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AN INQUIRY INTO THE RESULTS OF THE

LIVER TREATMENT OF PERNICIOUS ANÆMIA.

TWENTY-ONE CASES 1 TREATED AT

ST. BARTHOLOMEW’S HOSPITAL, LONDON.

Reported by Prof. F. R. FRASER, M.D., F.R.C.P.,DIRECTOR OF THE MEDICAL PROFESSORIAL CLINIC.

IN a preliminary report by the Medical Research Council published a few weeks ago (THE LANCET,March 10th, p. 514) it was stated that the treatment of pernicious anaemia by addition of liver to thediet, introduced in America by Minot and Murphy, has already been widely adopted with encouragingresults. In order to ascertain the nature of these results we asked a representative group of cliniciansto send us a schedule of cases showing the proportion of successes and failures, and to supply informationon the following points :-

1. The dose of whole liver employed.2. The efficiency of the liver extracts tested.

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3. The nature of any other treatment given simultaneously.4. Whether the cases which failed to respond were proven cases of pernicious anaemia

as judged by (a) history of previous relapse, (b) typical blood picture, (c) achlorhydria.5. If any cases of subacute combined degeneration (S.C.D.) were tested and with

’ what result.6. Any experience of liver treatment in cases of (a) secondary anaemia, (b) aplastic

anaemia.7. If any evidence was obtained of the disappearance of achlorhydria under treatment.

The replies, along with a number of interesting comments, are here set out.

Notes to Schedule.One case put on liver during remission produced

by arsenic kept well for four months, but subse-quently died of an intercurrent appendicitis withgeneral peritonitis.One case responded with a rise in reticulated red

-cells following whole liver administration, but owingto onset of severe heart failure treatment was

- abandoned. This patient is now dead.The three cases treated with liver extract were

,afterwards given liver diet following the productionof reticulocyte crisis by the extract used.

One of the cases which failed to respond had liver- extract as well as whole liver. -

Replies to Questions.Dose of Whole Liver.-Half a pound daily, either

lightly cooked or raw in form of pulp, reduced when:red blood cells reach a normal figure.

Extracts Tested.-(a) Eli Lilly and Co. ; (b) MedicalResearch Council. Both were efficient in a doseequivalent to 500 g. whole liver daily.

Simultaneous Treatment.-Of the (ten) cases which-came under observation in the stage of relapse orbefore the first remission, all had hydrochloric acid.after the immediate effects of liver were observed.The remainder comprise cases in which liver wasadded to pre-existing therapy-hydrochloric acid,or arsenic, or both-the patients being in a remission.’The value of these is that they have remained well.since the addition of liver, the longest interval nowof this series being 12 months. Five have red- cell counts of over 5,000,000, two of over 4,000,000,,and one of 3,500,000.

Failure to Respond.-In neither of the two caseswhich failed to respond was there a history of aprevious relapse. In both the blood picture was

1 These eases were reported in greater detail in the Brit.Med. Jour., Feb. 4th, 1928, p. 165.

compatible with a diagnosis of pernicious anaemia,and both showed achlorhydria with a low total chloridecontent in a fractional test-meal. A point of simi-larity in these two cases is the fact that in each theanaemia followed an acute respiratory infection;neither showed any signs of subacute combineddegeneration. The autopsy findings on one were,except for the absence of any degenerative changesin the nervous system, compatible with a diagnosisof pernicious anaemia. The other case is still underobservation.

Cases of S.C.D.-Of the (ten) cases which came underobservation in the stage of relapse, or before the firstremission, the eight who responded showed objectiveevidence of involvement of the nervous system. Sofar there have been no diminution in these signs.The two cases in this series whose anaemia did notrespond to liver had, as above stated, no signs ofsubacute combined degeneration.

Secondary and Aplastic Ancemias.-Five cases ofsecondary anaemia were given whole liver feeding.In none was there a characteristic response in reticu-lated red cells, and it was difficult to ascribe anyslight improvement to liver therapy. One case ofaplastic anaemia was treated with whole liver with nobenefit.

Achlorhydria.-In only one case were the stomachcontents examined both before and after treatment.The ashlorhydria has persisted. It has been notedthat several patients feel benefited by the con-

tinuance of the administration of hydrochloric acid,although their blood count has resumed a normalpicture.

TWENTY CASES TREATED AT

THE LONDON HOSPITAL.

