Hepatitis, colitis, and lupus manifestations

tlepatitis, Colitis, and Lupus Manifestations

NIGEL GRAY, M.B.,* IAN R. MACKAY, M.D.,t LEON I. TAFT, M.B., B.Sc.,t SARA WEIDEN, M.Sc., Ph.D.,t and IAN J. WOOD, M.D.~

T HE ASSOCIATION of chronic ulcerative colitis with liver disease has been the subject of frequent comment in the l i terature over the past two decades. ~-~ It is difficult to generalize about the nature of the association between the two conditions, due to the variety of pathological changes described in both organs, and the differences in diagnostic criteria employed by various authors.

A study has been made of 8 patients suffering from both ulcerative colitis and chronic active hepat i t is / The latter corresponds to postneerotie cirrhosis as defined by Popper and Schaffner/ Four of these had evidence of systemic lupus erythematosus (S.L.E.) and one had mult isystem disease suggestive of S.L.E. although the L.E. cell test was repeatedly negative. ]n the present study, the re- lationship between these eouditions has been examined to assess the r61e of immunological disturbances.

Cases 4 and 5 have also been reported elsewhere/' s

CASE REPORTS Case 1

Chrom;c ulcerative colitis assoc:iated with chro~dc hepalitis. A 16-year- old hairdresser presented in March, 1957, with a 21~ year history of mild, sometimes bloodstained, d iarrhoea and anaemia. There was no history of j~undice nor contact with v ira l hepatitis. She had suffered a severe haematemesis 9 months previously and had been diagnosed as having chronic hepatitis. Invest igat ions (Table 1) indicated chronic hepat i t is ; sigmoidoscopy showed an active ulcerative colitis of moderate degree. Neither bar ium meal nor splenic venogram revealed esophageal variees but the splenic venous pressure was elevated to 402 nnn. of water.

Progress: She was treated with cortisone and iron, and remained well unt i l Aug'ust, 1957, when she had a fur ther hematemesis. However, there

]?rom the Clinica.1 Research Unit of the Royal Melbourne Hospital and the WaFter and Eliza: Hall Institute of Medical Research, Melbourne, Victoria., Australia.

~Drug Houses of Australia, Fellow for 1957. IWorking with the aid of a grant from the National Health and Medical Research

Council of Australia. We wish to thank Dr. J. Bolton and Dr. M. Etheridge for permitting access to their

cases. Mr. R.. Inglis and Miss E. Earle assisted in the preparation of the photographs and sections.

NEW SERIES VOL. 3, NO. 7, I?S8 481

Gray et al.

was an improvement in bromsulphthalein excretion, blood sedimentation rate, and serum gamma globulin level. Cortisone was discontinued and she remained well, apart from mild diarrhea.

Case 2 Chronic ulcerative cotitis associated with chro~ic active hepatitis with

response to cortisone. A 51-year-old housewife had suffered from watery diarrhea for 10 years. She presented in May, 1954, with generalized edema and increasing ascites for 3 weeks. Recently there had been blood and mucus in the motions. There was hypergammaglobulinaemia and a low serum albumin ; liver biopsy showed chronic active hepatitis and sig- moidoseopy advanced ~lcerative colitis. Numerous antibiotics were given without improvement, t~owever, she responded dramatically to cortisone, the diarrhea, ascites, and edema subsided, and she was restored to health.

Case 3

Chronic hepatitis, possibly postviral, associated with fatal chro~ic ulcerative colitis, ,without respon, se to cortisone. A 23-year-old school- teacher presented in March, 1952, following 11 months jaundice of in- sidious onset. Laparotomy in the fourth month of her illness had revealed a cirrhotic liver (Fig. 1). Subsequently the jaundice improved slightly .but had recurred one month prior to admission. She was mildly jaundiced and there were numerous spider nevi. The liver and spleen were palpable 2 era. below the eostM margin. Investigations, inclnding liver biopsy, showed chronic hepatitis of presumably viral origin.

Progress: She ~mproved and remained well until July, 1955, when review indicated inactive chronic hepatitis. Iter bowel function was normal at this time. In March, 1957, she had severe diarrhea with blood and mucus. Sigmoidoscopy and barium enema revealed pronounced ulcerative colitis. Her liver function tests were substantially unchanged. A temporary improvement was obtained with transfusion, cortisone, and tetracycline, ttowever, she relapsed one month later and was readmitted with fulminating diarrhea. Treatment with cortisone, intravenous fluids, and antibiotics did not improve her condition and she was submitted to ileostomy and total eolectomy. The excised colon showed gross changes of ulcerative colitis (Fig. 2). Postoperatively size remained in peripheral circulatory failure which did not respond to resuscitative measures. At necropsy there was chronic hepatitis (Fig. 3).

