excluded. 6 subjects were immediately treated with thyroxine, although only 1 was clinically hypothyroid. Follow-up information was obtained on the other 21 for a mean of 38 months. 4 died. 5 were treated (again only 1 of these on a clinical basis) and 12 remained untreated. Of the 21 subjects not immediately treated, in 9 TSH returned to normal and overall the mean TSH fell from 7-9 to 59 mU/1 (p < 0-02), during the period of follow-up. There was no relation between the original TSH and individual doctors’ decisions to start thyroxine, nor did the absolute magnitude of TSH affect whether it had risen or fallen at follow-up. Autoantibody status was not known for all patients. The debate continues on the clinical advantage or otherwise of treating "subclinical hypothyroidism".2 In younger adults a raised TSH concentration does not seem to have any predictive value for 4 years, but overt hypothyroidism occurred at 5% yearly in women with both a raised TSH and antibodies.3 The predictive importance of substantially raised TSH or high titre antimicrosomal antibodies in the development of overt hypothyroidism has also been shown in healthy elderly people.’ Since mildly raised TSH concentrations can return to normal over overt

hypothyroidism

over

SIR,-Hepatitis B virus (HBV) infection is endemic in Thailand and 6-10% of the population are chronic symptom-free carriers who are at risk of chronic hepatitis, cirrhosis, and hepatoma and constitute a potential source of infection to the non-immune population. Eradication of the carrier state might be an important step in the control of HBV infection. Thyagarajan et aP suggested that Phyllanthus amarus (P nirur, a medicinal herb, eradicated the HBV carrier state permanently in 59 % of chronic carriers. Aqueous extracts inhibit the endogenous DNA polymerase of HBV and bind to the surface antigen.2 We have evaluated the efficacy of locally available P amarus in the eradication of the chronic HBV carrier state in Thailand. Blood donors found to be positive for HBsAg 6-12 months earlier were identified by the blood bank of Siriraj Hospital, and with their informed consent a blood sample was taken. Those in whom biochemical and haematological tests on the sample were normal and HBsAg positivity had persisted and who could comply with the follow-up plan took part in a randomised, blinded trial of P amarus placebo. Full-grown P amarus plants were selected and prepared as previously described.l The powder was dispensed as 200 mg capsules. Every patient took two P amarus capsules or placebo (glucose) three times a day for 30 days. Participants were asked to return to the clinic on days 15, 30, 60, and 180, when they were questioned about any discomfort; capsules were counted and a blood sample was collected. Samples were tested for HBsAg and HBeAg with ’Enzygnost-HBsAg micro’ and ’Enzygnost-HBe’ (Behring) on a Behring ELISA automatic processor. The cut-off was taken as the average for the three negative controls, plus 0,05 absorbance units. To calculate sample sizes we chose an efficacy rate of 30% (half that reportedl) and set type 1 and type 2 errors at 0-05 and 0-1. We estimated that 20% of participants would be lost to follow-up, so that we needed at least 42 carriers in each arm. 59 and 57 carriers were randomly assigned to the treatment and placebo groups, respectively. Capsule counts suggested that carriers forgot to take medication on average for 1 day in every 15.2 carriers in the placebo group felt worse after treatment whereas 6 felt better at days 15 and 30; in the P amarus group, 8 and 3 carriers felt better. Biochemical and haematological analysis revealed no significant versus

abnormal values. HBsAg was detected during treatment and follow-up period in every case except 1 in each group at day 180 (table). HBeAg levels (as mean [SD]) fell from 0-95 (0-43) to 0-63 (0-31) in the P amarus group (n = 18) 0,64 (0’40) after treatment and from 080 (0.47) to control group. The post-treatment decrease was significant only in the "active" treatment group (p < 0’01). However, mean levels of HBeAg in both groups at day 30 were very similar and by day 60 those who had been positive for HBeAg before the study still were.

