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somatically damaging. The complaints recur or become chronicwhether treated by orthodox or alternative practitioners, althoughthe latter have a slight edge because they are sometimes betterlisteners.NHS money and time will continue to be wasted in unnecessary

investigation and referrals and much-needed relief will be denied tosufferers until some skills in the management of psychosomaticdisorders are incorporated into the mainstream of clinical medicine.Such patients constitute a large section of society and, quite rightly,they do not see themselves as neurotic or abnormal. However, theydiffer in being more "uptight" and in being unable to relax whenfaced with certain life situations. Much "syndrome shift" occursamong patients with these so-called common afflictions, and manywill have experienced three or four of them over a period of years.These shifts depend on differing life situations and the individual’slearned responses to them rather than on any basic change inhimself.Most patients these days are well informed and the group

mentioned is no exception. Only when they feel their doctor haslistened fully to them, examined them, and investigated them-sufficiently but not too much-are they able to accept the

probability of a link between their somatic complaints and theirvarious emotional tensions, and from that point develop sufficientself awareness to obtain relief.

J. W. PAULLEY

SiR,—Dr Todd rightly draws attention to the physicians’ diseasesof overinvestigation and overprescribing. However, he does notnote that the conditions are often caused by failure to take a goodhistory and do a proper physical examination. I have lately seen twopatients, chronic complainers, who improved strikingly within 48 hwhen given co-trimoxazole for their pyelonephritis-or was it thediscontinuation of the vast range of psychotropic agents (one patienthad been prescribed twenty)? A large range of psychotropic drugsand unnecessary investigations had preceded the taking of a mid-stream urine, since neither complained of dysuria, only of back painand vomiting.When the diagnosis is neurosis, psychotropic drugs are ineffective

(although they work well in depression) but the person still has adisease of the mind that it is reasonable for the doctor to treat or referto someone who can.As Balint pointed out the most potent drug a doctor can prescribe

is himself. The phrase "I can find nothing physically wrong withyou, please see me again if the trouble continues" will reassure theminor worrier, but deeper familial or social psychopathology isoften hard to unravel, if rewarding in the end. Given time andsympathetic attention the true cause of complaint is often revealed,and the patient is reassured without resort to benzodiazepines. Thedoctor’s reward is that they no longer darken the surgery door, and ifhe is not prepared to do the job a psychotherapist often can.The true Munchhausen will not respond to this. Obtaining

attention by faked illness has been too rewarding for too long, andthe good ones will easily pass the questioning Todd outlines.However, it may be in the interests of the NHS to study theseindividuals and try to find ways to treat the underlying psycho-pathology.

G. P. EDLIN

SIR,-A close relative of mine, who had a fixation on illness,similar to the patient Dr Todd describes, at the age of 7 watched theslow deterioration and then death of her mother from diabetes and

pulmonary tuberculosis. In a large family she probably experiencedemotional deprivation together with prolonged overexposure toillness, and may even then have begun to develop symptoms toobtain attention - a subconscious process later.

In my life as a surgeon I found six more chronic complainers, all ofwhom, around the age of 7, had watched the slow progressive illnessculminating in death in the family home, of a mother, father, orsibling (in one case a twin dying of tuberculous meningitis).

Such patients, with endless complaints and massive hospitalnotes, develop symptoms at different times, related to all systems ofthe body, and some GPs, in desperation, refer them to specialistdepartments of the local hospital. The patients then move on toother district or teaching hospitals, with or without referral by theGP. Such people have an insatiable appetite to absorb symptomsand signs from other patients which they project later on to

themselves.The mind grows in the manner of a tree, but a branch cannot be

cut out or a deformity corrected. I have found it useless to try tomake these people understand that they are in any way peculiar. Anemotional outburst results, with angry rejection of the consultant orhospital, and they move on to another specialist in their desperatesearch for sympathy and security.Recognition that such patients have experienced prolonged

overexposure to illness in their formative years makes case handlingeasier. It takes only a few minutes to give them the reassurance theycrave, to last a few weeks or months. Sometimes a very simple,inexpensive investigation in addition can act as a placebo.

