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The Management of Ulcerative Colitis
The Management of Ulcerative Colitis PHILIP KRAMER, M.D.*
WHILE gratifying progress has been made in the therapy of ulcerative colitis, especially since the advent of steroids and the improvement in general medical, nursing and surgical care, the management of patients so afflicted remains a formidable task. Ulcerative colitis is a disease which is invested by a cloak of almost complete obscurity. Thus little is known of its etiology or pathogenesis. The course and response to therapy are unpredictable, remissions and exacerbations often occurring without apparent cause. Although there are characteristic clinical features that should make one suspect the diagnosis, this cannot always be made with certainty unless other specific diseases are excluded. To further complicate matters, colitis patients are brittle individuals, emotionally and physically, so that their state of health can deteriorate precipitously. Since the illness is chronic and recurring, frequent hospitalizations are often required; economic problems arise because of the expensive medical therapy needed and the inability of the individual to pursue a gainful occupation. Not only are these problems detrimental to the patient's emotional health, but they also make the task of the conscientious physician difficult because he often has to manipulate the sociological environment in order to render medical care. Unfortunately, the only definitive "medical" therapy is surgical removal of the diseased organ and creation of a discharging abdominal stoma, which is abhorrent to the average ulcerative colitis patient. In essence, the treatment of ulcerative colitis is symptomatic, supportive and corrective. A rational approach to management therefore involves (1) a correct diagnosis, (2) removing such etiological factors as exist, (3) remedying such abnormalities in the pathophysiology as have occurred.
From the Evans Memorial of the Massachusetts M emorial Hospitals and the Department of Medicine. Boston University School of Medicine, Boston.
* Assistant Professor of Medicine, Boston University School of Medicine; Associate Visiting Physician, Massachusetts Memorial Hospitals; Associate Member, Evans M emorial, Massachusetts M emorial Hospitals. 1401
Philip Kramer
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Fig. 170. CASE L This x-ray demollstrates the radiographic findings in a female patient aged 36 with a 14 year history of ulcerative colitis. During this period the patient was hospitalized six times and suffered at least an equal number of recurrences which were treated at home. Constipation associated with bloody discharges has been a frequent complaint requiring the use of mineral oil. Other therapy has consisted of Sulfasuxidine, Azulfidine, ACTH, cortisone and hydrocortisone. She responded favorably to each of these medications when given for 1 or 2 courses but subsequent courses were ineffective. Azulfidine had to be discontinued because of a severe maculopapular skin eruption. In spite of this long history and frequent recurrences the disease has remained confined to the rectum, rectosigmoid and probably terminal part of the descending colon. There is narrowing of the lumen in these areas, loss of haustral markings and normal mucosal pattern. The changes have been progressive but there has been no extension proximally. This case illustrates that ulcerative colitis may exist in a relatively benign form for a long period of time. DIAGNOSIS
The diagnosis of nonspecific ulcerative colitis is based upon: 1. The Clinical Picture. Diarrhea is the outstanding symptom; anywhere up to 30 or more loose stools per 24 hours may be passed containing blood and mucopurulent material. These stools have a characteristic appearance and much can be learned as to the severity of the illness, course and response to therapy from observing their gross appearance daily. When the pathologic process is confined to the rectum or rectosigmoid there may be constipation (10 per cent of patients) instead of diarrhea, with the passage of hard scybalous stools and bloody mucopurulent discharges independent of bowel movements (Fig. 170, Case I).
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Cramping abdominal pain relieved by bowel movements, tenesmus, varying degrees of fever and malnutrition, anorexia, anemia and a number of systemic complications, such as arthritis and erythema nodosum, complete the clinical picture. 2. Sigmoidoscopy. On sigmoidoscopy the mucosa is diffusely hyperemic, edematous, granular appearing, usually superficially but at times deeply ulcerated. Characteristically, the mucosa is friable and bleeds easily when rubbed with a swab. A negative sigmoidoscopy does not rule out the disease because in approximately 5 per cent of colitis patients the visualized mucosa is normal. These individuals are suffering from segmenta colitis, i.e., right-sided colitis or colitis in some area other than the rectosigmoid. 3. Barium Enema. Roentgenographic manifestations in mild cases are confined to changes in mucosal pattern; the mucosa appears fuzzy, feathery or may show a finely serrated saw-tooth appearance. In moderately advanced involvement the mucosal pattern is more distorted, larger ulcerations are seen and haustral markings are lost. Advanced disease is manifested by loss of mucosal pattern, giant ulcerations, pseudopolypoid changes, narrowing and shortening of the bowel so that the hepatic and splenic flexures tend to disappear. On the initial examination in a study reported by Ricketts, Kirsner and Palmer,l approximately 39 per cent of patients had a normal barium enema. 4. Absence of Known Pathogens from the Stool or Clinical Findings Suggestive of Another Disease. Other conditions may simulate either or both the radiologic or sigmoidoscopic appearance of ulcerative colitis. Diffuse amebic colitis, postbacillary dysentery colitis, the colitis and proctitis produced by Aureomycin and Terramycin, lymphopathia venereum, secondary amyloidosis, colonic changes produced by vascular lesions, regional enteritis involving the right colon and even tuberculosis of the colon are among the conditions that may be confused with ulcerative colitis. 2 , 3, 4, 6, 6 Therefore stool cultures, agglutination tests, and examination of stools for ova and parasites should be routinely done in suspected colitis; other diagnostic procedure such as a Frei test or a tuberculin test may have to be performed in occasional patients. ETIOLOGY
Although the cause of ulcerative colitis is unknown, a discussion of the prevalent theories of the etiology is necessary in order to justify certain of the therapeutic practices. For a detailed, readable review of the etiology the article by Warren and Berk is recommended. 7 Infectious Theory. The fever, toxemia, purulent rectal discharges, leukocytosis, microscopic abscesses in the colon and the occasional response to antibacterial agents suggest an infectious causation. Many bacteria, fungi and viruses have been incriminated but none has been confirmed by independent groups of investigators. Furthermore, the dis-
Philip Kramer ease has not been shown to be transmittable; spontaneous remission and exacerbation occur without use of anti-infectious agents or evidence of reinfection. Psychosomatic Theory. The following evidence is given to support the theory that ulcerative colitis is a psychosomatic disorder: (1) Colitis patients have an unusual personality pattern, Le., they are immature, abnormally dependent upon a so-called father or mother figure, unable to cope with adult problems, passive, overfastidious and display repressed hostility. These features persist even after a total colectomy.8 (2) Stress interviews in individuals with exteriorized colonic mucosa induce hyperemia, ulcerations and excessive secretions. (3) Parasympathomimetic agents produce colonic balloon kymographic motility patterns similar to that seen in persons with ulcerative colitis. This latter finding offers a simple but not necessarily correct explanation as to the way stress is mediated, Le., via the parasympathetic nervous system. (4) Patients treated exclusively by psychiatric techniques have responded as well if not better than those treated by conventional medical measures. 9 , 10 The mechanism by which the abnormal psyche causes somatic changes in the colon is unknown. Nor has it been shown that these characteristics are specific for individuals with ulcerative colitis in contrast to those with other chronic diseases. Allergy and Tissue Hypersensitivity. The response to steroids suggests that ulcerative colitis is a disease of hypersensitivity. Likewise, the systemic manifestations, Le., arthritis, iridocyclitis, erythema nodosum and the finding of abnormalities in the basement membrane can be used as additional evidence to emphasize this suspicion as to the etiology.ll Allergy to foods such as milk, wheat or eggs or to bacteria or the products of bacteria have been incriminated. However, remissions occur regardless of diet, without changes in bacteria, and the alteration in the basement membrane has been found in other diseases. Destructive Enzymes. Rectal discharges from colitis patients may contain excessive lysozyme or proteolytic substances. Attempts to reproduce the clinical and pathologic aspects of the disease with these products have not been successful. Furthermore, proteolytic substances have not been found in all persons with ulcerative colitis, and other disease states show excessive lysozyme and proteolytic enzymes in the stools. PATHOPHYSIOLOG Y
The degree of metabolic and motor abnormalities depends upon the severity of the illness. At one end of the spectrum the individual with proctosigmoiditis may show apparent good health; at the other extreme the patient with acute fulminant colitis may be literally at death's door with severe toxemia, prostration, malnutrition, anemia, protein and electrolyte depletion. The aberrations observed are of multiple and com-
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plex origin. They are due to (1) hyperirritability of the colon so that it cannot perform the normal motor functions involved in receiving and storing material from the ileum and then propelling and discharging this material when in proper physical form, (2) failure of the colon to absorb water and electrolytes, principally sodium, potassium, chloride and possibly calcium, (3) the excessive rectal discharges containing protein and blood, and (4) inadequate food intake. All gradations of water losses via the stools are possible, so that in severe colitis as much as 1500 to 3000 ml. or more of watery stools may be expelled. Whereas the normal sodium and potassium outputs in the stools per 24 hours are traces, 10 to 20 mEq. (0.4 to 0.8 gram) and 25 to 50 mEq. (0.5 to 1 gram) respectively, daily losses of sodium in severe colitis may be 20 to 265 mEq. (1.75 to 10.5 grams) with a concentration of 50 to 100 mEq./liter, potassium 20 to 80 mEq. (0.5 to 2 grams) with a concentration of 20 to 35 mEq./liter. J2 , 13, J4 In one patient 24 grams of potassium chloride per day by mouth were required to maintain a normal serum potassium. I3 Studies on stool calcium losses are meager; one report stated a loss of 85 mEq. or 1.6 grams/24 hours. l2 However, hypocalcemia and osteoporosis have been noted. 16 The loss of fluid and electrolyte per rectum leads to dehydration, hyponatremia, hypokalemia, hypoch10remia and acidosis. Loss of weight, malnutrition, and protein depletion (as measured by a decrease in total serum protein and serum albumin) result from excessive protein loss in stools, decreased food intake, and increased tissue breakdown and nutritional requirements because of the pyrexia and toxemia. Nitrogen losses from the bloody purulent exudate may vary from 1.9 to 9.30 grams/24 hours, the latter figure being found during active diarrhea (normal 0.7 to 1.5 grams/24 hours).14, 16, J6 This loss is equivalent to 11.8 to 58.2 grams of protein. There has been little question that protein depletion occurs in this manner, but the question of malabsorption of proteins and fats due to small intestinal malfunction has been controversial. Although abnormal fat losses are uncommon, as much as 16.3 per cent of fat intake may be excreted according to Welch et al. 14 Recent investigation with radioisotopic techniques suggest that there is malabsorption of protein and fat in the active phase of disease.I 7 Three types of anemia have been reported: (1) a microcytic, hypochromic anemia due to chronic blood loss and infection, (2) a normocytic, normochromic anemia due to depressed bone marrow activity, (3) a macrocytic anemia resulting from malabsorption of erythrocyte maturing factors. The evidence that a macrocytic anemia does occur is unsatisfactory. In 109 patients studied, anemia was found in 71 patients, 81.6 per cent having a microcytic, hyprochromic anemia and 18.4 per cent a normocytic, normochromic anemia, but none had a macrocytic anemia. 18 Blood loss via the bowel or from vaginal bleeding because of menstrua-
Philip Kramer
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tion and pregnancy in women, inadequate intake of iron, protein depletion, infection and toxemia were incriminated as the causes. PROGNOSIS
