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REFERENCES

1. Ford, P. M. Clin. exp. Immun. 1973, 14, 569.2. Miller, M., Dalakos, T., Moses, A. M., Fellerman, H., Streeten,

D. H. P. Ann. intern. Med. 1970, 73, 721.3. Morris, R. C., Fudenberg, H. H. Medicine, Baltimore, 1967, 46, 57.4. Wilson, I. D., Williams, R. C., Tobian, L. Am.J. Med. 1967, 43, 356.5. McCurdy, D. K., Cornwell, G. G., DePratti, V. J. Ann. intern. Med.

1967, 67, 110.6. Thalal, N., Zisman, E., Schur, P. H. Arthritis Rheum. 1968, 11, 774.7. Mason, A. M. S., McIllmurray, M. B., Golding, P. L., Hughes,

D. T. D. Br. med. J. 1970, iv, 596.8. Mason, A. M. S., Golding, P. L. ibid. 1970, iii, 143.

per hour), and the absorption of vitamin-B12 was impairedowing to intrinsic-factor deficiency (urinary excretion of1-0 g. dose was 4-0% when given alone and 39% whenrepeated with intrinsic factor).The serum contained antibodies against gastric parietal

cells and intrinsic factor, but was negative against thyroid,mitochondria, smooth muscle, and cell nuclei. The

patient responded well to vitamin-Biz therapy, haemo-

globin reaching 14-6 g. per 100 ml. and M.c.v. decliningto 8 3 fl.A fluorescent-labelled-antiglobulin technique with the

patient’s serum as a positive parietal-cell-antibody controlshowed a positive immunofluorescence of cells in the loopof Henle of rat kidney but only a weak reaction withhuman kidney. There were no mitochondrial antibodies.In view of these findings the patient was readmitted forrenal function tests 22 months after her first admission.

Second Admission

On readmission there were no abnormal findings. Urinewas normal, containing no protein, aminoacids, sugar,leucocytes, or organisms.

Total serum-protein concentration was 6-5 (albumin 4-1,globulin 2-4) g. per 100 ml. Immunoglobulin levelswere IgG 780, IgA 20, and IgM 114 mg. per 100 ml.

Blood-urea was 2-5 mmol. per litre, serum-creatinine67 limol. per litre, and 24-hour urinary creatinine 10-9mmol. Creatinine clearance was 143 inl. per minute.

There was no glycosuria after 50 g. of glucose orally.Following an intravenous injection of 1311-labelled hippurinthere was normal renal plasma-flow of 520 ml. per minute.Glomerular filtration-rate, measured with 5lCr-labelledethylene-diamine tetra-acetic acid (E.D.T.A.), was 173 ml.

per minute. There was no nephrocalcinosis or hyper-calciuria.The capacity of the kidney to concentrate urine after

10 hours of dehydration 2 was normal: urine osmolalitywas 749 mosmols per kg. at 7 hours, 970 at 8 hours, 843at 9 hours, and 926 at 10 hours. Serum osmolality at10 hours was 284 mosmols per kg.Urinary acidification after an oral ammonium-chloride

load (100 mg. per kg. body-weight) was tested. The pHof the urine in the 10 hours after the load was 6-63,6-33, 6-74, 6-67, 6-05, 6-12, 6-11, 6-22, 6-00, 6-22, and6-03-that is, she failed to acidify her urine adequately.A further serum sample for antibodies, taken while the

patient was in hospital, confirmed the presence of parietal-cell, intrinsic-factor, and loop-of-Henle antibodies butin addition showed the presence of non-organ-specificmitochondrial antibodies. Liver-function tests, which hadpreviously been normal, now showed elevated aspartate-transaminase (44 i.u. per litre). Alkaline-phosphatase(16-0 K.A. units per 100 ml.) and bilirubin levels (5 limol.per litre) were normal. ,

SECOND CASE

A woman, aged 42, presented to the surgical outpatientclinic with an enlarged thyroid gland. This was a benignnon-toxic goitre. In addition, she had an iron-deficiencyanxmia probably due to menorrhagia. The only otherabnormal findings were antibodies to gastric parietal cellsand the loop of Henle. Renal function, including abilityto acidify urine, was normal.

