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Sideropenic dysphagia in a patient with ulcerative colitis
Sideropenic Dysphagia in a Patient with Ulcerative Colitis* RALPH WRIGHT, M .D,, M .R .C .P .
Oxford, England
T
HE syndrome of dysphagia, glossitis, koilonychia and iron deficiency anaemia is
had continued . Sigmoidoscopy was repeated and changes typical of mild ulcerative colitis were observed ; these were confirmed histologically . A barium enema (July 16, 1962) showed fine contour irregularities in the rectum and lower sigmoid colon consistent with mild ulcerative colitis . The haemoglobin was 13 .8 gm . per 100 ml . and the erythrocyte sedimentation rate 6 mm . in 1 hour (Westergren) . Two weeks later diarrhoea developed for the first time . The patient was admitted to a "clinical trial" and was treated with 5 mg, of prednisolone given orally every 6 hours, a rectal infusion of 100 mg. of hydrocortisone hemisuccinate given nightly, and a milk-free diet . In the course of the clinical trial, patients are seen at intervals of approximately one month, when the frequency and nature of the stools are recorded, sigmoidoscopy and rectal biopsy performed, haemoglobin and erythrocyte sedimentation rate measured, and serum separated and stored at -20 ° c . in specially prepared containers for subsequent immunological testing. The patient's response to treatment was satisfactory, and both local and systemic corticosteroid therapy was discontinued after two months . The patient was kept under regular observation and remained well on treatment with a milk-free diet and vitamin supplements, although a fragile rectal mucosa was sometimes seen at sigmoidoscopy and she occasionally noticed blood in her stools . Six months later the diarrhoea recurred, with clear-cut changes of ulcerative colitis on sigmoidoscopy and a fall in the haemoglobin level to 9 .5 gm . per 100 ml . A further course of treatment with local and systemic corticosteroids was given and the diarrhoea settled . Six weeks after the onset of the relapse, while still receiving treatment with corticosteroids, the patient experienced acute dysphagia with choking bouts on eating dry solids . When seen at the clinic two weeks later, the haemoglobin was 9 .0 gm . per 100 ml . and a peripheral blood film showed changes of mild iron deficiency of the red cells . The patient's tongue and nails were normal but there were painful fissures at the corners of the mouth . The spleen was not palpable . A diagnosis of sideropenic dysphagia was made ;
known by several names including the PatersonKelly syndrome [1,2], the Plummer-Vinson syndrome [3) and sideropenic dysphagia [4) . The view is now generally held that a period of iron deficiency precedes the dysphagia although a normal haemoglobin and serum iron level may be present at the time the diagnosis is first made [5] . An oesophageal web can usually be demonstrated roentgenologically [6] and is thought to be the cause of the dysphagia but the mechanism of its formation is uncertain . The present case is reported because serial haemoglobin and serum iron values were available for several months before the development of the dysphagia, and the symptom appeared to have been precipitated by blood loss occurring during an attack of ulcerative colitis . A further point of interest is the family history of upper oesophageal carcinoma . CASE REPORT
A thirty-four year old woman was admitted to the Radcliffe Infirmary on March 21, 1962 ; her chief complaint was urgency of defaecation with blood and mucus in the stools for two months . There were no abnormal findings on general physical examination . A red, rather friable rectal mucosa was seen at sigmoidoscopy, and histologic examination of a biopsy specimen showed some inflammatory cell infiltration of the mucosa and submucosa . Roentgenologic examination of the colon with barium (barium enema) was within normal limits, and examination of the stools for pathogens and parasites was negative . The haemoglobin was 13 .8 gm . per 100 ml . and the peripheral blood film normal . No definite diagnosis was made and the patient was discharged on the twelfth day because her symptoms had diminished without treatment . When seen three months later, the patient was still passing only one stool daily but the rectal bleeding
* From the Nuffield Department of Clinical Medicine, University of Oxford, Oxford, England . Manuscript received February 11, 1964 .
274
AMERICAN JOURNAL OF MEDICINE
Sideropenic Dysphagia-Wright this was confirmed by a roentgenologic examination with barium which showed two pharyngeal webs of moderate size . (Fig . 1 .) These were also demonstrated by means of cineradiography performed by Dr . Gordon M . Ardran . I lie patient was closely questioned to determine whether she had had any symptoms of iron deficiency previously . Apart from pleurisy at the age of sixteen years, she had never had any serious illnesses and no difficulty with swallowing . Her diet was adequate and included meat at least three times a week, Menstrual loss had never been excessive . She had had three pregnancies fifteen, thirteen and eight years before . A sister had died two years previously at the age of thirty-one, of a squamous carcinoma of the upper portion of the oesophagus which was confirmed at postmortem examination . She had been given iron injections and blood transfusions for some time before her death . An oesophagoscopy was performed under general anaesthesia . A small pharyngeal web was seen anteriorly and a biopsy specimen was taken . Biopsy specimens were also obtained from the body of the stomach and the small intestine . Histologic sections of the specimens were examined by Dr . W . C . D . Richards who reported them to be normal in appearance . By a fortunate coincidence this patient had been selected for special study for another purpose and serial specimens of serum were available for a period of eight months preceding the dysphagia . The serum iron content was measured and in Table I and Figure 2 the values are related to the haemoglobin levels and the clinical course of the colitis . It can be seen clearly that the serum iron values were grossly below normal throughout, even when the haemoglobin level was normal or only slightly diminished .