Case 4 Ulcerative colitis, recurrent hepatitis, arthritis and a positive L.E.

~ell test, with response to cortisone. A 29-year-old housewife developed

AMERICAN JOURNAL OF 482 DIGESTIVE DISEASES

Hepatitis, Colitis, and Lupus

Fig. 1. Case 3. A female, aged 23 years, with chronic hepatit is, devel- oping severe ulcerative colitis 4 years later, and dying after coleetomy. Operative l iver biopsy showing nodu lar pattern and lymphocytic infi ltra- t ion characterist ic of active chronic hepatit is. Haematoxyl in and Eosin. X 50. Ffg, 2. Case 3.

Colectomy specimen. There is gross ulcerat ion and pseudopolyposis, due to severe ulcerative colitis. Fig. 3. Case 3. Upper surface o f the l iver at postmortem. There is fine nodular i ty and sl ight th ickening of the cap- sule due to chronic hepatit is.

diarrhea with blood and mucus in May, 1956. Sigmoidoscopy revealed active ulcerative colitis. The diarrhea settled after 5 months. She then developed what appeared to be viral hepatitis with moderate jaundice. After 8 weeks rest, she enjoyed good health until the onset of acute purulent appendicitis in February, 1957. Two weeks after appendec- tomy, she developed a pro,gressive fever, intermittent vomiting, edema of the ankles, aseites, mild jaundice and then suppurative peritonitis which required drMnage. An associated chronic hepatitis was suspected: the scrims albumin level was 1.6 Gm. per 100 ml. and the gamma globulin was 2.7 Gin, per 100 ml. She improved remarkably after operation but the serum proteins remained abnormal. In August, 1957, she was clinically well, but the gamma globulin was still elevated (3.1 Gin. per' 100 ml.) and the L.E. cell tests was positive on two occasions, She presented in Octo- ber, 1957, with a 3-weeks history of jaundice and migratory polyarthritis.

$The teehrAque employed for the L. E. ceil test was that described by Magath and Winkle. 9

N EW SERI ES VOL. 3, NO, 7, I?S8 483

Gray et aL

She now had many spider nevi and the left wrist and some finger joints were hot, swollen, and slightly tender. The I~.E. cell test was again positive. Biochemical tests and liver biopsy indicated active hepatitis. Serial plasma glutamie oxalaeetic-transaminase (P.G.O.-T.) levels remained highly elevated. Treatment with cortisone was effective, the jaundice disappearing withill two weeks and P.G.O.-T. levels falling from 500 units to less than 50 units within three days. 7 The arthritis rapidly improved and she remained well on maintenance cortisone therapy.

Case 5

A fatal case of hepatitis and subseq.~ent ulcerative colitis, with a posi. live L.E. cell test a~nd glomernlonep,hritis, in April, 1953, an apparenl attack of viral hepatitis in a 20-year-old housewife had persisted for 7 weeks. Biochemical tests and liver biopsy were in keeping with viral hepatitis. Despite cortisone the disease progressed. The L.E. cell test was positive in December, 1955. In May, 1956, proteinnria developed and a kidney biopsy showed a membranous nephritis. In October, 1956, she developed ulcerative colitis and improved with prednis01one. In Janu- ary, 1957, the diarrhea recnrred and she died one month later in hepatic coma. At necropsy there was chronic ulcerative colitis, hepatitis, and membranous g'lomerulonephritis.

Cas~

A p:roba~ble case of systemic lupus erythematos~s with severe ulcerative, colitis, hepatitis, thrombocytopenic pnrpura, ~ephritis, and: a rash; partial response to cortiso~tc. In November, 1953, a 51:year-old man bad suffered severe diarrhea for 20 months. The liver was enlarged and an erythematous rash was present on the extremities. Sigmoidoscopy re~ vealed active ulcerative colitis. He improved. One year later he developed diarrhea, frequent epistaxes, ulcerative stomatitis, recurrence of the rash, and the spleen was palpable. The L.E. cell test was positive once, and the liver biopsy showed chronic hepatitis (Fig. 4). He deteri- orated, and was found to have persistent thrombocytopenia which did not respond to ACTH therapy. He improved satisfactorily after splenec- tomy and, apart from occasional diarrhea, remained moderately well on cortisone for 2 years. In April, 1957, he had a prolonged exacerbation of the colitis. The liver was enlarged and biopsy again showed chronic hepatitis. Colectomy was considered but he responded to increased cortisone dosage, itowever he relapsed again in July, 1957, and total colectomy (Fig. 5), ileoreetal anastomosis and defunctioning ileostomy produced considerable improvement. Operative renal biopsy revealed an unusual nephritis with pronounced interstitial lymphocyte infiltration (Fig. 6). When last seen, six months later, he was moderately well.