We cannot therefore confirm activity of P amarus in the eradication of the HBsAg carriage from blood donors. Thyagarajan et all found that carriers without HBeAg were more likely to respond. In our study HBeAg was found only in 31-5% of HBsAg carriers but HBsAg remained detectable. The concentration of HBeAg decreased in our study but this is not clinically significant

1601

HBsAg POSITIVITY

RATE IN PREVIOUS STUDY

(T)’ AND

THAI

TRIAL (A)

They are, therefore, at risk of CFPI if pancreatic functional deteriorates, and thus having a pancreatic functional status consistent with their genetic analysis, as reported by Kerem et al. We would caution against the use of genetic analysis in the presumptive diagnosis of pancreatic functional status and the need for enzyme therapy. However, genetic analysis, like quantitative pancreatic secretory testing, may help to identify those patients with range.

reserve

CFPS

on

fat balance studies who

are at

greater risk for the

development of CFPI. McGill

University-Montreal Children’s Hospital Research Institute,

Montreal, Quebec H3H 1PE, Canada

HINDA KOPELMAN RIMA ROZEN

1. Kerem

because HBeAg did not disappear. The six-month follow-up we chose should have been long enough to reveal a therapeutic effect of 30 days’ ingestion of P amarus, had there been any.

Partly funded by Siriraj Foundation and Rockefeller Foundation. We thank Dr Richard Heller and Dr Michael Hensley for suggestions and Miss Joan Marsh for help with editing.

Departments of Medicine and Tranfusion Medicine, Faculty of Medicine, Siriraj Hospital; and Department of Pharmacognosy, Faculties of Pharmacy and Medical Technology, Mahidol University, Thailand

AMORN LEELARASAMEE SUWANNA TRAKULSOMBOON PAYOW MAUNWONGYATHI AIMON SOMANABANDHU PHANNEE PIDETCHA BUSABA MATRAKOOL TASSNEE LEBNAK WATANA RIDTHIMAT DASNAYANEE CHANDANAYINGYONG

Thyagarajan SP, Subramanian S, Thirunalasundar T, Venkateswaran PS, Blumberg BS. Effect of Phyllanthus amarus on chronic carriers of hepatitis B virus. Lancet 1988; ii: 764-66. 2. Venkateswaran PS, Millman I, Blumberg BS. Effects of an extract from Phyllanthus niruri on hepatitis B and woodchuck hepatitis B viruses: in vitro and in vivo studies. Proc Natl Acad Sci (USA) 1987; 84: 274-78. 1

Genetic analysis and pancreatic function in cystic fibrosis SiR,—Kerem et all reported that cystic fibrosis patients with preserved pancreatic function sufficient to maintain normal digestion (CFPS) were either heterozygous for the F508 mutation or had other unidentified mutations. Homozygosity for the severe F508 mutation was associated with pancreatic insufficiency (CFPI) and meconium ileus. Dr Stuhrmann and colleagues (March 24, p 738) report 5 of 30 CFPS patients with homozygous F508, but they determined CFPS status clinically. Their criteria may have differed from those of Kerem et al, and they report no quantitative pancreatic secretion studies. We report two patients with cystic fibrosis, meconium disease, and pancreatic sufficiency who are homozygous for the F508 severe CF mutation by hybridisation with allele specific oligonucleotides. Our two patients presented in the neonatal period, one with ileal obstruction and classic microcolon and the other with multiple impactions in the ileum and colon; these babies are described elsewhere.2 Both patients were diagnosed as CFPS in the first year of life, according to Kerem and colleagues’1 definition: 72 h fat balance studies with faecal fat losses of less than 7% of dietary intake and colipase output greater than 100 units/kg per hour on direct quantitative analysis of pancreatic secretions. Both patients continue to thrive without pancreatic extract supplementation, at almost 6 and 5 years of age, respectively. We would point out the potential for discrepancies between genetic analysis and pancreatic functional status as reported by Kerem et al,l especially in young children in whom pancreatic functional status (PI versus PS) may be evolving, and in CFPS patients with very low pancreatic functional reserve on quantitative secretory testing. Both our patients had a colipase secretory capacity sufficient to maintain normal digestion, but at the lower end of the

B-S, Rommens JM, Buchanan JA, et al. Identification of the cystic fibrosis gene: genetic analysis. Science 1989; 245: 1073-80. 2. Lands L, Zinman R, Wise M, Kopelman H. Pancreatic function testing in meconium disease in CF: two case reports. J Pediatr Gastroenterol Nutr 1988; 7: 276-79.

