535

tic 5-10 mm erythematous maculopapular lesions predomin-antly on the lower extremities and buttocks. Complete bloodcounts, serum creatinine, urea, and urinalysis were normal atthe start of each of the four cycles of chemotherapy (table).

2 months after day 1 of cycle 4, increased serum creatinine,urea, and bilirubin values and mean corpuscular volume wereobserved. Despite no further chemotherapy, when he was seen4 months after the start of cycle 4, macrocytosis, moderatelysevere ansemia, azotxmia, proteinuria, microhamaturia,pyuria, and severe hypertension had developed. No trans-fusions were given at any time during the patient’s illness. Thereticulocyte count was 4-9%, direct and indirect Coombs’

negative; serum folate and vitamin B12 normal; serum hapto-globin <35 (normal 60-170 mg/dl); red cell survival was short-ened to 21.5 days (normal 26-35). 10 months after the startof cycle 4, the anxmia had resolved; however, the patientremained hypertensive while on antihypertensives and,although improved, renal function remained abnormal (table).

Review of this case in light of the report of Jones et al.4 sug-gests that this patient may have also had a drug induced vascu-litis initially manifest by a rash predominantly involving thelower extremities, and followed by nephritis and haemolysis.Physicians treating patients with long-term chemotherapyregimens containing 5-fluorouracil and mitomycin-C should bealerted to the possibility of microangiopathic hamiolyticanaemia and urxmia which may become clinically apparentmonths after cessation of chemotherapy and may present as apruritic erythematous maculopapular rash. We believe thatchemotherapy should be discontinued at the first sign of a rashsuggestive of vasculitis, and agree with Jones et al. that ther-apy should also be terminated at the first sign of haemolysis,persistent proteinuria, and/or rising serum urea levels.

Incidentally the dose of mitomycin-C tabulated by Jones etal. seems to be an error since the figure is one thousand timestoo high and likely to result in fatal toxicity.

Department of Internal Medicine,Gastroenterology Section,M. D. Anderson Hospital

and Tumor Institute,Houston, Texas 77030, U.S.A.

DAVID A. KARLIN

JOHN R. STROEHLEIN

PRIMARY BILIARY CIRRHOSIS IS A DRY-GLANDSYNDROME

SIR,-The time-scale is all-important in distinguishingbetween primary biliary cirrhosis (PBC) and graft-versus-host(GVH) disease. Although Epstein and his colleagues’showed that the .two diseases have clinical and immune fea-tures in common, they evolve quite differently.

Transplantation is an acute event, in which a whole lifetimeof immune experience is crammed into a few months.2 PBC isthe end-result of an immune process, starting many years ear-

1. Epstein O, Thomas HC, Sherlock S. Primary biliary cirrhosis is a dry-glandsyndrome with features of graft-versus-host disease. Lancet 1980; i: 1166.

2. MacGregor GA. Aetiology of Burkitt’s lymphoma. Lancet 1973; i: 200.

lier3 and continuing by the induction of more immunity. Atfirst there are granulomas in the liver and elsewhere, and thesesooner or later resolve. The secondary "autoimmune" re-

sponse, which damages the bile canaliculi, appears later. Butwhy does the abnormal immunity continue, when in most casesof sarcoidosis, for instance, it regresses within ten years? Doesit persist because the response becomes autoimmune, or

because the sarcoid agent4 remains active in these rare cases?Pregnancy may be one reason why PBC is progressive. 92%

of patients are women and most of these have had children.The homonal changes in pregnancy may retard the healing ofpre-existing granulomas in the liver, and the inflammation islikely to be more aggressive post partum if healing wasdelayed. For example, a woman after being delivered, devel-oped arthralgia and erythema nodosum with sarcoid granu-lomas in her legs.5 The fall in her cortisone and oestrogen levelsmay have accentuated her immune response.

Rarely, sarcoidosis remains active for as long as 20 years. Ifit resolves incompletely the changes in the liver may becomeautoimmune. Granulomas in the thyroid gland may similarlytransform later into chronic thyroiditis. It is likely that PBCand sarcoidosis are one and the same.6 They share environ-mental factors and both are familial. Their blood contains cir-

culating immune complexes (which, however, disappear beforesarcoidosis heals). Both are associated with autoimmune dis-orders, such as thyroiditis,’ coeliac disease,8 hypercalcaemia,and Addison’s disease 79 and both may have the rheumatoidfactor. Salivary-gland involvement is probably as common insarcoidosis as in PBC. Neither condition is associated with anyspecific HLA-type, but the HL A1/B8 genotype is more com-mon in sarcoidosis with erythema nodosum and in PBC withscleroderma. The immune response is often particularly activein black patients with sarcoidosis. Five black men with histolo-gical evidence of PBC had no antimitochondrial antibodies intheir sera. 10 Absence of this humoral response was possibly dueto the acceleration in their cellular immunity. The cause ofPBC may be an infection," and if so, it is probably the trans-missible sarcoid agent.’St. Luke’s Hospital,Guildford, Surrey GU1 3NT GERALD A. MACGREGOR

3. Fox RA, Scheuer PJ, Sherlock S. Asymptomatic primary biliary cirrhosis.Gut 1973; 14: 444-47.

4. Mitchell DN, Rees RJ, Goswami KK. Transmissible agents from human sar-coid and Crohn’s disease tissues. Lancet 1976; ii: 761-65.

5. Ford FD. Puerperal erythema nodosum. Br Med J 1960; i: 400-01.6. MacGregor GA. Sarcoidosis and primary biliary cirrhosis. Lancet 1969; ii:

698.7. Sherlock S. 100 patients with primary biliary cirrhosis. New Engl J Med

1973; 280: 674-78.8. Logan RF, Ferguson A, Finlayson ND, Weir DG. Primary biliary cirrhosis

and coeliac disease. Lancet 1978; i: 230-33.9. MacGregor GA. Calcium metabolism in normocalc&aelig;mic sarcoidosis. Br Med

J 1977; i: 233.10. Rudzki C, Ishak KG, Zimmerman HJ. Chronic intrahepatic cholestasis of

sarcoidosis. Am J Med 1975; 59: 373-87.11. Hamlyn AN. Is primary biliary cirrhosis an immune complex disease? Lancet

1978; i: 149.