Changes over the years in the management of ulcerative colitis, the chronic prolonged nature of the disease which therefore invalidates shortterm statistics, and the extreme variability in clinical course create difficulties in attempting to make specific statements as to prognosis. I have selected several prognostic studies on the basis of size of patient population, length of follow-up and care exercised in tracing patients, to demonstrate the serious morbidity and mortality of this illness. Bargen, Sauer, Sloan and Gage 19 compared the survival curve of 1564 ulcerative colitis patients with the normal population of similar age and sex. Those who have had the disease 10 to 25 years after diagnosis have a 20 per cent less chance for normal survival when compared to the average population. The probability of carcinoma of colon is also 30 times greater than in the general population. Wheelock and Warren's20 figures are sobering and disturbing. Three hundred and forty-three patients seen between 1915 and 1943 were traced for ten years or until death; information concerning an additional 44 patients was available until time of operation. Of the 343 patients traced, 155 (45.3 per cent) were living and 188 (54.7 per cent) were dead. Ulcerative colitis was responsible for 153 death, or 45 per cent of the group. Two hundred and thirty-three or 60 per cent of 387 patients were eventually operated upon (the latter figure includes number of patients traced to the time of operation). Of the 81 patients who survived without operation, only 64 (19 per cent of 343) were well; whereas, of the 74 patients who had surgery, 69 were asymptomatic (20 per cent of 343). Perhaps more representative of the prognosis are the results of the study by Banks, Korelitz and Zetze1. 21 Two hundred and forty-five patients seen in the period 1931-1950 were traced, the average observation period being 12.1 years. Twenty per cent were well in respect to their colitis, 20 per cent had mild exacerbations, 20 per cent suffered severe exacerbations, 17 per cent were asymptomatic with definitive surgery, 3 per cent had a malfunctioning ileostomy and 20 per cent were dead. Approximately 34 per cent had required surgical therapy. While the findings since 1950, the beginning of the steroid era, are more encouraging, they are incomplete because the follow-up is much too short. Kirsner, Sklar and Palmer22 treated 180 patients with steroids, the observation period being less than two years in one-third of this group. The results expressed in whole percentage8 were excellent in 26 per cent, much improved in 43 per cent, course unchanged in 21 pet cent, surgical therapy required in 9 per cent, and 5 per cent died. In a Canadian series the medically treated presteroid era deaths were 38 per cent while the deaths in those treated with steroids were only 10 per cent. la
l he M ar~agelnent of Ulcerative ['(olitis 1
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MEDICAL THERAPY
General Measures
Since physical activity increases intestinal peristalsis, limitation of activity by imposing bed rest is recommended if the colitis is active. The degree of bed rest will depend on the severity of diarrhea, rectal discharges, fever, etc., and should continue until diarrhea and fever subside. Hospitalization becomes advisable if symptoms are more than mild in degree or if no response to bed rest at home has been observed. Two purposes are thereby accomplished: (1) removing the patient from probable noxious influences in the environment which more than likely were partially instrumental in precipitating the attack, (2) presenting the physician the opportunity for instituting a more intensive regimen. Some type of mild sedation will be required; phenobarbital 15 to 30 mg. q.i.d. is inexpensive and effective. Psychotherapy
Psychotherapy is supportive and essentially aimed at establishing a good doctor-patient relationship. Psychoanalytic methods aimed at exploring the psychodynamics are dangerous; they may cause the patient to leave treatment, become uncommunicative, develop overwhelming anxiety or regressive behavior such as defecating on the floor, experience psychotic manifestations such as auditory hallucinations or even severe exacerbation of diarrhea leading to death. 24 Formal psychiatric care is not necessary unless the patient is much improved, aware of emotional conflict, and requests such therapy; he or she should not be forced into extensive treatment. The physician's attitude should be one of kindness, encouragement and reassurance but also of firmness; he should retain complete control of the situation. Since colitis patients become so easily attached to hospital personnel whether they be interne, resident or dietitian, it is best that decisions emanate from one source, the responsible physician. In this way contradictory orders are avoided and the physician maintains a key role, the "father figure." Although no probing is done, patients should be encouraged to ventilate, assert themselves and discharge their aggressive feelings. Since they need support, frequent compliments even on minor matters aid greatly in building their ego. Under no circumstances should the physician betray his anxiety about a patient's condition. The social environment may have to be manipulated through discussions with parents, wife or husband, employer or nursing staff. Diet and Nutrition
Nutrition is of major importance in ulcerative colitis and therefore the diet should be high caloric (3000 calories per day), high protein (150 grams), palatable and attractive in appearance made so not only by the
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food content but also by the table accessories. Too often, and unnecessarily so, the diet becomes a major preoccupation of the patient, the physician and the dietetic staff. Thus the patient incriminates a variety of foods as either causing his disease or aggravating diarrhea; the physician and dietitian are frequently too rigid and unjustifiably eliminate foods they think are harmful. Consequently what is offered is an- unpalatable mess of pureed "slop" and "slush." Except for omitting the commonly known offenders listed below, the patient should be encouraged to eat a regular:diet, particularly if he expresses the desire for such. Frequent discussion between patient and dietitian will render the physician's task less difficult in achieving a satisfactory nutritional state. Foods which are obvious chemical or mechanical irritants and increase bowel activity should be eliminated. These foods are raw fruits and vegetables, high residue vegetables of the cabbage family, bran cereals, fruit juices except dilute orange juice, nuts, chocolates and cooked laxative fruits such as figs, raisins, prunes and carbonated beverages. Since cold increases intestinal peristalsis excessively, cold foods, especially iced drinks, are not to be served. ~< Vitamin B deficiencies are occasionally seen in the sick, toxic, malnourished individual with severe diarrhea and fever. Any of the supplemental vitamins may be used. Intravenous Feedings
In acute fulminant colitis or where severe diarrhea has been prolonged, the fluid and electrolyte depletion may be marked and require parenteral replacement. The admission serum Na, K, Co 2, Cl, Ca, blood urea nitrogen and hemogram will be a guide as to the need for, the type of and amount of intravenous fluid electrolyte therapy. During the first 24 hours correction of dehydration and other deficiencies may require 6 or more liters of fluid. The composition of the solution will depend upon the character of the electrolyte depletion and whether acidosis (diarrhea) or alkalosis (vomiting) is present. Liter solutions containing 5 per cent glucose alone or 5 per cent glucose, 0.9 per cent sodium chloride (150 mEq.) and 2.3 grams (30 mEq.) of potassium chloride given in quantities as needed should correct the dehydration and acidosis. (If necessary an ampule of Mj6lactate, 10 to 20 cc. of 10 per cent calcium gluconate and vitamins may be added.) Although more chloride and less sodium are required in alkalosis due to vomiting, the solutions mentioned should suffice. Daily electrolyte and fluid replacements can be estimated from daily determinations of the serum Na, K, Co~, Cl and an accurate record of intake and output. If special solutions are required because of severe alkalosis or acidosis, the article by Cooke and Crowley25 should be consulted. Proteins can also be given as 5 per cent protein hydrolysate, 5 per cent amino acid or 5 per cent salt-poor albumin solutions, provided 800 calories have been supplied in the form of glucose for energy require..
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ments so that the nitrogenous substances will not be metabolized for this purpose. Antidiarrheal Agents Including Antispasnlodics
Except for steroids, the opiates are the most useful group of medicinal a.gents in the symptomatic treatment. Opiates exert their effect because they initially enhance nonpropulsive motility by causing spasm or contraction of the colon; the spasm is then followed by a variable degree of colonic relaxation. Diarrhea, discharges and abdominal cramps are reduced thereby. rfwo major objections to their use have been voiced, the potentiality of habituation and the occasional production of ileus. Opiates should therefore be used when diarrhea is not controllable by other means and their effects supervised carefully. Deodorized tincture of opium, 8 to 10 drops in water every four to six hours, is the drug of choice because of its less obnoxious taste. Codeine sulfate in 15 to 30 mg. doses may be preferred. Antispasmodics on the whole have been disappointing in controlling the cramping and diarrhea. Occasionally they may be helpful by preventing the gastrocolic reflex and therefore should be tried and be given before meals. No particular anticholinergic drug is recommended but if used it must be given in adequate doses, i.e., doses which cause drying of the mouth. Other antidiarrheal agents such as I{aopectate (1 tablespoonful), Kaomagma (1 tablespoonful) or calcium carbonate (2 grams) every four hours may aid in the milder cases of diarrhea but are ineffective in the severer forms. It is to be emphasized that at times mild laxatives have to be used. In patients with proctosigmoiditis the stools may be constipated but because of the frequent discharges may be erroneously interpreted as being diarrheal. r-rherefore the degree of formation of the stool should always be elicited. Mineral oil 1 to 2 tablespoonfuls daily or as often as required is recommended for the constipation. Treatlllent of Ancll1ia
'1'ransfusions of whole blood may be the only practical method of combating anemia since it is principally due to blood loss and infection, the latter being generally unresponsive to any measures except control of infection. Colitis patients do not tolerate oral iron preparations too well. Whole blood also provides protein as well as hemoglobin. Recently a nontoxic, intramuscular, iron-dextran preparation, Imferon, has become available for use in individuals with iron deficiency anemia who cannot tolerate or absorb oral iron preparations. Since iatrogenic hemochromatosis is a potential hazard, Imferon should not be administered indiscriminately. Each milliter of this preparation contain 50 mg. of elemental iron. '1'he total dosage can be calculated from th
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formula recommended by McCurdy, Roth and Meerkrebs26 or the manufacturer. Antibiotics
Now that the infectious theory of etiology lies more or less dormant, it is generally agreed that antibiotics are not to be used in the uncomplicated case. Good results in 61.7 per cent of 167 cases treated with antibiotics have been reported. 27 (Parenthetically, it may be stated that apparently 60 per cent of patients respond to any new regimen be it sulfonamides, antibiotics, hog's stomach extract or the like.) However, the danger of developing resistant strains of bacteria and overwhelming Monilia infections and the ability of these drugs to aggravate and produce diarrhea and colitis constitute formidable contraindications to their use. Antibiotics should be reserved for those patients with severe toxemia who are being treated with steroids, suppurative complications, intestinal perforation, pericolitis and peritonitis. Aqueous penicillin 600,000 units q.i.d. with streptomycin, 0.5 gram b.i.d. intramuscularly, or one of the tetracyclines, 0.5 to 1 gram in 1000 cc. of 5 per cent glucose b.i.d. intravenously, is equally effective. Sulfonamides
Of 1275 cases treated with a variety of sulfonamides, 57.7 per cent were reported to show a favorable response. 27 It has been the author's experience that some mild or moderately ill patients respond to one or another of the sulfonamides in spite of the fact that infectious agents are not responsible for the disease. Sulfasuxidine 8 to 12 grams per 24 hours, Sulfathalidine 3 to 6 grams per 24 hours, and Azulfidine 4 to 8 grams per 24 hours in divided doses have induced remissions where other measures have failed (see case report which follows). Of the sulfonamides, Azulfidine is the most interesting because it has received the most enthusiastic reports.28, 29 This substance is an azo compound of salicylic acid and sulfapyridine and is supposed to have an affinity for connective tissue. Improvement usually occurs within a week, the number of stools are reduced, bleeding and discharges decrease and fever subsides. Unfortunately, Azulfidine causes a high incidence of skin eruptions and may have to be discontinued for this reason. Sulfonamides are indicated for patients with mild or moderately severe ulcerative colitis and sh~uld be continued for one to two months after a remission has been induced. They are sometimes used routinely with steroid therapy. CASE 11. T.M., a man aged 64, has had ulcerative colitis since 1949. He was hospitalized in 1950 and then in 1953 because of bloody diarrhea, abdominal cramps and a 10 to 20 pound loss of weight. In 1954 he was treated with ACTH intramuscularly on an outpatient basis because of another recurrence. After a month of therapy, he developed a thrombophlebitis of his right leg which wa~
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followed by t\VO pulmonary emboli for which he was hospitalized. Two subsequent recurrences of bloody diarrhea in 1955 were treated with oral cortisone, the patient continuing to work. Each time after 3 weeks of cortisone, his thrombophlebitis was reactivated; at one time the veins of his right arm were involved. Since these thrombotic episodes occurred only after steroid therapy and when the patient was not very ill, it was felt that the steroids were at fault and should not be used. His present admission in August 1957 was due to a 3-month history of bloody diarrhea consisting of 7 to 13 bowel movements in 24 hours, a weight loss of 23 pounds and anorexia. He was afebrile and his hemoglobin was 12.1 grams per cent. 13ed rest, bland diet, deodorized tincture of opium, and sedation were without effect and he lost 5 more pounds in 21 days. He was then started on 1.5 gram of Azulfidine q.i.d. 'Vithin a week he was passing only 3 or 4 formed bowel movements a day with occasional traces of blood. When last seen in January 1958, his bowel movements were the same and he had regained his lost vveight. He was being nlaintained on Azulfidine 1 gram q.i.d.