T. P. N. JENKINS

INTERSTITIAL FIBROSIS IN RENAL ALLOGRAFTS INPATIENTS TREATED WITH CYCLOSPORIN

SiR.—Dr Klintmalm and colleagues (Oct 27, p 950) report a highincidence of interstitial fibrosis in renal allografts in patients treatedfor over 12 months with cyclosporin. We have described this form ofinterstitial fibrosis in five patients, 1,2 in all of whom fibrosis

developed within 3 months of transplantation.We now have serial renal biopsy data on forty-one patients

transplanted 1-4 years ago who were treated with cyclosporin,without maintenance corticosteroids. Cyclosporin was started at adaily-dose of 17 mg/kg body weight then tapering to 10 mg/kg by 7weeks. Eight patients had evidence of interstitial fibrosis in the first3 months, during a period of post-transplant oliguria of 30-82 days,which was thought to have been prolonged by the use of

cyclosporin. Six of these patients had had biopsy-proven episodes ofrejection before the development of fibrosis, and many had vascularchanges similar to those which have been attributed to cyclosporintoxicity.3 Seven patients had their treatment changed to

azathioprine because of prolonged oliguria or, in the latest threecases, when fibrosis was found at biopsy. These patients all had adiuresis within 48 h, and a gradual improvement in renal function.Five had good long-term renal function. Biopsy in two of thesecases, done 2 years after the change in therapy, showed a markedreduction in the fibrosis. The other patients lost their grafts becauseof acute cellular rejection.A further sixteen kidneys were found to have interstitial fibrosis;

five acquired it in 3-12 months and eleven in 12-24 months aftertransplantation. Five of these sixteen patients had their treatmentchanged to azathioprine because of persistent poor function onreduced cyclosporin dose and concern about the fibrotic changes.They all had immediate and sustained improvement in their renalfunction. Eight of the sixteen, with milder fibrotic change, hadimproved renal function after reductions of their cyclosporin dosage(4-9 mg/kg daily) and have stable renal function 6-24 months later.The other four patients, who were thought to have chronic

rejection, subsequently lost their grafts.We ascribed the interstitial fibrosis to the nephrotoxicity of

cyclosporin because of the immediate improvement in renalfunction when the drug was withdrawn.1,2 Also in many biopsyspecimens fibrosis surrounded every tubule, which suggested it wassecondary to a toxin such as cyclosporin rather than to rejection,where fibrosis tends to be patchy. Interstitial fibrosis with such adiffuse distribution was not found on renal biopsy of fortyazathioprine-treated patients. The finding of interstitial fibrosis inthe kidneys of heart transplant recipients supports the notion thatcyclosporin is the cause.5

5

The possibility that rejection contributes must also be considered.Many of our patients had had episodes of rejection before fibrosisdeveloped. Similar fibrosis between myocardial cells has been

1471

identified in cardiac allografts in patients treated with cyclosporinbut not with conventional immunosuppressants. Thus we cannotrule out the possibility that a subacute form of cellular rejectionwhich occurs with cyclosporin and not conventional

immunosuppression contributes to the fibrosis in both the cardiacand renal allografts.A relation between cyclosporin dose and fibrosis, suggested by

Klintmalm et al, must also be questionetl. Even though theydemonstrated a correlation between the degree of fibrosis andcyclosporin levels, none of their patients had trough plasma levelsgreater than 200 ng/ml. Although our patients were given 17 mg/kgdaily over the first month, no patient with fibrosis had a troughplasma cyclosporin level over 300 ng/ml. Furthermore the hearttransplant patients had their cyclosporin doses lowered if theirplasma levels were high. These .findings suggest that interstitialfibrosis can develop even if doses are adjusted to the Sandozrecommended therapeutic trough plasma range of 50-300 ng/ml.In our experience the identification of interstitial fibrosis in renal

transplants is not a harbinger of permanent renal impairment inevery patient. Interstitial fibrosis is a definite marker for

cyclosporin nephrotoxicity and indicates a need for reduction indosage or a change in therapy. 1,2