SIR,-Kerem et all provided strong evidence that pancreatic insufficiency (PI) in cystic fibrosis is attributable to the presence of two severe alleles of the gene, one being &Dgr;F 508&ogr; Pancreatic sufficiency (PS) was attributed to the presence of at least one mild allele, which was dominant over the severe ones. This hypothesis was derived from 39 PI and 21 PS north American patients, none of the PS subjects being homozygotes for the deletion. Dr Stuhrmann and colleagues (March 24, p 738), however, report 5 PS homozygotes for the severe &Dgr;F 508 in 357 PI and 30 PS patients of German and Czechoslovakian origin. They conclude, against Kerem and colleagues’ hypothesis, that homozygosity for the &Dgr;F 508 mutation does not necessarily indicate a severe disease, and that other environmental and/or genetic factors determine the clinical course of cystic fibrosis. We do not agree. We have investigated 70 PI and 48 PS Italian patients with cystic fibrosis (unpublished). Although the frequency of the &Dgr;F508 mutation is much lower in southern European populations than in the north American population,2 the analysis of &Dgr;F 508 genotypes showed that only PI patients carry two copies of the mutation (11 of 70). None of the 48 PS patients were homozygotes for the deletion, but always carried at least one mild unknown cystic fibrosis allele. Pancreatic function was assessed by exocrine secretion tests3 (duodenal output of enzymes and bicarbonate after hormonal stimulation, serum pancreatic enzyme concentration, faecal chymotrypsin concentration) and by intestinal digestion tests (faecal fats, fat balance). No patient aged under 2 years was investigated, and the pancreatic status of all patients, especially of the older subjects said to be PS, was checked because of the relation between age and pancreatic damage. Kerem et al’s hypothesis therefore holds for our Italian population sample, which included a larger number of PS patients than did Stuhrmann and colleagues’ sample. These conflicting data may be attributable to the difficulty in obtaining a correct assessment of pancreatic involvement in cystic fibrosis. Pancreatic damage in cystic fibrosis is age-related and young patients could be erroneously classified as PS if direct testing of pancreatic function is not done. This could also apply in older patients if their pancreatic status is not checked; in fact slight residual pancreatic function is sufficient to prevent fat maldigestion, and non-pancreatic factors may control the degree of steatorrhoea.4 Regional Cystic Fibrosis Centre, Ospedale Civile Maggiore, 37126 Verona, Italy

GRAZIELLA BORGO GIANNI MASTELLA

Institute of Biological Science, Facoltá di Medicina e Chirurgia, Verona

PAOLO GASPARINI PIER FRANCO PIGNATTI

B-S, Rommens JM, Buchanan JA, et al. Identification of the cystic fibrosis genetic analysis. Science 1989; 245: 1073-80. 2. Estivil X, Chillon M, Casals T, et al. &Dgr;F508 gene deletion in cystic fibrosis in southern Europe. Lancet 1989; ii: 1404. 3. Mastella G, Barbato G, Trabucchi C, et al. The exocrine pancreas in cystic fibrosis: functional studies in 169 patients and 118 controls. Ital J Paediatr 1975; 1: 1. Kerem

gene:

109-30.

PR, Forstner G. Pathophysiology of the J R Soc Med 1989; 82 (suppl 16): 1-10.

4. Dune

exocrine pancreas

m

cystic fibrosis.