AMERICAN JOURNAL OF: 484 DIGESTIVE DISEASES


Fig. 4. Case 6. A male, aged 51 years, with severe ulcerative colitis. chronic hepatit is, thromhocytopenic purpura, nephrit is, skin rash, and a positive L.E. cell tes t . The l iver biopsy shows distent ion of structure with lymphocytic inf i l trat ion, fibrosis, bi le duct prol i ferat ion, and ir- regular ity of the polygonal cells. Haematoxyl in and Eosin. X 200. Fig. 5. Case 6. Microphotograph of mucosa of colectomy specimen showing gross in f lammatory inf i l trat ion. some ulceration, and exudat ion due to ulcerative colitis. Haematoxy l in and Eosin. X 150. Fig. 6. Case 6. Opera- tive renal b iopsy . .Fue l of glomerulosclerosis and per igtomerular lymphocytic inf i l trat ion. Haematoxyl ln and Eosin. X 150.

Case 7 Chronic ulcerative cotitis, hepatitis, asthma, and nephritis. L.E. cd~

test negative. Fair response to ~ortisonc. A 50-year-old woman was seen in December, 1954, suffering from ulcerative colitis with anemia for 10 years. She improved with transfusion. Three months later she relapsed with persistent diarrhea, malaise, anorexia, upper abdominal pain, and jatmdiee. The liver was enlarged and biochemical tests were in accord- ance with viral hepatitis, possibly homologous serum jaundice. She ira- proved with supportive treatment, but in June, 1956, she had jaundice for one week, severe asthma and simlsitis. I Ier bowel function was normal at this time. The liver was still enlarged. Biochemical tests and liver biopsy indicated chronic hepatitis. She improved rapidly and remained well unti l February, 1957. She was then investigated because of pro- teinuria.. At renal biopsy (Fig. 7), medulla only was obtained and this showed considerable interstitial fibrosis. In November, 1957, she had (~iarrhea, sinusitis, impetigo, and anemia. TI~e Coombs test was positive

NEW SERIES VOL. 3, NO. 7, 1958 485

Gray et al.

7 8

Fig. 7. Case 7. A female, aged 50 years, with chronic ulcerative colitis, hepatitis, asthma, and nephritis. The L.E. cell test was negative. Percutaneous renal biopsy showing interstitial fibrosis, tubular atrophy and hyaline casts in the medulla. Haematoxylin and Eosin. X I50. Fig. 8. Case 7. Rectal biopsy. There is inflammatory infiltration of the lamina propria by lymphocytes, plasma cells~ and some polymorphs. Haematoxylin and Eosin. )< 250.

but the L.E. cell test was repeatedly negative. Signmidoseopy showed recurrence of the ulcerative colitis (Fig. 8). She improved slowly with medical treatment including cortisone, and at discharge was well, apart from mild diarrhea.

Case 8 Hepatitis, ulcerative ~olitis, polyarthritis, pleurisy, pericarditis, and a

positive L.E. cell test. Fair response to cortisone. In July, 1952, a 30- year-old man complained of intermittent diarrhea for 2 years, polyarthritis for two months, and hemoptysis. He was slightly jaundiced and both liver and spleen were enlarged. Sigmoidoscopy showed ulcerative colitis; biochemical tests and liver biopsy revealed active hepatitis. He was treated with cortisone and the jaundice decreased over the next 12 months. However he continued to have intermittent diarrhea and polyarthritis. In May, 1954, Raynaud's phenomenon and changes in the skin of his fingers suggestive of scleroderma were observed. In July, 1954, he developed pleurisy, periearditis, congestive cardiac failure, and the L.E. cell test and Coombs test were positive. In November, 1956, his symptoms became more pronounced., he had pleural effusions and ascites, and there was biochemical evidence of impaired renal function. Necropsy showed cirrhosis and chronic ulcerative colitis.