ACTH and Adrenocortical Steroids
As more experience in the use of ACTH and adrenocortical steroids accumulates, it has become apparent that these drugs are the most effective medicinal agents in the therapy of ulcerative colitis. Whether this note of optimism will persist and whether steroids* will alter the longterm course of the disease and the mortality rate cannot be answered, since present experience is of relatively short duration. Unquestionably they induce a rapid remission in a large percentage in the first course of treatment-85 per cent of 180 patients in a study reported by Kirsner, Sklar and Palmer. 22 In a carefully controlled but not comparable study, Truelove and Witts30 also demonstrated the superiority of steroids (cortisone) over the usual medical methods. Relatively small doses of cortisone were given for six weeks to three months to one group of individuals who were followed for 18 months. Cortisone induced more rapid and frequent remissions and recurrences were fewer. Unfortunately, the relapse rate after cessation of treatment is 70 to 80 per cent. The response to a second course is often not so dramatic, nor is the effectiveness so great. Facts like these make one wonder about the ultimate role of the steroids. It is commonly agreed that steroids are most potent when administered early in the course of the disease, if the attack is the first one and especially if the colon is only superficially involved rather than being fibrotic and thickened. 31 In part, therefore, the decreasing responsiveness may be due to worsening of the pathological process. Steroids are thought to induce a remission because of their antiinflammatory effect, i.e., a reduction in the vascular and tissue responses to inflammation. A rapid and almost immediate drop in temperature and disappearance of toxemia occurs (Fig. 171, Case Ill) which is followed in a few days to a week by a decrease in diarrhea, discharges and
* In conformity with general usage the meaning of the term "steroid" is broadened in this discussion to include ACTH, which chemically is not a steroid.
Philip Krarner
1412 PULSE 160 107
ACTH STARTED
~
140 105
120 103
100
101
80
99
60
97
40
PULSE ••••• TEMR95 ......._ _....L.-_ _- I -_ _- - ' -_ _---II....-_ _.&--_ _- ' - -_ _---'-_ _
2
3
4
5
6
7
~
8
TEM~o~ DAYS Fig. 171. CASE Ill. In this chart the draIllatic response which followed the administration of ACTH gel intramuscularly can be seen. This patient, a woman aged 30, entered the hospital with a 2~ lllonths' history of diarrhea. One and one-half years and again 4 months previously, occasional rectal bleeding was observed but attributed to hemorrhoids. Two and one-half months prior to admission her bowel movements increased to 4 or 5 per day, they were looser than usual and occasionally contained blood. Three days prior to adnlission she began to have severe abdominal cramps, 7 or 8 loose profu8ely bloody movernents per day, chills and fever. On hospital admission she appeared dehydrated, acutely ill, toxic and lethargie. Her temperature was 102°, her pulse 112. Her abdonlen was generally tender and there was peritoneal rebound referred to the lower left quadrant. The hemoglobin was 12.6 gm. per cent, the W.B.C. 7600 and the serum sodium 129 mEq./liter. The latter was the only chemical abnormality. I)uring the first 5 days she was rehydrated, the low serum sodium was corrected and she was treated with intramuscular penicillin and strept(Hllycin. She was not given steroids because of the fear that she had pericolitis. She continued to have a spiking fever to 104°, severe abdominal cranlps and bloody dial'rhea. On the sixth hospital day ACTH gel 40 units every 8 hours, intrallluscularly, was started with an irnmediate drop in fever, pulse rate and improvenlent in her general condition. lIer diarrhea decreased Inore slowly over a period of 3 weeks.
abdominal discomfort and a return in appetite and sense of well-being. Sigmoidoscopic improvement may lag for weeks to months and may be complete or Inay never return to nornluJ despite a complete clinical renlission. If a good symptolnatic response to optimum steroid therapy does not occur in two weeks, then the chances for success with further treatment are remote. lJnless specific contraindications exist, any patient can be considered deserving of trial with these drugs if it is realized that they are expensive and indefinite prolonged usage may be required once therapy is initiated. It is because of this latter situation and the high incidence of side effects
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that steroids are not unreservedly recommended. Attempts at reducing dosage may be attended by an immediate relapse so that therapy in terms of years may have to be contemplated. Steroid therapy is indicated in patients with (1) acute fulminant colitis, (2) recurrent chronic disease whether ITlild or severe which haR not responded to Inedical management in the hospital, (3) systelnic corIlplications such as erythema nodosum, iridocyclitis and arthritis. COlltraindications are few and apply principally when pyogenic cOlnplications, intestinal perforations or impending perforations, peritonitis, abdominal abscesses and fistulas exist. In patients with severe malnutrition, marked electrolyte imbalance, anemia and colonic distention, steroids should be withheld until these complications can in part be corrected because steroids may aggravate the electrolyte abnormalities and also unnecessarily defer immediately required surgery. Brooke32 has observed marked thinning and almost complete disintegration of the colon in this severely ill group when steroids were used so that surgical removal of the colon became extremely hazardous. Giant ulcerations of the colon, peptic ulcer and massive hemorrhage from the colon have been reported as resulting from steroid therapy. Should the presence of these complications contraindicate the use of these drugs? Healing of giant ulcerations has occurred, massive hemorrhages which are not exsanguinating have stopped and peptic ulcers have not been reactivated during therapy.33 rrherefore, if steroids are indicated they can be given if proper supervision and precautions are pursued. ACTH is unequivocally the drug of choice; it may be injected as a gel, 40 units' intramuscularly every eight hours; as an aqueous solution, 30 units intramuscularly every six hours; or as an intravenous aqueous solution containing 20 units of ACTH dissolved in 500 cc. of 5 per cent glucose, every 12 hours. l-'he last is the optimum way of giving ACTH from the standpoint of potency and cost, but unfortunately it is the most inconvenient to the patient. If no response is observed with oral steroids or other modes of administering ACTH, then the intravenous route should be tried before considering steroid therapy to be unsuccessful. Oral steroids in decreasing order of effectiveness are hydrocortisone 200 rng. daily, prednisone 40 to 80 mg. daily, prednisolone 40 to 80 mg. daily and cortisone 300 mg. daily; doses of this magnitude are used at the start of treatment. Cortisone is approxiInately 70 per cent as effective as ACTH. The initial dose of each drug is continued for one to two weeks and then reduced by one-quarter or one-third in weekly or bimonthly intervals depending upon the response. If treatment was begun with ACTH, then once the dose is 40 units it can be replaced entirely by oral steroids over a two to three day period, both being given concomitantly; one unit of ACT!I equals approximately 1 rng. of prednisone or prednilsolone, 2 mg. of hydrocortisone, and 2.5 nlg. of cortisone. Daily maintenance doses
Philip Kramer are ACTH 20 to 40 units intramuscularly, hydrocortisone 40 to 80 mg. by mouth, prednisone or prednisolone 15 to 30 mg. by mouth. Final discontinuation of therapy should be gradual over a period of two to three months when bowel function is normal, blood remains absent from the stools, a sense of well-being persists and the pathological process in the rectum or sigmoidoscopy shows regression. Unfortunately, side effects are seen in a large proportion of patients when treated with the dosage schedule outlined. These are edema, acne, hirsutism, hypertension, obesity, electrolyte abnormalities (hypokalemic, hypochloremic alkalosis), hyperglycemia, glycosuria, infections and emotional disturbances such as anxiety attacks, agitation and even schizoid, manic or depressive states. With adrenocortical steroids, endogenous adrenal function may become suppressed for as long as three to six months after discontinuance of the drug. Adrenal hypofunction may be overtly apparent clinically (weakness, hyporeflexia, etc.) or appear only when stress or infection supervenes. These adverse effects can be managed, in general, by salt restriction, mercurial injections, oral potassium chloride 3 to 6 grams per day as tablets or as a 10 per cent solution added to orange juce, antibiotics or absorbable sulfonamides, dermatologic preparations and sedatives. If the side effects are incapacitating or endangering to either physical or mental health, the dosage of steroid will have to be reduced or even discontinued. One must be on constant guard for adrenal hypofunction whether during therapy or after the drugs have been discontinued; adrenocortical steroids have to be reinstituted in the latter situation or increased in the former. In fact, emergency measures such as are used in an adrenal crisis occasionally may be necessary. Local hydrocortisone as a slow drip into the rectum has been recommended in patients with mild left-sided disease. 34 Hydrocortisone 120 mg. is dissolved in 250 m!. of saline; half the amount is given the first night and thereafter the size of the enema increased until the total 250 m!. is given. The treatment is given nightly for two weeks. Remission or improvement in symptoms was induced in 15 of 21 cases but no change in the rectal mucosa was noted grossly or histologically. Relapses in four patients after cessation of therapy required treatment. In patients personally observed, this method of therapy has been successful in 50 per cent but has not altered the course of disease. INDICATIONS FOR SURGICAL INTERVENTION