Royal Prince Alfred Hospital,Camperdown, NSW 2050, Australia

ANNABELLE FARNSWORTHBRUCE M. HALLGEOFFREY G. DUGGIN

JOHN S. HORVATHDAVID T. TILLER

1. Farnsworth A, Hall BM, Ng ABP, et al. Renal biopsy morphology in renal

transplantation. A comparative study of the light-microscopic appearances ofbiopsies from patients treated with cyclosporin A or azathioprine prednisone andantilymphocyte globulin Am J Surg Pathol 1984, 8: 243-52.

2. Farnsworth A, Hall BM, Kirwan P, et al Pathology in renal transplant patients treatedwith cyclosporin. Transplant Proc 1983; 15: 2852-54.

3. Shulman H, Striker G, Joachim Deeg H, et al. Nephrotoxicity of cyclosporin A afterallogenic bone marrow transplantation. N Engl J Med 1981; 23: 1392-95.

4. Bennett WM, Pulliam JP. Cyclosporin nephrotoxicity Ann Intern Med 1983; 99:801-04

5 Myers BD, Ross J, Newton L, Luetscher J, Perlroth M. Cyclosporin-associated chronicnephropathy. N Engl J Med 1984, 311: 699-704.

6. Oyer PE, Stinson EB, Jamieson SW, et al. One year experience with cyclosporin A inclinical heart transplantation. Heart Transplant 1982; 1: 285-90

RANITIDINE AND HEPATOTOXICITY

SIR,-Idiosyncratic liver injury is a rare but well-known side-effect of cimetidine.1 Ranitidine has been associated with a mildtoxic hepatitis resolving spontaneously despite continuation oftherapy or promptly on withdrawal of the drug.3-6 However, inpreviously reported cases of suspected ranitidine hepatotoxicity thepatients were anicteric and a liver-biopsy specimen showing slightmorphological changes was obtained in only two of these. We reporta case of histologically proven severe hepatotoxicity and jaundiceprobably induced by ranitidine.An 81-year-old man presented with melaena due to a prepyloric

ulcer, confirmed by endoscopy. He had been completely healthyapart from a duodenal ulcer 30 years previously and had taken nodrugs or alcohol. The patient received four transfusions of blood(healthy volunteer donors from the island of Funen) and treatmentwith ranitidine 150 mg twice daily was started before discharge. Hisliver function tests were completely normal. 6 weeks after dischargeendoscopy showed complete ulcer healing but the patient wasseverely jaundiced and was readmitted for full investigation. Hehad no other symptoms and was normal on physical examination.The alanine aminotransferase was 650 U/1 (normal 5-40 U/1),alkaline phosphatase 724 U/1 (normal 80-275 U/1), bilirubin271 mol/1 (normal <20 mol/1), and albumin 39 g/1 (normal 36-50g/1). The erythrocyte sedimentation rate" coagulation profile, andwhite-cell count remained normal. An abdominal ultrasoundexamination showed that the liver and biliary ducts were normal.Serological studies showed no evidence of hepatitis B infection andindicated only previous exposure to hepatitis A (IgG antibodies, butnot IgM-specific antibodies to hepatitis A). Assays for serumantinuclear antibody, mitochondrial antibody, smooth muscle

antibody, and cytomegalovirus antibody were negative. A

percutaneous liver biopsy of 15 mm showed severe inflammatory

changes with collagenous septa beginning to form after

pronounced centrilobular and bridging necrosis. In the parenchymathere was focal liver cell necrosis with some accumulation of

histiocytic elements and slight steatosis and cholestasis. No Mallorybodies or ground-glass hepatocytes were found. The portal tractsshowed some fibrosis, bileduct proliferation, and an infiltrate

consisting of lymphocytes, plasma cells, polymorphs, and

eosinophils. Ranitidine treatment was stopped. 4 weeks later theserum bilirubin was 79 mol/1, but the liver enzyme levels wereunchanged. However, during the next 4 weeks all laboratory valuesgradually returned to normal. We consider non-A, non-B viralhepatitis unlikely, and believe the liver injury was most probablycaused by a hypersensitivity-type reaction to ranitidine. A challengewith ranitidine was not considered justified.Although the overall frequency of ranitidine-induced liver injury

appears to be low, physicians should, as for cimetidine, be aware ofthe possible adverse effects of treatment on the liver.

