937

Letters

to

hepatitis-like illness, and most of these cases have been during the past 4 or 5 years despite the fact that most of these hasmophiliacs have been receiving factor-viu-replacement therapy

the Editor

LIVER DISEASE IN HÆMOPHILIACS p.

SiR,—The article by Dr Preston and colleagues (Sept. 16, 592) was of great interest to us. Their patient population

differ from the haemophiliacs we studied’ in that a greater percentage of Preston’s patients have persistently abnormal S.G.P.T.s and the values are higher; none of our patients had an abnormal bilirubin; and our patients were younger. However, the demonstration of abnormal hepatic morphology in four of eight individuals confirms our finding of serious chronic liver disease in several symptom-free hxmophiliac patients treated with multidonor products. The main question is whether these findings represent an increase in the incidence of chronic liver disease in haemophiliacs resulting from the use, since the late 1960s, of fraction concentrates to treat bleeding episodes. While there are adequate data to confirm that there was an initial increase in the incidence of acute hepatitis,2 little information is available concerning liver function tests (L.F.T.) before the large-scale use of pooled products. Preston et al. cite two papers as providing such infortion. The first is a publication from this centre in 1970.2 In fact, that article related only to hepatitis B viral markers and did not include L.F.T. data. Furthermore, the 11.7% figure cited probably arose from a later publication3 addressed at the incidence of icteric hepatitis and not asymptomatic L.F.T. abnormalities. Nor can we find L.F.T. results in the paper by Biggs4 which Preston et al. cite as reporting a 3-8% frequency of abnormal L.F.T.: the frequency referred to seems to be for acute hepatitis rather than chronic L.F.T. abnormalities. If such early L.F.T. data exist they are very important. We are all faced with the decision whether to use corticosteroid therapy to treat haemophiliacs with asymptomatic chronic active hepatitis. Unfortunately, the natural course of the disease in symptom-free individuals will probably not be known for some time. Among our patients none has symptomatic, end-stage liver disease. If we knew that haemophiliacs had a similar incidence of chronic L.F.T. abnormalities as they did a decade ago, we would probably be justified in witholding a potentially dangerous therapy with corticosteroids and keeping the patients under observation. On the other hand, if the present situation has developed subsequent to the use of pooled products, a stronger argument could be made for steroid therapy, based upon the known poor outlook for untreated chronic active hepatitis in patients with symptoms. One possibility in the absence of such information, is the setting-up of a long-term, multicentre, controlled study of the use of steroid therapy in symptom-free haemophiliacs with chronic active seems to

hepatitis. JOEL JOEL A. SPERO H. LEWIS

Central Blood Bank of Pittsburgh and Department of Medicine, Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15219, U.S.A.

Umverslty of Pitts burgh School of Medicine, ***This letter has been shown whose reply follows.-ED.L.

to

JESSICA

S

tj Br H. VAN T THIEL UAV!DM.VAN DAVID UTE HASIBA

Dr Preston and his

colleagues,

SIR,-Dr Spero and his colleagues rightly draw attention

to

the fact that published data suggest a recent increase in the incidence of hepatitis in haemophiliacs rather than an increase in abnormality in liver-function tests. We apologise for this mistake. As we stated, 50% of our haemophiliacs have experienced a 1. Spero, J. A., Lewis, J. H., Van Thiel, D. H., Hasiba, U., Rabin, B. S. New Eng. J. Med. 1978, 298, 1373. 2. Lewis, J. H. Vox Sang. 1970, 19, 406. 3. Lewis, J. H., Maxwell, N. G., Brandon, J. M. Transfusion, 1974, 14, 203. 4. Biggs, R. Br J. Hæmat. 1974, 26, 313.

for many years. The fact that many haemophiliacs may have had abnormal liver-function for a long time may be of interest but is itself not essential since an abnormal liver-function test per se has no diagnostic or prognostic significance. We used liver-function tests merely as a screening device to select patients for liver biopsy. We tried to distinguish between patients with chronic persistent hepatitis-which is generally thought to be a benign lesion-and chronic aggressive hepatitis, which is more likely to be a progressive lesion in which steroids may play a role. Our experience suggests that these two lesions cannot be distinguished by clinical or biochemical means, and histology is needed. We agree that the natural history of chronic aggressive hepatitis in symptom-free haemophiliacs is unknown but experience in non-haemophiliacs suggests that this lesion, as we have defined it, is usually progressive. Although we are now trying corticosteroids in our patients with chronic aggressive hepatitis, we welcome the suggestion of a multicentre trial in symptom-free haemophiliacs. Because of the complexity of the hepatic lesions, however, such a study would require careful planning and would need to be based on histological rather than biochemical criteria of liver disease. Department of Haematology,