Regardless of the quality and intensiveness of medical therapy, surgical intervention may be necessary either as a lifesaving measure or to rescue the patient from a life of chronic invalidism. Actually, surgery probably should be employed more frequently than it is. At present the operative mortality is less than 5 per cent, ileostomy complications 4 per cent or less, and late postoperative deaths 3 per cent. as - as Only three
The Management of Ulcerative Colitis
1415
operative procedures are currently recommended: (1) an initial ileostomy and partial colectomy followed by a proctectomy at a later date,S6 (2) an initial ileostomy and then colectomy and proctectomy in one or two stages,37 (3) a colectomy and ileorectal anastomosis in several stages. S8 An ileostomy once performed is permanent and the patient should be so warned since recurrence of disease is over 50 per cent when reanastomosis is attempted. Ileostomy alone as definitive therapy has been abandoned because the possibility of toxemia, protein and electrolyte depletion, perforation, carcinomatous degeneration and hemorrhage persists unless the diseased colon and rectum are removed. The indications for sugery are: 1. Chronic Invalidism. The decision as to when a patient fits into this category is one most difficult to make. So many patients smolder along with both the physician and patient hoping for improvement that never happens. In part the physician can be guided by the attitude of the individual, Le., if he or she expresses a desire for operative treatment. If a patient requires two or more hospitalizations per year, then an active stand should be taken to abandon medical therapy. 2. Acute Fulminant Colitis. When a patient with fulminant colitis fails to respond to optimum medical therapy within two weeks, surgical treatment should be strongly advised. The major mortality, whether medical or surgical, falls into this group. 3. Intestinal Perforation or Impending Perforation. If the perforation is acute, peritonitis ensues; if subacute or chronic, then localized abscesses or fistulas may occur. Except for rectovaginal fistulas in women, fistulas between viscera are rare. 4. Carcinoma, or Suspicion of Carcinoma. The incidence of carcinoma is said to be between 3 and 10 per cent. However, in patients who have had ulcerative colitis for over ten years a higher incidence has been reported. 39 No relationship exists between the severity of illness and the development of carcinoma, since some patients develop this complication after they had considered themselves cured of colitis. 40 5. Systemic Complications. Arthritis, uveitis, the various skin disorders, liver disease, etc., are secondary to the colitis but in themselves may cause permanent disability. Their failure to respond to medical treatment therefore constitutes an indication for colectomy before permanent damage ensues. Actually, the lack of therapeutic results also suggests intractability of the colitis. 6. Massive Hemorrhage. This complication constitutes an imperative indication and is evident by the passage of large blood clots and the need for repeated transfusions to maintain normal hemoglobin levels. Immediate colectomy is the operation of choice. 7. Intractable Perianal Abscesses and Fi8tulas. Except for simple drainage procedures, local surgery is often not advisable because healing usually fails. 8. Strictures. On rare occasions, strictures may cause intestinal ob-
Philip Kra'fner
1416
struction. lVlore often, this cOInplication is an indication for surgical intervention because it is confused with careinonul. SUMMARY AND CONCLUSIONS
'T'he nlanagenlent of nonspecific ulcerative colitis is symptomatic and depends upon the establishment of a good doctor-patient relationship. Bed rest, minor dietary restrictions, sedatives and opiates form the background for medical therapy. If the attack is of mild or moderate severity, Azulfidine or one of the other sulfonamides may be tried. A favorable response should be observed in one to two weeks if sulfonamides are to be effective in inducing a remission. Steroid therapy is indicated in patients (1) with acute fulminant colitis, (2) who are hospitalized and have failed to respond to other medical measures, (3) with systemic complications. While steroids are the most effective medicinal agents presently available, they are not unreservedly recommended in all cases because of expense, side effects and inability to foresee duration of therapy that will be required. Whether steroids will alter the unfavorable long-term prognosis cannot be stated as yet because the follow-up period has been relatively short when one considers the chronic course of the disease. Improvement in operative techniques, preoperative preparation and postoperative care has greatly reduced the operative and postoperative nlorbidity and mortality. Therefore surgical intervention should not be delayed until the patient is moribund. REFERENCES 1. llicketts, W. E., Kirsner, J. B. and Palmer, W. L.: Chronic Nonspecific Ulcerative Colitis. A Roentgenologic Study of its Course. Gastroenterology 10: 1, 1948. 2. Manson-Bahr, P.: Itectal Biopsy as an Aid to the Diagnoses of Amoebic Dysentery and Allied Disease of the Colon. Lancet 1: 763, 1957. 3. Felsen, J. and Wolarsky, W.: Acute and Chronic I~acinary Dysentery and Chronic Ulcerative Colitis. J.A.M.A. 153: 1069, 1053. 4. Chewning, C. C..Jr.: Colitis Following the Oral Administration of Aureonlycin and Terramycin. Virginia M. Month. '/'9: 136, 1952. 5. Goldgraber, M. B. and Kirsner, J. B.:. "Specific" Diseases Simulating "N 011specific" Ulcerative Colitis (Lyml>hopathia Venereum, Acute Vasculitis, Scleroderma and Secondary Anlyloidosis). Ann. Int. Med. 47: 939, 1957. 6. Kogan, E. and Janovitz, H. D.: Intestinal Tuberculosis: Difficulties in Diagnoses in Absence of Florid Pulmonary Involvement. J. lVlt. S'inai Hosp. 23: 597, 1956. 7. Warren, 1. A. and Berk, J. E.: The Etiology of Chronic Nonspecific Ulcerative Colitis. A Critical Review. Gastroenterology 33: 395, 1957. 8. White, B. V.: The Effect of Ileostomy and Colectomy on the Personality Adjustment of Patients with Ulcerative Colitis. New England J. Med. 244: 537, 1951. 9. Groen, J. and Bastiaans, J.: PRychotherapy of Ulcerative Colitis. Gastroenterology l'l: 344, 1951. ID. Grace, W. J., Pinsky, R. H. and Wolff, H.: The Treatment of Ulcerative Colitis. 11. Gastroenterology 26: 462, 1954.
The M anage'rnc'nt of Ulcerat'ive Colitis
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11. Levine, 1\1. ])., l(irsner, J. B. and I{lotz, A. P.: A New Concept of the Pathogenesis of Ulcerative Colitis. Science lllt: 552, 1951. 12. Crawford, N. and Brooke, 13. N.: Ileostomy Chemistry. Lancet 1: 864-, 1957. 13. Lubran, 1\1. and 1\1eAllcn, P. M.: Potassium Deficiency in Ulcerative Colitis. Quart. J. IVled. 20: 221, 1951. 14. Welch, C. S., Adams, M. and Wakefield, C. (i.: Metabolic Studies on Ulcerative Colitis..J. Clin. Invest. 16: 161, 1~)37. 15. Poscy, F~. L. and Bargen, J. A.: Metabolic ])erangelnents ill Chronic lJlcerative Colitis. (Jastroenterology 16: 39, 1950. Hi. Nappington, T. S. and Bockus, H. L.: Nitrogen Metabolislll in Chronic Idiopathic Ulcerative (~olitis and Its 'I'herapeutic Significance. Ann. Int. 1\led. 31: 282, 1949. 17. Sandweiss, I). J. and Levy, S. H.: Gastrointestinal Absorption with Oleic Acid-P31 and l-Methionine-S 35 in Patients with Ulcerative Colitis. Proc. Soc. Expel'. BioI. & Med. 95: 259, 1H57. 18. Pollard, H. 1\1., Block, M. and Bachrach, W. 11.: Causes and Managenlcnt of Anemia Associated with Chronic lJleerative Colitis. J.A.M.A. 134: 341, 1~)47. 19. Bargen, J. A., Sauer, W. Cl., Sloan, W. P. and Gage, H,. P.: The Developrnent of Cancer in Chronic Ulcerative Colitis. Gastroenterology 26: 32, 1954. 20. Wheelock, F. C. Jr. and Warren R.: Ulcerative Colitis-Follo,v-up Studies. New England J. Med. 252: 421, 1~)55. 21. l~anks, B. M., I{orelitz, B. 1. and Zetzel, L.: "'fhe Course of Non-specific Ulcerative Colitis: Review of Twenty Years Experience and La.te llesults. Gastroenterology 82: 983, 1957. 22. I(irsner, J. B., Sklar, M. and Palmer, W. L.: The Use of AC1'1H, Cortisone, Hydrocortisone and llelated Compounds in the Management of Ulcerative Colitis. Anl . .T. Med. 22: 264, 1957. 23. Maltby, E. J., Dickson, R. C. and O'Sullivan, P. 1\1.: The Use of AC1'1H and Cortisone in Idiopathic Ulcerative Colitis. Canad. M .A.J. 74: 4, 1956. 24. Lindeman, I~.: Psychiatric Aspects of the Treatment of lJlcerative Colitis. Arch. Neurol. & Psychiat 58: 322,1945. 25. Cooke, R. I~. and Crowley, L. G-.: Ileplacement of Gastric and Intestinal Fluid ]~osses in Surgery. Ne,v F~ngland J. Med. 246: 637, 1952. 26. McCurdy, P. Il., Ilath, C. 1£. and Meerkrebs, G. :E.: Parenteral Iron Therapy with Special Iteference to a New Preparation for Intramuscular Injection. New England .T. l\1ed. 257: 1147, 1957. 27. Machella, T. E., Problems in Ulcerative Colitis. Am. J. Med. 18: 760, 1H52. 28. Bargcn, J. A.: The Management of Patients with IJlcerative Colitis. M. CLIN. NORTH AMERICA 40: 541, 1956. 29. Svartz, N.: The Treatment of IJlcerative Colitis. Gastroenterology 26: 26, 1954. 30. Truelove, S. C. and WiUs, L. J.: Cortisone in lJlcerative Colitis, Final Report on a Therapeutic Trial. Brit. IV!. .1. 2: 1041, 1055. 31. Jlalsted, J. A., Adanls, W. S., Sloan, S., vValtel's, l~,. L. and Bassett, S. 11.: SYlnposiunl on A(~TH and Cortisone as llelated to Gastrointestinal Tract: Clinical FXfects of A(jTlf in lJlcerative Colitis. (}astroenterology 2,9: 6H8, IH51. 32. Brooke, B.N.: (})ltiSOIH~ tllHl lJlcerative Colitis an Adverse E-ffect. Lancet 2: 1175, 1056. 33. l(risner, .J. B.: IJlcerative Colitis; Observations on Its Etiology, Course and Managenlent. Postgrad. Med. 22: 132, 1~)57. 34. Truelove, S. C.: l'reatment of Ulcerative Colitis with Locnl lIydrocortisone. Brit. M. J. 2: 1267, 1056. 35. I)ukes, C. E. and Lockhart-l\fumlnery, IL E.: Pl'actical Points in the Pathology and Surgical 'rreatment of Ulcerative Colitis. Brit. J. Surg. 45: 25, 1957. 36. Ripstein, C. B.: Primary Itesection of the Colon in Acute lncerative Colitis. J.A.M.A. 15,03: 1093, 1953. 37. Cattell, It. B. and Colcock, B. P.: Surgical TreatInent of Ulcerative Colitis. Postgrad. Med. 17: 114, 1955.