Discussion

The association of defective urinary acidificationwith antibodies to the cells of the loop of Henle

suggests a possible autoimmune pathogenesis fordistal tubular dysfunction. There is other evidenceindicating the probable autoimmune nature of at leastone form of renal tubular acidosis. Thus these

patients often have raised y-globulin levels.3-7 Theymay have autoantibodies to thyroid, lungs, liver,salivary glands, and synovial tissue.5-7 The conditionis associated with other autoimmune disorders suchas fibrosing alveolitis, primary biliary cirrhosis, thyroiddisease, and Sjogren’s syndromesThe first of the present two patients has pernicious

ana:mia with antibodies to gastric parietal cells andintrinsic factor, renal tubular acidosis with antibodiesto the loop of Henle, and abnormal liver-functiontests with mitochondrial antibodies compatible withprimary biliary cirrhosis. The second patient hadparietal-cell and loop-of-Henle antibodies associatedwith a goitre and iron-deficiency anxmia, but at

present has normal renal function.

Although we have only one example of loop-of-Henle antibodies and renal tubular acidosis, this

antibody should be sought in all patients with thisrenal defect.

HYPOSPLENISM IN ULCERATIVE COLITIS

F. P. RYANF. E. PRESTON

R. C. SMARTC. D. HOLDSWORTH

Departments of Medicine, Medical Physics, andHœmatology, Royal Infirmary, Sheffield S6 3DA

Summary Hyposplenism was demonstrated inthree patients with ulcerative colitis.

This association has not been reported before. Itseems likely that the hyposplenism developed duringthe course of the illness.

Introduction

REMOVAL of the spleen in man results in an

abnormal blood-film characterised by Howell-Jollybodies and target cells 1 Similar morphologicalchanges were found in the blood of patients withadult coeliac disease-in five out of eighteen patientsin one series and five out of twenty-five in another.3By measuring the rate of clearance of 5lCr-labelledheat-damaged red blood-cells from the circulation,pronounced hyposplenism in patients with adultcoeliac disease and Howell-Jolly bodies in their blood-film was confirmed.2 In the same series lesser degreesof hyposplenism were found by this test in fourteenout of eighteen patients with adult cceliac disease.

Hyposplenism was also found in patients with der-matitis herpetiformis,4 a condition which shares manyother features with adult coeliac disease. It has notbeen reported in other gastrointestinal conditions.The finding of Howell-Jolly bodies in the blood-

film of a patient with ulcerative colitis prompted us

319

to examine more carefully the blood-films of patientswith ulcerative colitis.

Method

Peripheral-blood-films were stained by the Leishmanmethod and examined for Howell-Jolly bodies and targetcells. The clearance of 5lCr-labelled heat-damaged redblood-cells was measured by a method slightly modifiedfrom that of Marsh et a1.5

Autologous red blood-cells were labelled with 150 ,uCiof 5’Cr and damaged by heating for 30 minutes at 49-5 ±0’5°C. The labelled cells were reinjected and blood-samples were taken at 2-5, 5, 10, 20, 30, 45, and 60minutes, with an extra sample at 2 to 3 hours in some

patients. The cells were then haemolysed by the additionof saponin and the radioactivity counted in an automaticwell-scintillation counter. The results were fitted by a

computer to a double exponential function using a functionminimisation program of Powell 6 and the clearance half-time (Tt) and its 95% confidence limits determined.The radioactivity over the liver and spleen was continu-ously recorded for hour after injection by placing twocollimated scintillation counters over these organs.Ten normal people were tested as controls.

Results

On retrospective examination of their records, allthree patients were reported as having normal blood-films when they first presented with colitis. Each

patient had a minimum of 5 normal films during thecourse of the colitis before Howell-Jolly bodies

appeared. No patient had had abdominal surgery.It seems that hyposplenism developed in each patientduring the course of his colitis.

Clinical Details and HaematologyCase Loin case 1 ulcerative colitis developed at the

age of 28, with total colonic involvement radiologically.Initially he was treated with sulphasalazine, but the drugcaused nausea and was discontinued after 4 months. Afterthis, continuous systemic steroid therapy was required tocontrol his symptoms, and he relapsed if such treatmentwas discontinued. In addition he took regular prednisoloneenemas. He required inpatient therapy on four occasionsover 4 years. Howell-Jolly bodies were first noticed onthe third admission during a relapse 3 years after theonset of colitis. This abnormal blood-film has persistedsince. Panproctocolectomy was carried out 4 years afterthe onset of symptoms and pronounced splenic atrophywas found at surgery, the spleen measuring 5 X 2 cm.