Royal Infirmary, Sheffield S6 3DA

F. E. PRESTON D. R. TRIGER J. C. E. UNDERWOOD

PROSTAGLANDINS IN PATENT DUCTUS ARTERIOSUS

SIR,-Patent ductus arteriosus (P.D.A.) is

a

significant

con-

of morbidity and mortality in preterm infants. We have identified abnormal plasma levels of prostaglandins in this condition’-in particular, a substantial increase in prostaglandin E (p.G.E), a prostaglandin which exerts a dilator ininfluence on the ductus.2 It remained to be established, however, whether increased p.G.E levels and the development of clinical signs ofp.D.A. are causally related. We have now made serial measurements, of plasma P.G.E and p.G.F in two pre-term infants, born at 30 weeks gestation, who had clinical and radiological signs of P.D.A. with cardiac failure due to a large left-to-right shunt, indicated by tachycardia, systolic murmur, collapsing pulses, and, on X-ray, cardiomegaly and pulmonary plethora. In both cases classical hyaline-membrane disease had been diagnosed, and the infants required assisted ventilation and added inspired oxygen during the study period. Blood sampling and assay techniques were those described previously.3.4 In both infants plasma p.G.E concentration rose above normal4 before development of significant clinical evidence of shunting through a P.D.A. (figure). Moreover, the normal E:F ratio4 was reversed, p.G.E concentrations exceeding those of p.G.F. In case 1, resolution was achieved by fluid restriction and diuretics; in case 2 surgical ligation of the ductus was required. The disappearance of physical signs of P.D.A. was accompanied by a gradual return of P.G.E towards normal and progressive reduction of the E:F ratio. In hyaline-membrane disease P.G.F is raised,5.6 as in our two patients, and its descent towards normal parallels clinical recovery from respiratory disease. However, we have not found p.G.E to be increased in hyaline-membrane disease, un-

tributing

cause

‘

1. Lucas, A., Mitchell, M. D. Lancet, 1978, ii, 130. 2. Elliott, R. B., Starling, M. B., Neutz, J. M. ibid. 1975, i, 140. 3. Mitchell, M. D., and others. J. clin. Endocr. Metab. 1978, 46, 947. 4. Mitchell, M. D., and others. Prostaglandins, 1978, 16, 319. 5. Mitchell, M. D., and others. Prostaglandins Med. 1978, 1, 207. 6. Friedman, Z., Demers, L. Pediatrics, 1978, 61, 341.

938

A.M.S. DURING EVEREST TREKS

1975

I

AND

1977

I

N.s.=Not significant.

Prostaglandins in P.D.A. Case 1 (left) birthweight

1600 g;

case

2

(right) birthweight

1230 g.

P.D.A., and the E:F ratio remains below unity.5 In these two cases, the temporal relationship between P.G.E increase and the development of cardiac failure due to P.D.A. is further evidence that a rise in plasma-P.G.E may cause increased shunting through the ductus. The tissue source of the raised plasma-P.G.E found in P.D.A. remains to be established, and the pathophysiological events which trigger P.G.E release need to be defined. The identification of such a trigger mechanism might suggest prophylactic measures in this important neonatal condition.

complicated by

We thank Prof. A. C. Turnbull for the

use

University Department of Pædiatrics, John Radcliffe Hospital, Department University of Oxford

of Obstetrics and

departmental

facili-

A. LUCAS

Oxford OX3 9DU Nuffield

of

Gynæcology, M. D. MITCHELL

AVOIDING MOUNTAIN SICKNESS

SIR,-Acute mountain sickness (A.M.S.) is always unpleasant

and

can

be fatal. It is common, and its incidence and

directly correlated with speed of ascent and exertion and inversely correlated with age.’ It can be largely prevented by slow ascent. Two years after our 1975 study in the Himalayas,2we looked at the effect of preventive measures. We used questionnaires identical to those used in 1975 and the same criteria for diagnosing and scoring A.M.S. according to symptoms and signs. We noted the incidence and severity of A.M.S. in a similar group of hikers, who were not taking diuretics, as they passed through the same village, Pheriche, Nepal (4243 m), on their walk up to view Mount Everest (8848 m) severity

are

from around 5400 m. Preventive measures adopted since the 1975 study on A.M.S.2 included widespread dissemination of recommendations at seminars on mountain medicine and in mountaineering journals in the United States, Canada, and the U.K. Written recommendations were given to clients by the more responsible trekking companies, and, in Nepal, posters and pamphlets in English, German, and French were placed in Kathmandu, at airstrips, and in all the villages in the area. Information was also available from members of the Himalayan Rescue Association staff at Pheriche. Hikers were advised to spend two consecutive nights at the same altitude twice during the ascent from 2800 m to 5400 m and to keep up their fluid intake to maintain a copious urinary output. The early symptoms and signs of A.M.S. were detailed and the tourists were encouraged to look for these in themselves and their companions and to 1. 2.

Rennie, D. Lancet, 1976, ii, 1177. Hackett, P. H., Rennie, D., Levine, H. D. ibid. 1976, ii, 1150.

stop the ascent and rest or descend if any were present. Diuretics were not recommended for prophylaxis. Non-parametric statistical tests were used for comparison of the 1975 and 1977 groups.2 Both groups were similar in age and sex distribution (see table). Despite the fact that a higher proportion of people flew to 2800 m in 1977, the frequency of A.M.S. was lower that year, though of those who flew 49% had A.M.S. compared with 31% of those who walked in from Kathmandu. The lower frequency of A.M.S. in 1977 is even more striking when the 1977 group is compared with the 159 controls from 1975, of whom 69% hadA.M.S. (p