DISCUSSION

Fat ty inf i l trat ion of the liver is the commonest pathological change found in pat ients with chronic ulcerative colitis. Est imates of its occurrence vary ; Kimmelst ie l et al. 1 reported 15 per cent of



93 cases, and Jones et a l /52 per cent of 91 cases. The incidence of cirrhosis in association with ulcerative colitis was shown to be 4 per cent of 284 cases by Hoffbauer et al2 and 19 per cent of 32 cases by Kleclmer et al. 4 In each of the above series histological con- firmation of the liver lesion was obtained.

The outstanding problem is the mechanism whereby the liver disease and colitis occur together. It is uncertain whether one of these conditions is primary, or whether there is a common etiologi- cal factor. It is frequently suggested that ulcerative colitis is the initial lesion/ and that the hepatitis is due either to a conditioned nutritional deficiency or to portal toxemia. However in two of our cases (Cases 3 and 5) the hepatitis preceded the colitis and in certain others (Cases 1, 2, 4, 6, and 8) it may well have been latent. Moreover in three of our cases (Cases 1, 4, and 5) the colitis was not severe and a nutritional deficiency was not apparent. In view of these facts we wish to present an alternative concept whereby an immunological disturbance may be responsible for both lesions.

We are influenced in this regard by our previous experience with chronic hepatitis unassociated with ulcerative colitis. Persistence of viral activity had been postulated as a cause of nonnutritional chronic active hepatitis, but such a process finds no parallel among other viral diseases. An alternative hypothesis was provided by Joske and Kin. g n and l~Iackay et al. ~2 who found a positive L.E. cell test in a group of cases of chronic hepatitis. The process was termed hpoid hepatitis and it was suggested that continuing activity of the disease was due to an immunological reaction. Further evidence relevant to this concept was obtained by study of the auto- immune complement fixation (A.I.C.F.) reaction developed by Gajdusek ~ at this Institute. This reaction was frequently positive in classical S.L.E. and lupoid hepatitis. ~3

If it is accepted that immunological mechanisms are concerned in the pathogenesis of S.L.E. and in the continuance of active hepatitis in certain cases, then a similar immunological process may be involved in the etiology of the ulcerative colitis in our cases. With this thought in mind it is of interest to summarize some of the relevant features of the eight cases in this study (see Table 2). A raised serum gamma globulin level was found in all cases, the L.E. cell test was positive in four cases, the A.I.C.F. reaction was posi- rive in six cases and a significant clinical response to cortisone was observed in five cases. In addition other phenomena thought to

NEW SERIES VOL. 3, NO. 7, 1958 487

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have an immunological basis such as thrombocytopenia, arthralgia, asthma, a positive Coombs test, and visceral lesions characterized by lymphocyte activity were seen in some cases.

It is interesting to speculate o~ the nature of the factors initiating the multi- system disease exemplified by the present group of eases. It has been suggested that the pr imary disturbance in such diseases is in the mesenchymal antibody producing system, a* Alternatively, it is possible that induced autoantigenicity of some body component is responsible. If this is so, pr imary damage to the liver may be the initiating mechanism.

"Other ease studies favouring an immunological factor in chronic ulcerative colitis were reported by Kirsner and Palmer 1"~ who described the occurrence of colitis in a patient who developed arthritis, possible scleroderma, pneumonitis, and febrile episodes suggestive of S.L.E., and also in a patient with rheumatic fever, pneumonitis, hepatitis, hyperglobulinemia, and hemolytic anemia. These patients, particularly the second, would fall into the clinical pattern of S.L.E. although results of the L.E. cell test were not recorded. Kirsner and Palmer 1~ suggested bowel hypersen- sitivity to an initial bacterial invasion as a possible causative factor in ulcerative colitis, but this does not necessarily account for the other lesions.

No attempt has been made here to as- certain how often chronic hepatitis and ulcerative colitis are associated, nor is it suggested that the association of the two conditions necessarily depends on ira-

489

Gray et al.

TABLE 2. Clinical and Laboratory Data Relevant to the Immunologica l Basis of Hepatit is Associated with Colitis

Serum gamma g lobul in l~esponse

Case g . /100 ml. L .E . cell A . I .C .F / Coombs to no. (max imum level) test t i te r test Ar thr i t i s cort isone

1 3.5 - - - - - - :No Poor 2 3.2 .. 4 - - No Exce l lent 3 1.8 - - 4 - - :No Poor 4 3.1 -I- 4 - - Yes Exce l lent 5 3.9 -~- 8 - - No Poor 6 2.1 + 64 - - No ]Y[oderate 7 ].8 - - - - + Yes 1Y[oderate 8 2.8 + .. + Yes ~oderate

aExpressed as rec iproca l of max imum pos i t ive serum t i ter .

munological mechanisms. Itowever, the occurrence in eight patients of hepatitis and colitis, with other probable auto-immune dis- orders in some of them, appears to be more than fortuitous. It may even be that cases such as these are, in fact, variants of true systemic lupus erythematosus.