Case 2.-In case 2 ulcerative colitis developed at the

age of 65 years, with severe changes of deep and extensiveulceration from mid-transverse colon to rectum demon-strated on barium enema. He was controlled with sulpha-salazine and prednisolone enemas for the first year of hisillness, and then went into symptomatic remission for 2years, when he took no regular therapy. 3 years afterthe onset he was readmitted to hospital in severe relapserequiring corticotrophin and sulphasalazine. During thisadmission a severe Heinz-body haemolytic ansemia was

caused by the sulphasalazine. Howell-Jolly bodies werefirst noticed during this episode, but they persisted in hisblood-film after full recovery from the haemolysis.Parenteral steroids brought an initial improvement buthis colon became perforated and he had an emergencyhemicolectomy. The spleen was not measured. He died3 days later after 2 days of hypotension, probably due tooverwhelming infection. Permission for necropsy wasrefused.

Case 3.-In case 3 ulcerative colitis developed at the

CLEARANCE OF 6lCf-LABELLED HEAT-DAMAGED RED BLOOD-CELLS

*T! is the half clearance time from the circulation.

age of 52 years, with total colitis indicated by bariumenema. He had taken sulphasalazine continuously for 16years and had had mild chronic symptoms during thistime. He had been treated as an outpatient. Operation

had been advised because of the chronicity, but the patienthad refused. 16 years after the onset he required admissionto hospital with an exacerbation of his colitis, and Howell-Jolly bodies were then first noticed in his film. His con-dition improved after treatment with steroids, blood-transfusion, and a total-dose infusion of iron dextran.He is now attending as an outpatient, taking sulphasalazineonly, and has mild chronic symptoms. His blood-filmhas persistently shown Howell-Jolly bodies since they werefirst noted.

Heat-damaged Red-blood-cell Clearance StudiesThe results in the three patients and ten controls

are summarised in the accompanying table. The

range for the controls of 9 to 17.5 minutes accordswell with that of 10 to 16 minutes reported by Marshet a1.5 Each patient had severe splenic hypofunctionby this test and there was no uptake measurable overthe spleen in any patient, confirming that the spleenwas not clearing the damaged red blood-cells fromthe circulation.

Discussion

Hyposplenism has not been previously reported inulcerative colitis, but there is no doubt about its

presence in the three patients described. In each

patient a blood-film characteristic of hyposplenismwas accompanied by isotopic evidence of severe

splenic hypofunction. In the one patient whosespleen was measured there was pronounced splenicatrophy. It is tempting to compare these results withthose reported in a series of patients with adultcoeliac disease in whom, although Howell-Jolly bodieswere only found in five out of eighteen patients,2some degree of splenic hypofunction was much morecommon. We have found only three patients withHowell-Jolly bodies on inspection of the blood-filmsof over fifty patients with ulcerative colitis, but thepreliminary results of a systematic study of splenicfunction which we have undertaken in twenty-sevenof these patients indicate that some degree of splenichypofunction is common in such patients.Hyposplenism probably developed during the

course of the colitis, but its cause is not clear. In

patients with sickle-cell disease and with hyper-coagulable states, such as thrombocythaemia, recurrentsplenic infarction is probably responsible for hypo-splenism, but there is no reason to suspect this inour patients. Prolonged folate deficiency, suggestedby McCarthy et a13 as the cause of splenic atrophyin adult coeliac disease, is equally unlikely. General-ised lymphoreticular atrophy has been demonstrated

320

by the same workers together with hyposplenism inadult coeliac disease and may also occur in. colitis.It may be significant that all three of our patientshad relatively severe disease, two coming to colectomy,and this procedure having been advised in the third.The clinical importance of hyposplenism in these

patients cannot be assessed from our small study. Inchildren loss of the spleen increases the risk of severebacterial infection 7,8 and, although less well estab-

lished, this is probably also true for adults 9n° Oneof our patients died from probable bacteraemic shockafter perforation of the colon, but the other twodemonstrated no evidence of increased susceptibilityto infection.As in adult coeliac disease, the cause and importance

of hyposplenism in ulcerative colitis are thereforeunknown. The systematic study which we are under-taking will help to determine the frequency and

importance of hyposplenism in ulcerative colitis.