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Philip Kramer
38. Aylett, S.: Total Colectomy and Ileo-Rectal Anastomosis in Diffuse Ulcerative Colitis. Brit. M. J. 1: 489, 1957. 39. Counsell, P. B. and Dukes, C. E.: The Association of Chronic Ulcerative Colitis and Carcinoma of the Rectum and Colon. Brit. J. Surge 39: 1, 1952. 4:0. Svartz, N.: The Pathogenesis and Treatment of Ulcerative Colitis. Acta. med. Scandnav. 141: 172, 1951. 65 E. Newton Street Boston 18, Massachusetts
WHILE gratifying progress has been made in the therapy of ulcerative colitis, especially since the advent of steroids and the improvement in general medical, nursing and surgical care, the management of patients so afflicted remains a formidable task. Ulcerative colitis is a disease which is invested by a cloak of almost complete obscurity. Thus little is known of its etiology or pathogenesis. The course and response to therapy are unpredictable, remissions and exacerbations often occurring without apparent cause. Although there are characteristic clinical features that should make one suspect the diagnosis, this cannot always be made with certainty unless other specific diseases are excluded. To further complicate matters, colitis patients are brittle individuals, emotionally and physically, so that their state of health can deteriorate precipitously. Since the illness is chronic and recurring, frequent hospitalizations are often required; economic problems arise because of the expensive medical therapy needed and the inability of the individual to pursue a gainful occupation. Not only are these problems detrimental to the patient's emotional health, but they also make the task of the conscientious physician difficult because he often has to manipulate the sociological environment in order to render medical care. Unfortunately, the only definitive "medical" therapy is surgical removal of the diseased organ and creation of a discharging abdominal stoma, which is abhorrent to the average ulcerative colitis patient. In essence, the treatment of ulcerative colitis is symptomatic, supportive and corrective. A rational approach to management therefore involves (1) a correct diagnosis, (2) removing such etiological factors as exist, (3) remedying such abnormalities in the pathophysiology as have occurred.
From the Evans Memorial of the Massachusetts M emorial Hospitals and the Department of Medicine. Boston University School of Medicine, Boston.
* Assistant Professor of Medicine, Boston University School of Medicine; Associate Visiting Physician, Massachusetts Memorial Hospitals; Associate Member, Evans M emorial, Massachusetts M emorial Hospitals. 1401
Philip Kramer
14-02
Fig. 170. CASE L This x-ray demollstrates the radiographic findings in a female patient aged 36 with a 14 year history of ulcerative colitis. During this period the patient was hospitalized six times and suffered at least an equal number of recurrences which were treated at home. Constipation associated with bloody discharges has been a frequent complaint requiring the use of mineral oil. Other therapy has consisted of Sulfasuxidine, Azulfidine, ACTH, cortisone and hydrocortisone. She responded favorably to each of these medications when given for 1 or 2 courses but subsequent courses were ineffective. Azulfidine had to be discontinued because of a severe maculopapular skin eruption. In spite of this long history and frequent recurrences the disease has remained confined to the rectum, rectosigmoid and probably terminal part of the descending colon. There is narrowing of the lumen in these areas, loss of haustral markings and normal mucosal pattern. The changes have been progressive but there has been no extension proximally. This case illustrates that ulcerative colitis may exist in a relatively benign form for a long period of time. DIAGNOSIS
The diagnosis of nonspecific ulcerative colitis is based upon: 1. The Clinical Picture. Diarrhea is the outstanding symptom; anywhere up to 30 or more loose stools per 24 hours may be passed containing blood and mucopurulent material. These stools have a characteristic appearance and much can be learned as to the severity of the illness, course and response to therapy from observing their gross appearance daily. When the pathologic process is confined to the rectum or rectosigmoid there may be constipation (10 per cent of patients) instead of diarrhea, with the passage of hard scybalous stools and bloody mucopurulent discharges independent of bowel movements (Fig. 170, Case I).
The Management of Ulcerative Colitis
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Cramping abdominal pain relieved by bowel movements, tenesmus, varying degrees of fever and malnutrition, anorexia, anemia and a number of systemic complications, such as arthritis and erythema nodosum, complete the clinical picture. 2. Sigmoidoscopy. On sigmoidoscopy the mucosa is diffusely hyperemic, edematous, granular appearing, usually superficially but at times deeply ulcerated. Characteristically, the mucosa is friable and bleeds easily when rubbed with a swab. A negative sigmoidoscopy does not rule out the disease because in approximately 5 per cent of colitis patients the visualized mucosa is normal. These individuals are suffering from segmenta colitis, i.e., right-sided colitis or colitis in some area other than the rectosigmoid. 3. Barium Enema. Roentgenographic manifestations in mild cases are confined to changes in mucosal pattern; the mucosa appears fuzzy, feathery or may show a finely serrated saw-tooth appearance. In moderately advanced involvement the mucosal pattern is more distorted, larger ulcerations are seen and haustral markings are lost. Advanced disease is manifested by loss of mucosal pattern, giant ulcerations, pseudopolypoid changes, narrowing and shortening of the bowel so that the hepatic and splenic flexures tend to disappear. On the initial examination in a study reported by Ricketts, Kirsner and Palmer,l approximately 39 per cent of patients had a normal barium enema. 4. Absence of Known Pathogens from the Stool or Clinical Findings Suggestive of Another Disease. Other conditions may simulate either or both the radiologic or sigmoidoscopic appearance of ulcerative colitis. Diffuse amebic colitis, postbacillary dysentery colitis, the colitis and proctitis produced by Aureomycin and Terramycin, lymphopathia venereum, secondary amyloidosis, colonic changes produced by vascular lesions, regional enteritis involving the right colon and even tuberculosis of the colon are among the conditions that may be confused with ulcerative colitis. 2 , 3, 4, 6, 6 Therefore stool cultures, agglutination tests, and examination of stools for ova and parasites should be routinely done in suspected colitis; other diagnostic procedure such as a Frei test or a tuberculin test may have to be performed in occasional patients. ETIOLOGY
Although the cause of ulcerative colitis is unknown, a discussion of the prevalent theories of the etiology is necessary in order to justify certain of the therapeutic practices. For a detailed, readable review of the etiology the article by Warren and Berk is recommended. 7 Infectious Theory. The fever, toxemia, purulent rectal discharges, leukocytosis, microscopic abscesses in the colon and the occasional response to antibacterial agents suggest an infectious causation. Many bacteria, fungi and viruses have been incriminated but none has been confirmed by independent groups of investigators. Furthermore, the dis-
Philip Kramer ease has not been shown to be transmittable; spontaneous remission and exacerbation occur without use of anti-infectious agents or evidence of reinfection. Psychosomatic Theory. The following evidence is given to support the theory that ulcerative colitis is a psychosomatic disorder: (1) Colitis patients have an unusual personality pattern, Le., they are immature, abnormally dependent upon a so-called father or mother figure, unable to cope with adult problems, passive, overfastidious and display repressed hostility. These features persist even after a total colectomy.8 (2) Stress interviews in individuals with exteriorized colonic mucosa induce hyperemia, ulcerations and excessive secretions. (3) Parasympathomimetic agents produce colonic balloon kymographic motility patterns similar to that seen in persons with ulcerative colitis. This latter finding offers a simple but not necessarily correct explanation as to the way stress is mediated, Le., via the parasympathetic nervous system. (4) Patients treated exclusively by psychiatric techniques have responded as well if not better than those treated by conventional medical measures. 9 , 10 The mechanism by which the abnormal psyche causes somatic changes in the colon is unknown. Nor has it been shown that these characteristics are specific for individuals with ulcerative colitis in contrast to those with other chronic diseases. Allergy and Tissue Hypersensitivity. The response to steroids suggests that ulcerative colitis is a disease of hypersensitivity. Likewise, the systemic manifestations, Le., arthritis, iridocyclitis, erythema nodosum and the finding of abnormalities in the basement membrane can be used as additional evidence to emphasize this suspicion as to the etiology.ll Allergy to foods such as milk, wheat or eggs or to bacteria or the products of bacteria have been incriminated. However, remissions occur regardless of diet, without changes in bacteria, and the alteration in the basement membrane has been found in other diseases. Destructive Enzymes. Rectal discharges from colitis patients may contain excessive lysozyme or proteolytic substances. Attempts to reproduce the clinical and pathologic aspects of the disease with these products have not been successful. Furthermore, proteolytic substances have not been found in all persons with ulcerative colitis, and other disease states show excessive lysozyme and proteolytic enzymes in the stools. PATHOPHYSIOLOG Y
The degree of metabolic and motor abnormalities depends upon the severity of the illness. At one end of the spectrum the individual with proctosigmoiditis may show apparent good health; at the other extreme the patient with acute fulminant colitis may be literally at death's door with severe toxemia, prostration, malnutrition, anemia, protein and electrolyte depletion. The aberrations observed are of multiple and com-
The Management of Ulcerative Colitis
1405
plex origin. They are due to (1) hyperirritability of the colon so that it cannot perform the normal motor functions involved in receiving and storing material from the ileum and then propelling and discharging this material when in proper physical form, (2) failure of the colon to absorb water and electrolytes, principally sodium, potassium, chloride and possibly calcium, (3) the excessive rectal discharges containing protein and blood, and (4) inadequate food intake. All gradations of water losses via the stools are possible, so that in severe colitis as much as 1500 to 3000 ml. or more of watery stools may be expelled. Whereas the normal sodium and potassium outputs in the stools per 24 hours are traces, 10 to 20 mEq. (0.4 to 0.8 gram) and 25 to 50 mEq. (0.5 to 1 gram) respectively, daily losses of sodium in severe colitis may be 20 to 265 mEq. (1.75 to 10.5 grams) with a concentration of 50 to 100 mEq./liter, potassium 20 to 80 mEq. (0.5 to 2 grams) with a concentration of 20 to 35 mEq./liter. J2 , 13, J4 In one patient 24 grams of potassium chloride per day by mouth were required to maintain a normal serum potassium. I3 Studies on stool calcium losses are meager; one report stated a loss of 85 mEq. or 1.6 grams/24 hours. l2 However, hypocalcemia and osteoporosis have been noted. 16 The loss of fluid and electrolyte per rectum leads to dehydration, hyponatremia, hypokalemia, hypoch10remia and acidosis. Loss of weight, malnutrition, and protein depletion (as measured by a decrease in total serum protein and serum albumin) result from excessive protein loss in stools, decreased food intake, and increased tissue breakdown and nutritional requirements because of the pyrexia and toxemia. Nitrogen losses from the bloody purulent exudate may vary from 1.9 to 9.30 grams/24 hours, the latter figure being found during active diarrhea (normal 0.7 to 1.5 grams/24 hours).14, 16, J6 This loss is equivalent to 11.8 to 58.2 grams of protein. There has been little question that protein depletion occurs in this manner, but the question of malabsorption of proteins and fats due to small intestinal malfunction has been controversial. Although abnormal fat losses are uncommon, as much as 16.3 per cent of fat intake may be excreted according to Welch et al. 14 Recent investigation with radioisotopic techniques suggest that there is malabsorption of protein and fat in the active phase of disease.I 7 Three types of anemia have been reported: (1) a microcytic, hypochromic anemia due to chronic blood loss and infection, (2) a normocytic, normochromic anemia due to depressed bone marrow activity, (3) a macrocytic anemia resulting from malabsorption of erythrocyte maturing factors. The evidence that a macrocytic anemia does occur is unsatisfactory. In 109 patients studied, anemia was found in 71 patients, 81.6 per cent having a microcytic, hyprochromic anemia and 18.4 per cent a normocytic, normochromic anemia, but none had a macrocytic anemia. 18 Blood loss via the bowel or from vaginal bleeding because of menstrua-
Philip Kramer
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tion and pregnancy in women, inadequate intake of iron, protein depletion, infection and toxemia were incriminated as the causes. PROGNOSIS