SUMMARY

1. An analysis has been made of eight cases in which hepatitis and ulcerative colitis occurred together. Current explanations of this association, including conditioned nutrit ional deficiency and portal toxemia causing liver damage, failed to account for all the features of our particular cases.

2. Of the eight patients, three had chronic hepatitis of uncertain pathogenesis and concurrent ulcerative colitis of varying severity and five others had, in addition, systemic lesions including nephritis, pleurisy, pericarditis, polyarthritis, and thromboeytopenic purpura. 3. Evidence for an auto-immune pathogenesis in these cases in- eluded elevated serum gamma globulin levels, positive L.E. cell tests in four cases, and positive "auto- immune complement fixa- t ion" reactions in six cases. Five patients responded well to cortisone. The dense lymphocytic aggregates seen in histological sections of affected tissues were also thought to be of significance.

4. This immunological disturbance may depend upon induced auto-antigenicity of some body component as a result of initial



tissue damage--alternatively there may be a fundamental anomaly of antibody producing tissues.

REFERENCES

1. IfIMlkIELSTIEL, P., LARGE, It. L., and ERNER, H. D. Liver damage in ulcerative eo]itis. A~. J. Path. 28/259, 1952.

2. JONES, G. W., BAGeENSTOSS, A. H., and I~_~RGEN, J. A. iEIepatie lesions and dysfunc- tion associated with chronic ulcerative colitis. Am. J. Med. Sci. 221:279, 1951.

3. t{OFFBAUEa, F. W., McCa~TNEX', J. S., DENNIS, C., and K.SRLSON, If. The relation- ship of chronic ulcerative colitis and cirrhosis. Ann. Int. Med. 39:267, 1953.

4. I~LECKNEI% ~. S., STAUFFER, iVl. H., ]~ARGEN, J. A., and DOCKEI~Ty, l~. B. Hepatic lesions in the living patient with chronic ulcerative colitis as demonstrated by needle biopsy. Gaztroenterology 22:13, 1952.

5. SAINT, E. G,, IfING, W. E., JOSKE, R. A., and F INCKH, E. S. The course of infectious hepatitis with special reference to prognosis and the chronic stage. Aust. Ann. Med. 2:113, 1953.

6. PoP~'E]~, H., and SCHAF~NEI%, F. Liver: Struetu~'e and Function. New York, Mc- Graw-ttill, 1957.

7. O'BIglEN, E. N., GOBLE, A. J., and 5~ACKAY, IaN R. Plasma transaminase activity as an index of effectiveness of cortisone in chronic hepatitis. Lancet (in press), 1958.

8. TAFT, L. I., MACKAY, LxN R., and L~,kI~KIN, LOIS. Hepatitis complicated by mani- festatious of lupus erythematosus. J. Path. Bact. 75:399, 1958.

9. IV[AGATH, T. B., and WINKLE, V. Technic for demonstrating 'L .E. ' (Lupus Erythe- matosus) cells in blood. A~n. J. Clin. Path. 22:586, 1952.

10. SHEI~LOCK, S. Diseases of the Liver and Biliary System. Oxford, Blaekwell Scientific Publications, 1955.

11. JOSKE, R. A., and I~ING, W. E. The 'L.E. cell' phenomenon in active chronic viral hepatitis. Lancet 2:477, 1955.

12. MACKAY, I.aN 1~., TAFT, L. I., and C0WLINO, D. C. Lupoid hepatitis. Lancet 2:1323, 1956.

13. GAJDUSEK, D. C. An 'auto-immune' reaction against human tissue a~tigens in certain chronic diseases. Natwrc 179:666, 1957.

14. MACKAY, IAN 1~., and LAaKISr, LOIS. The significance of the presence in human serum of complement fixil~g antibodies to human tissue antigens. Submitted for publication, 1958.

15. KmsNEa, J. B., and PALMEI% W. L. Ulcerative colitis. Considerations of its aetiol- ogy and treatment. J .A.M.A. 155:341, 1954:.

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Hepatitis, colitis, and lupus manifestations