Reported by P. N. PANTON, M.B.,DIRECTOR OF THE HALE CLINICAL LABORATORIES;

AND

F. C. O. VALENTINE, M.R.C.P.,ASSISTANT DIRECTOR.

1 A TRUE estimation of the value of the Minot-Murphy diet can scarcely be arrived at in a periodof less than ten years, and any conclusions reachedfrom a consideration of the cases presented by usmust carry less weight than those described in theAmerican literature owing to the small number of

I our patients and the short periods during whicbI thev were observed

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J1 ethods of Comparison.Two methods are open to us. By the first we may

compare the effect of the treatment during arbitraryperiods over a series of patients and for this purposewe have divided the cases into groups correspondingto the length of observation. If it can be shownthat there is a fairly constant response to the livertreatment, as indicated by the temporary rise inthe reticulocyte count, the steady increase in red.cell and haemoglobin content, improvement in thegeneral health and freedom from relapse, we helpto corroborate the prima facie case which has alreadybeen made out for the value of the treatment. Bythe second method we may compare the condition-of these patients during these periods with that ofanother series of patients treated by other methods.Such comparison may be most fallacious if we depend.upon our recollection of the effect of treatment inpernicious anaemia before the discovery of the liver- diet but we are fortunate in having at our disposalthe complete data of a large series of cases, 1 Such- comparison appears to us to be justifiable and tolead to conclusions which admit of little doubt.

The Present Series.The present series of cases includes 20 examples

,of pernicious anaemia, and of these eight showed.evidence of spinal cord involvement, one case of,sprue with a typical primary anaemia blood picture,.one case of subacute combined degeneration of the- cord without blood changes, and one case of haemo-lytic icterus. The old series comprised 114 consecu-tive cases of pernicious anaemia seen between theyears 1909 and 1919 inclusive.

The only patient of this series known to be still survivingis a man first seen in 1909 with a typical blood picture,achylia, and definite cord changes. Now, nearly 20 yearslater, he is in active employment and good physical con-dition with a normal blood state, the spinal condition beingunaltered. During this period the patient has taken an i

ordinary diet of average protein content and states that he ’,dislikes liver and has rarely eaten it.

Table of Progress as Shown by Red Cell Count.

The 20 examples of pernicious anaemia treated with Iliver, either in the fresh state or as the extract, aredivided into four groups. Group 1, of seven casesobserved for three months or less ; Group 2, of eightcases observed from three to six months ; Group 3,of three cases observed from six to nine months ; and

1 Panton, P. N., Maitland-Jones, A. G., and Riddoch, G. :Pernicious Anæmia : An Analysis of 117 Cases, THE LANCET,1923, i., 274.

Group 4, of two cases observed for over nine months.The red cell count is a fair guide to progress undertreatment, and the table gives a brief summary ofthe cases in their four groups.

Replies to Questions.

I Dosage.-Of the 20 cases, four were treated withliver extract. In these patients daily reticulocytecounts were made, and in each case the usual rise andsubsequent fall in the percentage of these cells wereobserved. In two of these cases HCl was addedto the treatment about a fortnight later, after theactivity of the extract had been demonstrated by thereticulocyte curve and a definite increase in the redcell count. Of the remaining 16 cases, five were puton liver alone and 11 on arsenic or HC1, or both inaddition. One case was originally treated (in July,1926) with a high protein diet, including liver, andwas subsequently placed on liver diet. The averageamount of liver given was lb. a day, and of liverextract the equivalent of 1 lb. of fresh liver daily,while in hospital. The liver was given both lightlycooked and in the raw state as " cocktails." Bothforms appeared to be effective, the cocktails beingperhaps the more palatable. The amount taken bythe patients in their own homes varied considerablyin individual cases. It is known that Cases 1 and 6failed to take their liver regularly.

Cases of S.C.D.-Eight of these cases of perniciousanaemia showed in varying degree the symptomsand signs of subacute combined degeneration of thecord. We consider that these cases have been underobservation for far too short a time to warrant astatement that the cord changes do or do notprogress under liver treatment. One additionalcase, however, of subacute combined degenerationin which there was no anaemia is of interest as hehas been on liver for 15 months. Careful examinationmade at the beginning and end of this period by thesame observer showed that no change had occurredin the physical signs, though the patient himselfconsidered that he was slightly weaker. It shouldalso be mentioned that in the one surviving case

quoted above, from the earlier series, the cord lesionsfrom the time of disappearance of anaemia—i.e.,during 19 years-have remained unaltered. _ _ ,