Changes over the years in the management of ulcerative colitis, the chronic prolonged nature of the disease which therefore invalidates shortterm statistics, and the extreme variability in clinical course create difficulties in attempting to make specific statements as to prognosis. I have selected several prognostic studies on the basis of size of patient population, length of follow-up and care exercised in tracing patients, to demonstrate the serious morbidity and mortality of this illness. Bargen, Sauer, Sloan and Gage 19 compared the survival curve of 1564 ulcerative colitis patients with the normal population of similar age and sex. Those who have had the disease 10 to 25 years after diagnosis have a 20 per cent less chance for normal survival when compared to the average population. The probability of carcinoma of colon is also 30 times greater than in the general population. Wheelock and Warren's20 figures are sobering and disturbing. Three hundred and forty-three patients seen between 1915 and 1943 were traced for ten years or until death; information concerning an additional 44 patients was available until time of operation. Of the 343 patients traced, 155 (45.3 per cent) were living and 188 (54.7 per cent) were dead. Ulcerative colitis was responsible for 153 death, or 45 per cent of the group. Two hundred and thirty-three or 60 per cent of 387 patients were eventually operated upon (the latter figure includes number of patients traced to the time of operation). Of the 81 patients who survived without operation, only 64 (19 per cent of 343) were well; whereas, of the 74 patients who had surgery, 69 were asymptomatic (20 per cent of 343). Perhaps more representative of the prognosis are the results of the study by Banks, Korelitz and Zetze1. 21 Two hundred and forty-five patients seen in the period 1931-1950 were traced, the average observation period being 12.1 years. Twenty per cent were well in respect to their colitis, 20 per cent had mild exacerbations, 20 per cent suffered severe exacerbations, 17 per cent were asymptomatic with definitive surgery, 3 per cent had a malfunctioning ileostomy and 20 per cent were dead. Approximately 34 per cent had required surgical therapy. While the findings since 1950, the beginning of the steroid era, are more encouraging, they are incomplete because the follow-up is much too short. Kirsner, Sklar and Palmer22 treated 180 patients with steroids, the observation period being less than two years in one-third of this group. The results expressed in whole percentage8 were excellent in 26 per cent, much improved in 43 per cent, course unchanged in 21 pet cent, surgical therapy required in 9 per cent, and 5 per cent died. In a Canadian series the medically treated presteroid era deaths were 38 per cent while the deaths in those treated with steroids were only 10 per cent. la
l he M ar~agelnent of Ulcerative ['(olitis 1
1407
MEDICAL THERAPY
General Measures
Since physical activity increases intestinal peristalsis, limitation of activity by imposing bed rest is recommended if the colitis is active. The degree of bed rest will depend on the severity of diarrhea, rectal discharges, fever, etc., and should continue until diarrhea and fever subside. Hospitalization becomes advisable if symptoms are more than mild in degree or if no response to bed rest at home has been observed. Two purposes are thereby accomplished: (1) removing the patient from probable noxious influences in the environment which more than likely were partially instrumental in precipitating the attack, (2) presenting the physician the opportunity for instituting a more intensive regimen. Some type of mild sedation will be required; phenobarbital 15 to 30 mg. q.i.d. is inexpensive and effective. Psychotherapy
Psychotherapy is supportive and essentially aimed at establishing a good doctor-patient relationship. Psychoanalytic methods aimed at exploring the psychodynamics are dangerous; they may cause the patient to leave treatment, become uncommunicative, develop overwhelming anxiety or regressive behavior such as defecating on the floor, experience psychotic manifestations such as auditory hallucinations or even severe exacerbation of diarrhea leading to death. 24 Formal psychiatric care is not necessary unless the patient is much improved, aware of emotional conflict, and requests such therapy; he or she should not be forced into extensive treatment. The physician's attitude should be one of kindness, encouragement and reassurance but also of firmness; he should retain complete control of the situation. Since colitis patients become so easily attached to hospital personnel whether they be interne, resident or dietitian, it is best that decisions emanate from one source, the responsible physician. In this way contradictory orders are avoided and the physician maintains a key role, the "father figure." Although no probing is done, patients should be encouraged to ventilate, assert themselves and discharge their aggressive feelings. Since they need support, frequent compliments even on minor matters aid greatly in building their ego. Under no circumstances should the physician betray his anxiety about a patient's condition. The social environment may have to be manipulated through discussions with parents, wife or husband, employer or nursing staff. Diet and Nutrition
Nutrition is of major importance in ulcerative colitis and therefore the diet should be high caloric (3000 calories per day), high protein (150 grams), palatable and attractive in appearance made so not only by the
1408
Philip Kramer
food content but also by the table accessories. Too often, and unnecessarily so, the diet becomes a major preoccupation of the patient, the physician and the dietetic staff. Thus the patient incriminates a variety of foods as either causing his disease or aggravating diarrhea; the physician and dietitian are frequently too rigid and unjustifiably eliminate foods they think are harmful. Consequently what is offered is an- unpalatable mess of pureed "slop" and "slush." Except for omitting the commonly known offenders listed below, the patient should be encouraged to eat a regular:diet, particularly if he expresses the desire for such. Frequent discussion between patient and dietitian will render the physician's task less difficult in achieving a satisfactory nutritional state. Foods which are obvious chemical or mechanical irritants and increase bowel activity should be eliminated. These foods are raw fruits and vegetables, high residue vegetables of the cabbage family, bran cereals, fruit juices except dilute orange juice, nuts, chocolates and cooked laxative fruits such as figs, raisins, prunes and carbonated beverages. Since cold increases intestinal peristalsis excessively, cold foods, especially iced drinks, are not to be served. ~< Vitamin B deficiencies are occasionally seen in the sick, toxic, malnourished individual with severe diarrhea and fever. Any of the supplemental vitamins may be used. Intravenous Feedings
In acute fulminant colitis or where severe diarrhea has been prolonged, the fluid and electrolyte depletion may be marked and require parenteral replacement. The admission serum Na, K, Co 2, Cl, Ca, blood urea nitrogen and hemogram will be a guide as to the need for, the type of and amount of intravenous fluid electrolyte therapy. During the first 24 hours correction of dehydration and other deficiencies may require 6 or more liters of fluid. The composition of the solution will depend upon the character of the electrolyte depletion and whether acidosis (diarrhea) or alkalosis (vomiting) is present. Liter solutions containing 5 per cent glucose alone or 5 per cent glucose, 0.9 per cent sodium chloride (150 mEq.) and 2.3 grams (30 mEq.) of potassium chloride given in quantities as needed should correct the dehydration and acidosis. (If necessary an ampule of Mj6lactate, 10 to 20 cc. of 10 per cent calcium gluconate and vitamins may be added.) Although more chloride and less sodium are required in alkalosis due to vomiting, the solutions mentioned should suffice. Daily electrolyte and fluid replacements can be estimated from daily determinations of the serum Na, K, Co~, Cl and an accurate record of intake and output. If special solutions are required because of severe alkalosis or acidosis, the article by Cooke and Crowley25 should be consulted. Proteins can also be given as 5 per cent protein hydrolysate, 5 per cent amino acid or 5 per cent salt-poor albumin solutions, provided 800 calories have been supplied in the form of glucose for energy require..
The Management of Ulcerative Colitis
1409
ments so that the nitrogenous substances will not be metabolized for this purpose. Antidiarrheal Agents Including Antispasnlodics
Except for steroids, the opiates are the most useful group of medicinal a.gents in the symptomatic treatment. Opiates exert their effect because they initially enhance nonpropulsive motility by causing spasm or contraction of the colon; the spasm is then followed by a variable degree of colonic relaxation. Diarrhea, discharges and abdominal cramps are reduced thereby. rfwo major objections to their use have been voiced, the potentiality of habituation and the occasional production of ileus. Opiates should therefore be used when diarrhea is not controllable by other means and their effects supervised carefully. Deodorized tincture of opium, 8 to 10 drops in water every four to six hours, is the drug of choice because of its less obnoxious taste. Codeine sulfate in 15 to 30 mg. doses may be preferred. Antispasmodics on the whole have been disappointing in controlling the cramping and diarrhea. Occasionally they may be helpful by preventing the gastrocolic reflex and therefore should be tried and be given before meals. No particular anticholinergic drug is recommended but if used it must be given in adequate doses, i.e., doses which cause drying of the mouth. Other antidiarrheal agents such as I{aopectate (1 tablespoonful), Kaomagma (1 tablespoonful) or calcium carbonate (2 grams) every four hours may aid in the milder cases of diarrhea but are ineffective in the severer forms. It is to be emphasized that at times mild laxatives have to be used. In patients with proctosigmoiditis the stools may be constipated but because of the frequent discharges may be erroneously interpreted as being diarrheal. r-rherefore the degree of formation of the stool should always be elicited. Mineral oil 1 to 2 tablespoonfuls daily or as often as required is recommended for the constipation. Treatlllent of Ancll1ia
'1'ransfusions of whole blood may be the only practical method of combating anemia since it is principally due to blood loss and infection, the latter being generally unresponsive to any measures except control of infection. Colitis patients do not tolerate oral iron preparations too well. Whole blood also provides protein as well as hemoglobin. Recently a nontoxic, intramuscular, iron-dextran preparation, Imferon, has become available for use in individuals with iron deficiency anemia who cannot tolerate or absorb oral iron preparations. Since iatrogenic hemochromatosis is a potential hazard, Imferon should not be administered indiscriminately. Each milliter of this preparation contain 50 mg. of elemental iron. '1'he total dosage can be calculated from th
1410
Philip Kramer
formula recommended by McCurdy, Roth and Meerkrebs26 or the manufacturer. Antibiotics
Now that the infectious theory of etiology lies more or less dormant, it is generally agreed that antibiotics are not to be used in the uncomplicated case. Good results in 61.7 per cent of 167 cases treated with antibiotics have been reported. 27 (Parenthetically, it may be stated that apparently 60 per cent of patients respond to any new regimen be it sulfonamides, antibiotics, hog's stomach extract or the like.) However, the danger of developing resistant strains of bacteria and overwhelming Monilia infections and the ability of these drugs to aggravate and produce diarrhea and colitis constitute formidable contraindications to their use. Antibiotics should be reserved for those patients with severe toxemia who are being treated with steroids, suppurative complications, intestinal perforation, pericolitis and peritonitis. Aqueous penicillin 600,000 units q.i.d. with streptomycin, 0.5 gram b.i.d. intramuscularly, or one of the tetracyclines, 0.5 to 1 gram in 1000 cc. of 5 per cent glucose b.i.d. intravenously, is equally effective. Sulfonamides
Of 1275 cases treated with a variety of sulfonamides, 57.7 per cent were reported to show a favorable response. 27 It has been the author's experience that some mild or moderately ill patients respond to one or another of the sulfonamides in spite of the fact that infectious agents are not responsible for the disease. Sulfasuxidine 8 to 12 grams per 24 hours, Sulfathalidine 3 to 6 grams per 24 hours, and Azulfidine 4 to 8 grams per 24 hours in divided doses have induced remissions where other measures have failed (see case report which follows). Of the sulfonamides, Azulfidine is the most interesting because it has received the most enthusiastic reports.28, 29 This substance is an azo compound of salicylic acid and sulfapyridine and is supposed to have an affinity for connective tissue. Improvement usually occurs within a week, the number of stools are reduced, bleeding and discharges decrease and fever subsides. Unfortunately, Azulfidine causes a high incidence of skin eruptions and may have to be discontinued for this reason. Sulfonamides are indicated for patients with mild or moderately severe ulcerative colitis and sh~uld be continued for one to two months after a remission has been induced. They are sometimes used routinely with steroid therapy. CASE 11. T.M., a man aged 64, has had ulcerative colitis since 1949. He was hospitalized in 1950 and then in 1953 because of bloody diarrhea, abdominal cramps and a 10 to 20 pound loss of weight. In 1954 he was treated with ACTH intramuscularly on an outpatient basis because of another recurrence. After a month of therapy, he developed a thrombophlebitis of his right leg which wa~
The Management of Ulcerative Colitis
1411
followed by t\VO pulmonary emboli for which he was hospitalized. Two subsequent recurrences of bloody diarrhea in 1955 were treated with oral cortisone, the patient continuing to work. Each time after 3 weeks of cortisone, his thrombophlebitis was reactivated; at one time the veins of his right arm were involved. Since these thrombotic episodes occurred only after steroid therapy and when the patient was not very ill, it was felt that the steroids were at fault and should not be used. His present admission in August 1957 was due to a 3-month history of bloody diarrhea consisting of 7 to 13 bowel movements in 24 hours, a weight loss of 23 pounds and anorexia. He was afebrile and his hemoglobin was 12.1 grams per cent. 13ed rest, bland diet, deodorized tincture of opium, and sedation were without effect and he lost 5 more pounds in 21 days. He was then started on 1.5 gram of Azulfidine q.i.d. 'Vithin a week he was passing only 3 or 4 formed bowel movements a day with occasional traces of blood. When last seen in January 1958, his bowel movements were the same and he had regained his lost vveight. He was being nlaintained on Azulfidine 1 gram q.i.d.