Department of Medical Gastroenterology,Odense University Hospital,DK-5000 Odense C,Denmark

KARSTEN LAURITSENTROELS HAVELUND

J&Oslash;RGEN RASK-MADSEN

Department of Pathology,Odense University Hospital CLAUS FENGER

1 Freston JW. Cimetidine II. Adverse reactions and patterns of use Ann Intern Med

1982, 97: 728-342. Barr GD, Piper DW. Possible ranitidine hepatitis. Med J Aust 1981; ii: 4213 Proctor JD Hepatitis associated with ranitidine. JAMA 1984, 251: 15544 Offit K, Sojka DA. Ranitidine. N Engl J Med 1984; 310: 1603.5 Lima MAS. Hepatitis associated with ranitidine. Ann Intern Med 1984; 101: 207-08.6 Black M, Scott WE, Kanter R Possible ranitidine hepatotoxicity. Ann Intern Med

1984; 101: 208-10

FOOD-INDUCED DOSE DUMPING OF ONCE-A-DAYTHEOPHYLLINE

SIR,-An 11-year-old girl had been taking a slow-release

theophylline product (’Theo-Dur’) for several months at a total dailydose of 700 mg (28 mg/kg daily) as three doses every 8 h. On thisregimen she had no side-effects, and a serum concentration wasreported to be 16-4 4 glml. All doses were administered by hermother. Subsequently, the theophylline preparation was changed,for increased convenience, to a once-a-day product (’Theo-24’,’Pulmo-Timelets’). She took the same dose of 700 mg daily forseveral weeks at 0700 hours and ate breakfast at 0800 hours withoutill-effect. On the new regimen, a serum concentration of 17-3 3 /-Ig/mlwas reported. However, on April 22, 1984, she ate two bowls of’Cheerios’ cereal immediately after taking her theophylline doseand later that day had a headache and mild nausea. The nextmorning she ate some candy from her Easter basket within 15 minof her dose. Later that day she had a severe headache and projectilevomiting, and was taken to an emergency room. Her serumconcentration, l111z hours after the dose, was 41-7 7 /-Ig/ml (analysedtwice). She was admitted to intensive care and given intravenousanticonvulsants prophylactically and activated charcoal every 3 hto increase the rate of elimination of the drug. Symptoms oftheophylline toxicity disappeared about 6 h after admission.This pattern of change in theophylline concentration is consistent

with the results of a study in eight volunteers, where absorption wasslow and incomplete (71%) when the drug was taken fasting, buthalf the dose was dumped, beginning after 6-8 h when the dose wastaken with a bacon-and-eggs breakfast.2 The mechanism for the dose-dumping is likely to be the pH change in the duodenum that occursin response to food, since the coating on the beads rapidly dissolvesat pH 7-4.College of Pharmacy,University of Florida,Gainesville, Florida 32610, USA LESLIE HENDELES

Jacksonville, Florida PAUL WUBBENA

University of Iowa MILES WEINBERGER

1. Berlinger WG, Spector R, Goldberg MJ, Johnson GF, Quee CK, Berg MJ.Enhancement oftheophylline clearance by oral activated charcoal. Clin PharmacolTher 1983; 33: 351-54.

2 Vaughan L, Milavetz G, Hill M, Weinberger M, Hendeles L Food-induced dose-dumping of Theo-24, a "once-a-day" slow-release theophylline product Drug IntellClin Pharmacol 1984, 15: 510 (abstr).