Achlorhydria.-All these cases had achylia. eightbeing examined by means of a fractional test-meal, the rest by the ordinary Ewald meal. Nore-examination of the gastric juice has been madeup to the present.Two other cases should also be described.The first had had sprue for 20 years and when first seen

his red count was 400,000. After a blood transfusion of200 c.cm. he was put on liver soup, and the count rose to1,800,000 in one week. After nine months the red cellcount was 6,150,000. Incidentally, three weeks afterstarting on liver, he had an attack resembling acute goutaffecting the toe-joint.The second case was that of a wmnan suffering from

hsemolytic icterus. She was only kept on liver diet forabout ten days, and no rise in the red cell count could betraced. The percentage of reticulocytes rose from about45 per cent. to 65 per cent. while she was taking liver, butthis was not necessarily due to the diet, since considerablevariation occurred when this factor was absent.

Comments.

Anyone acquainted with the results of. treatmentin pernicious anaemia before the discovery of liverdiet would regard the results recorded in this smallseries of cases as encouraging, but would recall semepatients in whom unexpected and rapid remissionsoccurred, and others in whom the disease dragged outa long course of many years. In making a com-parison with the course of the disorder observed inthe older and longer series, we believed that deductionsmight be drawn if we considered all the cases at thesame intervals of time and noted how many patientsimproved, relapsed, or died in these intervals.

It was found that at the end of three months after theirfirst admission to hospital, out of 114 cases in the earlier series,37, or 31-2 per cent..,were dead ; after six months, 50, or 43-9per cent., were dead ; and four others, or 3-5 per cent., had

874

relapsed ; after nine months 60, or 52-6 per cent., weredead, and eight, or 7 per cent., had relapsed.A conceivable explanation of the overwhelming

difference between the results in the two series maylie in the possibility that, owing to the general interestaroused by the new treatment, patients present them-selves for examination at an earlier stage. Such ’,

explanation may be true in part, and is perhapsreasonably examined by comparing the average redcell count on admission to hospital in the two series.This average in the first series was 1,387,000, and inthe second 1,790,000. The difference is in favourof the second series, but is hardly greater than, owingto the smaller numbers, might occur by chance, andis certainly not sufficient to account for the discrepancyin the courses run.We do not yet know if patients with pernicious

anaemia will respond indefinitely to liver taken bythe mouth, or if they will ever be able to leave offthe treatment, but the remarkable experience infollowing up the first series of cases of interviewinga succession of sick persons or sad relatives, and inthe second series of seeing nothing but hopefulpatients, convinces us that the Minot-Murphydiscovery ranks as a therapeutic advance of the firstimportance.Our thanks are due to the physicians of the London

Hospital for allowing us to publish these results.

SIX CASES TREATED AT

ST. MARY’S HOSPITAL, LONDON.Reported by Prof. F. S. LANGMEAD, M.D., F.R.C.P.,

and C. M. WILSON, M.D., F.R.C.P.,PHYSICIANS TO THE HOSPITAL.

Replies to Questions.Dose of ’Whole Liver.-Half a pound of cooked

liver daily, preceded in one case by lb. cooked liverdaily.

Simultaazeous Treatment.-None in two, hydro-chloric acid in four. Arsenic in one, during a periodwhen only 1/4 lb. of liver was given daily, but improve-ment was enhanced when the dose of liver wasincreased to lb. daily and the arsenic was stopped.

Cases of S.C.D.-No cases of subacute combineddegeneration were treated, but symptoms referableto the nervous system were present in four ; thesed sappeared under treatment in three, whilst in thefourth the subjective symptoms went but the knee-and ankle-jerks remained absent. ’

Achlorhydria.-The gastric contents were examined I

in three before and after treatment, achlorhydriawas present in one and achylic gastrica in two; in noinstance were these abnormalities corrected by thetreatment.

Comme32ts.In one case the patient, after ten weeks of liver

treatment, walked without effort and returned toactive life after having been in bed for two years. Inthree considerable improvement had already followedother treatment. In one of these ultra-violet lighthad been used with arsenic, in another treatment bya blood extract (specially prepared by Dr. A. C. Alport)and later by arsenic, and in the third by an initialtransfusion followed by ultra-violet light. Whenthese treatments were superseded by liver alone,slow, but definite, improvement was replaced byrapid improvement leading to apparent cure.