ACTH and Adrenocortical Steroids
As more experience in the use of ACTH and adrenocortical steroids accumulates, it has become apparent that these drugs are the most effective medicinal agents in the therapy of ulcerative colitis. Whether this note of optimism will persist and whether steroids* will alter the longterm course of the disease and the mortality rate cannot be answered, since present experience is of relatively short duration. Unquestionably they induce a rapid remission in a large percentage in the first course of treatment-85 per cent of 180 patients in a study reported by Kirsner, Sklar and Palmer. 22 In a carefully controlled but not comparable study, Truelove and Witts30 also demonstrated the superiority of steroids (cortisone) over the usual medical methods. Relatively small doses of cortisone were given for six weeks to three months to one group of individuals who were followed for 18 months. Cortisone induced more rapid and frequent remissions and recurrences were fewer. Unfortunately, the relapse rate after cessation of treatment is 70 to 80 per cent. The response to a second course is often not so dramatic, nor is the effectiveness so great. Facts like these make one wonder about the ultimate role of the steroids. It is commonly agreed that steroids are most potent when administered early in the course of the disease, if the attack is the first one and especially if the colon is only superficially involved rather than being fibrotic and thickened. 31 In part, therefore, the decreasing responsiveness may be due to worsening of the pathological process. Steroids are thought to induce a remission because of their antiinflammatory effect, i.e., a reduction in the vascular and tissue responses to inflammation. A rapid and almost immediate drop in temperature and disappearance of toxemia occurs (Fig. 171, Case Ill) which is followed in a few days to a week by a decrease in diarrhea, discharges and
* In conformity with general usage the meaning of the term "steroid" is broadened in this discussion to include ACTH, which chemically is not a steroid.
Philip Krarner
1412 PULSE 160 107
ACTH STARTED
~
140 105
120 103
100
101
80
99
60
97
40
PULSE ••••• TEMR95 ......._ _....L.-_ _- I -_ _- - ' -_ _---II....-_ _.&--_ _- ' - -_ _---'-_ _
2
3
4
5
6
7
~
8
TEM~o~ DAYS Fig. 171. CASE Ill. In this chart the draIllatic response which followed the administration of ACTH gel intramuscularly can be seen. This patient, a woman aged 30, entered the hospital with a 2~ lllonths' history of diarrhea. One and one-half years and again 4 months previously, occasional rectal bleeding was observed but attributed to hemorrhoids. Two and one-half months prior to admission her bowel movements increased to 4 or 5 per day, they were looser than usual and occasionally contained blood. Three days prior to adnlission she began to have severe abdominal cramps, 7 or 8 loose profu8ely bloody movernents per day, chills and fever. On hospital admission she appeared dehydrated, acutely ill, toxic and lethargie. Her temperature was 102°, her pulse 112. Her abdonlen was generally tender and there was peritoneal rebound referred to the lower left quadrant. The hemoglobin was 12.6 gm. per cent, the W.B.C. 7600 and the serum sodium 129 mEq./liter. The latter was the only chemical abnormality. I)uring the first 5 days she was rehydrated, the low serum sodium was corrected and she was treated with intramuscular penicillin and strept(Hllycin. She was not given steroids because of the fear that she had pericolitis. She continued to have a spiking fever to 104°, severe abdominal cranlps and bloody dial'rhea. On the sixth hospital day ACTH gel 40 units every 8 hours, intrallluscularly, was started with an irnmediate drop in fever, pulse rate and improvenlent in her general condition. lIer diarrhea decreased Inore slowly over a period of 3 weeks.
abdominal discomfort and a return in appetite and sense of well-being. Sigmoidoscopic improvement may lag for weeks to months and may be complete or Inay never return to nornluJ despite a complete clinical renlission. If a good symptolnatic response to optimum steroid therapy does not occur in two weeks, then the chances for success with further treatment are remote. lJnless specific contraindications exist, any patient can be considered deserving of trial with these drugs if it is realized that they are expensive and indefinite prolonged usage may be required once therapy is initiated. It is because of this latter situation and the high incidence of side effects
TYke Management of Ulcerative Colitis
1418
that steroids are not unreservedly recommended. Attempts at reducing dosage may be attended by an immediate relapse so that therapy in terms of years may have to be contemplated. Steroid therapy is indicated in patients with (1) acute fulminant colitis, (2) recurrent chronic disease whether ITlild or severe which haR not responded to Inedical management in the hospital, (3) systelnic corIlplications such as erythema nodosum, iridocyclitis and arthritis. COlltraindications are few and apply principally when pyogenic cOlnplications, intestinal perforations or impending perforations, peritonitis, abdominal abscesses and fistulas exist. In patients with severe malnutrition, marked electrolyte imbalance, anemia and colonic distention, steroids should be withheld until these complications can in part be corrected because steroids may aggravate the electrolyte abnormalities and also unnecessarily defer immediately required surgery. Brooke32 has observed marked thinning and almost complete disintegration of the colon in this severely ill group when steroids were used so that surgical removal of the colon became extremely hazardous. Giant ulcerations of the colon, peptic ulcer and massive hemorrhage from the colon have been reported as resulting from steroid therapy. Should the presence of these complications contraindicate the use of these drugs? Healing of giant ulcerations has occurred, massive hemorrhages which are not exsanguinating have stopped and peptic ulcers have not been reactivated during therapy.33 rrherefore, if steroids are indicated they can be given if proper supervision and precautions are pursued. ACTH is unequivocally the drug of choice; it may be injected as a gel, 40 units' intramuscularly every eight hours; as an aqueous solution, 30 units intramuscularly every six hours; or as an intravenous aqueous solution containing 20 units of ACTH dissolved in 500 cc. of 5 per cent glucose, every 12 hours. l-'he last is the optimum way of giving ACTH from the standpoint of potency and cost, but unfortunately it is the most inconvenient to the patient. If no response is observed with oral steroids or other modes of administering ACTH, then the intravenous route should be tried before considering steroid therapy to be unsuccessful. Oral steroids in decreasing order of effectiveness are hydrocortisone 200 rng. daily, prednisone 40 to 80 mg. daily, prednisolone 40 to 80 mg. daily and cortisone 300 mg. daily; doses of this magnitude are used at the start of treatment. Cortisone is approxiInately 70 per cent as effective as ACTH. The initial dose of each drug is continued for one to two weeks and then reduced by one-quarter or one-third in weekly or bimonthly intervals depending upon the response. If treatment was begun with ACTH, then once the dose is 40 units it can be replaced entirely by oral steroids over a two to three day period, both being given concomitantly; one unit of ACT!I equals approximately 1 rng. of prednisone or prednilsolone, 2 mg. of hydrocortisone, and 2.5 nlg. of cortisone. Daily maintenance doses
Philip Kramer are ACTH 20 to 40 units intramuscularly, hydrocortisone 40 to 80 mg. by mouth, prednisone or prednisolone 15 to 30 mg. by mouth. Final discontinuation of therapy should be gradual over a period of two to three months when bowel function is normal, blood remains absent from the stools, a sense of well-being persists and the pathological process in the rectum or sigmoidoscopy shows regression. Unfortunately, side effects are seen in a large proportion of patients when treated with the dosage schedule outlined. These are edema, acne, hirsutism, hypertension, obesity, electrolyte abnormalities (hypokalemic, hypochloremic alkalosis), hyperglycemia, glycosuria, infections and emotional disturbances such as anxiety attacks, agitation and even schizoid, manic or depressive states. With adrenocortical steroids, endogenous adrenal function may become suppressed for as long as three to six months after discontinuance of the drug. Adrenal hypofunction may be overtly apparent clinically (weakness, hyporeflexia, etc.) or appear only when stress or infection supervenes. These adverse effects can be managed, in general, by salt restriction, mercurial injections, oral potassium chloride 3 to 6 grams per day as tablets or as a 10 per cent solution added to orange juce, antibiotics or absorbable sulfonamides, dermatologic preparations and sedatives. If the side effects are incapacitating or endangering to either physical or mental health, the dosage of steroid will have to be reduced or even discontinued. One must be on constant guard for adrenal hypofunction whether during therapy or after the drugs have been discontinued; adrenocortical steroids have to be reinstituted in the latter situation or increased in the former. In fact, emergency measures such as are used in an adrenal crisis occasionally may be necessary. Local hydrocortisone as a slow drip into the rectum has been recommended in patients with mild left-sided disease. 34 Hydrocortisone 120 mg. is dissolved in 250 m!. of saline; half the amount is given the first night and thereafter the size of the enema increased until the total 250 m!. is given. The treatment is given nightly for two weeks. Remission or improvement in symptoms was induced in 15 of 21 cases but no change in the rectal mucosa was noted grossly or histologically. Relapses in four patients after cessation of therapy required treatment. In patients personally observed, this method of therapy has been successful in 50 per cent but has not altered the course of disease. INDICATIONS FOR SURGICAL INTERVENTION
Regardless of the quality and intensiveness of medical therapy, surgical intervention may be necessary either as a lifesaving measure or to rescue the patient from a life of chronic invalidism. Actually, surgery probably should be employed more frequently than it is. At present the operative mortality is less than 5 per cent, ileostomy complications 4 per cent or less, and late postoperative deaths 3 per cent. as - as Only three