Hypothesis

RENAL ABNORMALITY OF ESSENTIAL

HYPERTENSION

J. J. BROWN A. F. LEVER

J. I. S. ROBERTSON

Medical Research Council Blood Pressure Unit,Western Infirmary, Glasgow G11 6NT

M. A. SCHALEKAMP

Department of Internal Medicine, Zuiderziekenhuis,Rotterdam 24, Netherlands

Summary Although homœostatic mechanismsrelate sodium balance, renin, and

arterial pressure, the reduction of renin sometimesseen in essential hypertension cannot be attributedto abnormal sodium retention. It is proposed insteadthat renin decreases and sodium status remains nor-mal because the pressure-natriuretic mechanismwithin the kidney is reset by increased filtrationfraction. Neurogenic factors may raise blood-pressureand cause resetting by some other means at an early(labile) stage of essential hypertension, but, once filtra-tion fraction is raised and remains elevated on with-drawal of the neurogenic component, essential hyper-tension will have a renal cause. A similar mechanism

may account for the failure of secondary hypertensionto fall when its cause is removed.

INTRODUCTION

A PROPORTION of patients with essential hyper-tension have reduced plasma-renin (low-reninhypertension). Because renin, sodium balance, andarterial pressure interact in other circumstances, itis widely believed that low-renin hypertension resultsfrom abnormal sodium retention (see Dunn and

Tannen 1). We and our colleagues 2,3 have found nobasis for this belief; exchangeable sodium, plasmavolume, and extracellular-fluid volume are normalin low-renin hypertension.We present here an alternative explanation for the

R. C. S. acknowledges the support of the Trent RegionalHealth Authority.

Requests for reprints should be addressed to C. D. H.,Clinical Research Institute, Royal Infirmary, Sheffield S6 3DA.

REFERENCES

1. Singer, K., Miller, E. B., Damashek, W. Am.J. med. Sci. 1941, 202,171.

2. Marsh, G. W., Stewart, J. S. Br. J. Hæmat. 1970, 19, 445.3. McCarthy, C. F., Fraser, I. D., Evans, K. T., Read, A. E. Gut,

1966, 7, 140.4. Pettit, J. E., Hoffbrand, A. V., Seah, P. P., Fry, L. Br. med. J.

1972, ii, 438.5. Marsh, G. W., Lewis, S. M., Szur, L. Br. J. Hœmat. 1966, 12, 161.6. Powell, M. J. D. Computer J. 1964, 7, 155.7. Eraklis, A. J., Kevy, S. V., Diamond, L. K., Gross, R. E. New

Engl. J. Med. 1967, 276, 1225.8. Ellis, E. F., Smith, R. T. Pediatrics, Springfield, 1966, 37, 111.9. Lowdon, A. G. R., Stewart, R. H. M., Walker, W. Br. med. J.

1966, i, 446.10. Whitaker, A. N. Med. J. Aust. 1969, 24, 1213.

normality of sodium status, decrease of renin, and therise of blood-pressure. The hypothesis derives froma known abnormality of renal function in essentialhypertension.4

OUTLINE

Normally a rise of arterial pressure leads to a promptincrease in the urinary excretion of sodium andwater.5-7 Because sodium and volume status are nor-mal in essential hypertension,2,3 the relation of pressureand sodium excretion is shifted to the right (fig. 1)and pressure-natriuresis is " reset ".8-11We propose that pressure-natriuresis results from

a reduction of tubular sodium reabsorption caused bytransmission of increased hydrostatic pressure fromthe renal artery into the peritubular capillary circula-tion (fig. 2A). Dilatation of precapillary vessels with-out change of arterial pressure would have the sameeffect.

For the resetting process in essential hypertensionwe suggest that increased resistance of preglomerularand postglomerular vessels in the presence of hyper-tension leads to increased filtration fraction (fig. 2B)and that this raises the oncotic pressure of plasma inthe peritubular capillaries, thereby enhancing sodium

Fig. 1-Resetting of pressure-natriuresis in hypertension.Derived from observations and views of Selkurt et a)./

Thompson and Dickinson,8 and Guyton et al. 9