Two Cases Related.CASE 1.—Male aged 41. Duration of illness five

months before admission. Increasing pallor, weakness,

palpitation. Exhausted after five minutes’ walk to business..Achlorhydria. No nervous symptoms. Blood count: Redblood cells, 1,320,000 ; Hb., 32 per cent. ; colour-index,.1-25 ; white blood cells, 5500. Differential count : Poly-morphs, 66 per cent. ; small lymphocytes, 32 per cent. ;.

large lymphocytes, 1 per cent. ; eosinophils, 1 per cent. ;characteristic changes in red blood cells.

Treatment.-l. Ultra-violet light, arsenic, hydrochloricacid. Two weeks later little or no improvement. Redblood cells, 1,500,000 per c.mm. ; Hb., 32 per cent. ; C.I.,1-1 ; white blood cells, 6100. Differential count: Poly-morphs, 69 per cent. ; small lymphocytes, 20 per cent. ;.large lymphocytes, 8 per cent. ; hyalines, 1 per cent. ;mast cells, 2 per cent.

2. Several teeth removed after X ray examination hadrevealed considerable apical sepsis, and afterwards the sametreatment followed. Considerable improvement, and when.discharged five weeks later, blood examination as follows Red blood cells, 2,960,000 ; Hb., 76 per cent. ; C.I., 1-25.

3. After discharge, continued on same treatment and took,also, lb. cooked liver daily. Continued to improve andreturned to work. Blood count six months after discharge rRed blood cells, 3,280,000 ; Hb., 76 per cent. ; C.I., 1-2 ;white blood cells, 4400. Appearances of red cells nearlynormal.

4. Liver increased to lb. daily, arsenic and ultra-violetlight stopped, HCl continued. Continued improvement.Blood count ten weeks later : Red blood cells, 4,500,000 ;Hb., 92 per cent. ; C.I., 1-02 ; white blood cells, 7500.Differential count: Polymorphs, 58 per cent. ; smalllympho-cytes, 14 per cent. ; large lymphocytes, 13 per cent. ; hyalines,14 per cent. ; eosinophils, 1 per cent. ; red blood cells showvery few changes.He is in full work, looks well, and says that he feels better-

than he has done for many years. Achlorhydria still present.Result.-No improvement until removal of focal sepsis,

but improvement with As., HCI, and ultra-violet light afterthis was done. It continued after ultra-violet light replacedby lb, liver daily ; enhanced when As. also stopped andliver increased to Ib. daily. HCl given throughout.Apparent cure except for persistent achlorhydria.CASE 2.-Woman aged 53. Many partial remissions.

since onset of illness in 1912. In February, 1916, the redblood cells numbered 1,724,000, the haemoglobin 35 percent., whites 4800, and the differential count was as follows :Polymorphs, 50 per cent. ; small mononuclears, 42-8 per-cent. ; large mononuclears, 4-4 per cent. In 1923 the redcells had fallen to 1,500,000 and the haemoglobin to 30 percent. At that time she complained of numbness of thefeet and arms and the ankle-jerks and knee-jerks were-

absent. In September, 1927, the red cells numbered1,900,000, and the hsemoglobin 40 per cent., normoblastswere present and the red cells were irregular in size andshape ; she was admitted to hospital, where blood trans-fusion was carried out twice at intervals of a fortnight.There was a slight improvement in the blood picture.Fourteen days later she was put on i lb. cooked liver daily,which she has taken regularly since-that is, from Nov. lst,1927, until the present time. On March 25th, 1928, the redblood cells numbered 5,608,000 ; haemoglobin, 85 per cent. ;colour-index, 0-78 ; white blood cells, 11,000. The redcells were normal in size and shape, and no abnormal cellswere seen in the film. In the differential white count thepolymorphs numbered 44-3 per cent. ; small mononuclears,49 per cent ; and the large mononuclears, 3-3 per cent.The nervous symptoms, such as numbness, were no longerpresent, but the knee-jerks and ankle-jerks were absent.Dr. W. G. Johnston, of Brixton, with whom I had seen thepatient originally in consultation, tells me that during thetime she was taking the liver there was no other treatment ofany kind and that her diet was not altered except for theaddition of liver.

FOUR CASES TREATED AT

ST. THOMAS’S HOSPITAL, LONDON.

Reported by Prof. H. MACLEAN, M.D., F.R.C.P.,DIRECTOR OF THE CLINICAL MEDICAL UNIT.

Replies to Questions.Dose of ’Whole Liver.-Half a pound, cooked, daily.Extracts Tested.-One early extract used in one

case of pernicious anaemia and in one case of myeloid