The Management of Ulcerative Colitis
1415
operative procedures are currently recommended: (1) an initial ileostomy and partial colectomy followed by a proctectomy at a later date,S6 (2) an initial ileostomy and then colectomy and proctectomy in one or two stages,37 (3) a colectomy and ileorectal anastomosis in several stages. S8 An ileostomy once performed is permanent and the patient should be so warned since recurrence of disease is over 50 per cent when reanastomosis is attempted. Ileostomy alone as definitive therapy has been abandoned because the possibility of toxemia, protein and electrolyte depletion, perforation, carcinomatous degeneration and hemorrhage persists unless the diseased colon and rectum are removed. The indications for sugery are: 1. Chronic Invalidism. The decision as to when a patient fits into this category is one most difficult to make. So many patients smolder along with both the physician and patient hoping for improvement that never happens. In part the physician can be guided by the attitude of the individual, Le., if he or she expresses a desire for operative treatment. If a patient requires two or more hospitalizations per year, then an active stand should be taken to abandon medical therapy. 2. Acute Fulminant Colitis. When a patient with fulminant colitis fails to respond to optimum medical therapy within two weeks, surgical treatment should be strongly advised. The major mortality, whether medical or surgical, falls into this group. 3. Intestinal Perforation or Impending Perforation. If the perforation is acute, peritonitis ensues; if subacute or chronic, then localized abscesses or fistulas may occur. Except for rectovaginal fistulas in women, fistulas between viscera are rare. 4. Carcinoma, or Suspicion of Carcinoma. The incidence of carcinoma is said to be between 3 and 10 per cent. However, in patients who have had ulcerative colitis for over ten years a higher incidence has been reported. 39 No relationship exists between the severity of illness and the development of carcinoma, since some patients develop this complication after they had considered themselves cured of colitis. 40 5. Systemic Complications. Arthritis, uveitis, the various skin disorders, liver disease, etc., are secondary to the colitis but in themselves may cause permanent disability. Their failure to respond to medical treatment therefore constitutes an indication for colectomy before permanent damage ensues. Actually, the lack of therapeutic results also suggests intractability of the colitis. 6. Massive Hemorrhage. This complication constitutes an imperative indication and is evident by the passage of large blood clots and the need for repeated transfusions to maintain normal hemoglobin levels. Immediate colectomy is the operation of choice. 7. Intractable Perianal Abscesses and Fi8tulas. Except for simple drainage procedures, local surgery is often not advisable because healing usually fails. 8. Strictures. On rare occasions, strictures may cause intestinal ob-
Philip Kra'fner
1416
struction. lVlore often, this cOInplication is an indication for surgical intervention because it is confused with careinonul. SUMMARY AND CONCLUSIONS
'T'he nlanagenlent of nonspecific ulcerative colitis is symptomatic and depends upon the establishment of a good doctor-patient relationship. Bed rest, minor dietary restrictions, sedatives and opiates form the background for medical therapy. If the attack is of mild or moderate severity, Azulfidine or one of the other sulfonamides may be tried. A favorable response should be observed in one to two weeks if sulfonamides are to be effective in inducing a remission. Steroid therapy is indicated in patients (1) with acute fulminant colitis, (2) who are hospitalized and have failed to respond to other medical measures, (3) with systemic complications. While steroids are the most effective medicinal agents presently available, they are not unreservedly recommended in all cases because of expense, side effects and inability to foresee duration of therapy that will be required. Whether steroids will alter the unfavorable long-term prognosis cannot be stated as yet because the follow-up period has been relatively short when one considers the chronic course of the disease. Improvement in operative techniques, preoperative preparation and postoperative care has greatly reduced the operative and postoperative nlorbidity and mortality. Therefore surgical intervention should not be delayed until the patient is moribund. REFERENCES 1. llicketts, W. E., Kirsner, J. B. and Palmer, W. L.: Chronic Nonspecific Ulcerative Colitis. A Roentgenologic Study of its Course. Gastroenterology 10: 1, 1948. 2. Manson-Bahr, P.: Itectal Biopsy as an Aid to the Diagnoses of Amoebic Dysentery and Allied Disease of the Colon. Lancet 1: 763, 1957. 3. Felsen, J. and Wolarsky, W.: Acute and Chronic I~acinary Dysentery and Chronic Ulcerative Colitis. J.A.M.A. 153: 1069, 1053. 4. Chewning, C. C..Jr.: Colitis Following the Oral Administration of Aureonlycin and Terramycin. Virginia M. Month. '/'9: 136, 1952. 5. Goldgraber, M. B. and Kirsner, J. B.:. "Specific" Diseases Simulating "N 011specific" Ulcerative Colitis (Lyml>hopathia Venereum, Acute Vasculitis, Scleroderma and Secondary Anlyloidosis). Ann. Int. Med. 47: 939, 1957. 6. Kogan, E. and Janovitz, H. D.: Intestinal Tuberculosis: Difficulties in Diagnoses in Absence of Florid Pulmonary Involvement. J. lVlt. S'inai Hosp. 23: 597, 1956. 7. Warren, 1. A. and Berk, J. E.: The Etiology of Chronic Nonspecific Ulcerative Colitis. A Critical Review. Gastroenterology 33: 395, 1957. 8. White, B. V.: The Effect of Ileostomy and Colectomy on the Personality Adjustment of Patients with Ulcerative Colitis. New England J. Med. 244: 537, 1951. 9. Groen, J. and Bastiaans, J.: PRychotherapy of Ulcerative Colitis. Gastroenterology l'l: 344, 1951. ID. Grace, W. J., Pinsky, R. H. and Wolff, H.: The Treatment of Ulcerative Colitis. 11. Gastroenterology 26: 462, 1954.
The M anage'rnc'nt of Ulcerat'ive Colitis
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11. Levine, 1\1. ])., l(irsner, J. B. and I{lotz, A. P.: A New Concept of the Pathogenesis of Ulcerative Colitis. Science lllt: 552, 1951. 12. Crawford, N. and Brooke, 13. N.: Ileostomy Chemistry. Lancet 1: 864-, 1957. 13. Lubran, 1\1. and 1\1eAllcn, P. M.: Potassium Deficiency in Ulcerative Colitis. Quart. J. IVled. 20: 221, 1951. 14. Welch, C. S., Adams, M. and Wakefield, C. (i.: Metabolic Studies on Ulcerative Colitis..J. Clin. Invest. 16: 161, 1~)37. 15. Poscy, F~. L. and Bargen, J. A.: Metabolic ])erangelnents ill Chronic lJlcerative Colitis. (Jastroenterology 16: 39, 1950. Hi. Nappington, T. S. and Bockus, H. L.: Nitrogen Metabolislll in Chronic Idiopathic Ulcerative (~olitis and Its 'I'herapeutic Significance. Ann. Int. 1\led. 31: 282, 1949. 17. Sandweiss, I). J. and Levy, S. H.: Gastrointestinal Absorption with Oleic Acid-P31 and l-Methionine-S 35 in Patients with Ulcerative Colitis. Proc. Soc. Expel'. BioI. & Med. 95: 259, 1H57. 18. Pollard, H. 1\1., Block, M. and Bachrach, W. 11.: Causes and Managenlcnt of Anemia Associated with Chronic lJleerative Colitis. J.A.M.A. 134: 341, 1~)47. 19. Bargen, J. A., Sauer, W. Cl., Sloan, W. P. and Gage, H,. P.: The Developrnent of Cancer in Chronic Ulcerative Colitis. Gastroenterology 26: 32, 1954. 20. Wheelock, F. C. Jr. and Warren R.: Ulcerative Colitis-Follo,v-up Studies. New England J. Med. 252: 421, 1~)55. 21. l~anks, B. M., I{orelitz, B. 1. and Zetzel, L.: "'fhe Course of Non-specific Ulcerative Colitis: Review of Twenty Years Experience and La.te llesults. Gastroenterology 82: 983, 1957. 22. I(irsner, J. B., Sklar, M. and Palmer, W. L.: The Use of AC1'1H, Cortisone, Hydrocortisone and llelated Compounds in the Management of Ulcerative Colitis. Anl . .T. Med. 22: 264, 1957. 23. Maltby, E. J., Dickson, R. C. and O'Sullivan, P. 1\1.: The Use of AC1'1H and Cortisone in Idiopathic Ulcerative Colitis. Canad. M .A.J. 74: 4, 1956. 24. Lindeman, I~.: Psychiatric Aspects of the Treatment of lJlcerative Colitis. Arch. Neurol. & Psychiat 58: 322,1945. 25. Cooke, R. I~. and Crowley, L. G-.: Ileplacement of Gastric and Intestinal Fluid ]~osses in Surgery. Ne,v F~ngland J. Med. 246: 637, 1952. 26. McCurdy, P. Il., Ilath, C. 1£. and Meerkrebs, G. :E.: Parenteral Iron Therapy with Special Iteference to a New Preparation for Intramuscular Injection. New England .T. l\1ed. 257: 1147, 1957. 27. Machella, T. E., Problems in Ulcerative Colitis. Am. J. Med. 18: 760, 1H52. 28. Bargcn, J. A.: The Management of Patients with IJlcerative Colitis. M. CLIN. NORTH AMERICA 40: 541, 1956. 29. Svartz, N.: The Treatment of IJlcerative Colitis. Gastroenterology 26: 26, 1954. 30. Truelove, S. C. and WiUs, L. J.: Cortisone in lJlcerative Colitis, Final Report on a Therapeutic Trial. Brit. IV!. .1. 2: 1041, 1055. 31. Jlalsted, J. A., Adanls, W. S., Sloan, S., vValtel's, l~,. L. and Bassett, S. 11.: SYlnposiunl on A(~TH and Cortisone as llelated to Gastrointestinal Tract: Clinical FXfects of A(jTlf in lJlcerative Colitis. (}astroenterology 2,9: 6H8, IH51. 32. Brooke, B.N.: (})ltiSOIH~ tllHl lJlcerative Colitis an Adverse E-ffect. Lancet 2: 1175, 1056. 33. l(risner, .J. B.: IJlcerative Colitis; Observations on Its Etiology, Course and Managenlent. Postgrad. Med. 22: 132, 1~)57. 34. Truelove, S. C.: l'reatment of Ulcerative Colitis with Locnl lIydrocortisone. Brit. M. J. 2: 1267, 1056. 35. I)ukes, C. E. and Lockhart-l\fumlnery, IL E.: Pl'actical Points in the Pathology and Surgical 'rreatment of Ulcerative Colitis. Brit. J. Surg. 45: 25, 1957. 36. Ripstein, C. B.: Primary Itesection of the Colon in Acute lncerative Colitis. J.A.M.A. 15,03: 1093, 1953. 37. Cattell, It. B. and Colcock, B. P.: Surgical TreatInent of Ulcerative Colitis. Postgrad. Med. 17: 114, 1955.
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38. Aylett, S.: Total Colectomy and Ileo-Rectal Anastomosis in Diffuse Ulcerative Colitis. Brit. M. J. 1: 489, 1957. 39. Counsell, P. B. and Dukes, C. E.: The Association of Chronic Ulcerative Colitis and Carcinoma of the Rectum and Colon. Brit. J. Surge 39: 1, 1952. 4:0. Svartz, N.: The Pathogenesis and Treatment of Ulcerative Colitis. Acta. med. Scandnav. 141: 172, 1951. 65 E. Newton Street Boston 18, Massachusetts