275
Fle_ 1 . Lateral roentgenogram with )arium showing pharyngeal webs. Tests of gastric and small intestinal function were made . An augmented histamine test showed hypochlorhydria with a low volume of gastric juice . The total acid secretion was 1 .07 mEq . hydrochloride in 1 hour after the subcutaneous administration of 1 .5 mg . histamine acid phosphate (normal range 2 .57 to 46 .75 mEq . hydrochloride per hour 7]) . Faecal fat
TABLE I HAEMOGLOBIN AND SERUM IRON VALUES IN RELATION TO TILE CLINICAL COURSE OF THE COI I] IS
Signs of Inflammation No. of Stools Daily
Date
Sigmoidoscopy
Rectal
Haemoglobin (gm . per 100 MI .)
Biopsy
7/6/62 8/3/62 8/18/62 9/8/62 10/13/62 11/10/62 2/9/63 3/16/63 4/19/63 6/28/63
2-3 2-3 2-3
+ + t f t
1-2
+
"Normal value >60 . t Ulcerative colitis in relapse. On treatment with corticosteroids . VOL .
38,
FEBRUARY
1965
+
I 13 .8 11 .7
++ + ++ ++ f ++ ++
Serum Iron* (µg,/100 ml .)
12 .0 12 .3 12 .1 14 .2 11 .0 10 .4 9 .5 9 .0
51 15t 81 12t 13 3 0 3t 4t
276
Sideropenic Dysphagia- Wright CORTCOS :EROIJ TREATMENT
Hb .(gm/100mL)
0 ; HEMOOLORIN
14 0
I RELAPSE OF ULCERATIVE COLITIS
0
SERUM IRON ~
7
3
4
5
9
10
9
0
II
I 12
Month, order ob,,rvorian .
Serial serum iron and haemoglobin values in relation to the clinical course of the colitis and the onset of the dysphagia. A low serum iron value was present throughout the period of observation and preceded the onset of the dysphagia . FIG. 2 .
excretion was 2 .1 gm . in 24 hours based on a four day collection . The absorption of CoRE-labeled vitamin B o was normal . Almost the entire dose of Fesslabeled haemoglobin [8] administered orally appeared in the blood after ten days, indicating greatly increased absorption compatible with severe iron deficiency-In view of the finding of hypochlorhydria, gastric parietal cell antibodies were looked for in the patients' serum using a fluorescent technic [9] . The result was negative . Antibodies to thyroglobulin were detected at a titre of 1/25,000 by means of the tanned erythrocyte haemagglutination technic according to the method of Fulthorpe and associates [10] . Imrnunofluorescent tests for antinuclear factor, thyroid cytoplasmic antibodies [11] and antibodies to the second colloid antigen [72] were negative . The dysphagia disappeared after oesophagoscopy and a course of intramuscular iron injections, although the colitis remained active with some rectal bleeding. Cineradiographic examination of the pharynx and oesophagus was repeated two months later and only slight ridging was observed at the original site of the webs. COMMENTS
Several aspects of the present case are of particular interest and will be commented upon under three separate headings . Sideropenic Dypphagia in Ulcerative Colitis . Iron deficiency as a result of blood loss is the most important cause of anaemia in ulcerative colitis [13] . In a retrospective survey Truelove and Edwards (14] found that 127 (20 .4 per cent) of 624 patients with ulcerative colitis had a haemoglobin level of 9 .0 gm . per 100 ml . or less at some time during the course of their illness . In none of their patients was a diagnosis
of sideropenic dysphagia made and the association is probably rare . The very low serum iron values found in this patient despite a normal haemoglobin level illustrate the limitations of the haemoglobin level as an index of iron depletion in the presence of chronic blood loss . Family History of Pharyngeal Carcinoma . Paterson and Kelly [7,2] first drew attention to the liability of patients with the syndrome of iron deficiency anaemia and dysphagia to the development of postcricoid carcinoma, and Simpson [15] reported the occurrence of the two conditions in different members of the same family . A neoplasm in the upper part of the oesophagus, with the histologic features of a squamous carcinoma, was the cause of death at the age of thirty-one of a sibling of the patient described herein . She had been treated previously for chronic iron deficiency anaemia . One other patient with sideropenic dysphagia seen in this Department had a sister who died of a squamous carcinoma of the pharynx at the early age of twenty-eight years, and it is of interest (aide infra) that there was, in addition, a strong family history of thyrotoxicosis, a sibling and an aunt being affected . The occurrence of upper oesophageal or pharyngeal carcinoma in young siblings of some patients with sideropenic dysphagia supports the view that similar genetic and/or environmental factors may he of importance in their aetiology . The Role of Iron Deficiency in Producing Dysphagia .
The main evidence favouring the possibility that iron deficiency is responsible for producing dysphagia in the Paterson-Kelly syndrome is the fact that the symptom may diminish or disappear when the iron deficiency is corrected [4,16,17] . A unique feature of the present case is that it has been possible to show clearly that the serum iron values were extremely low for at least eight months before the onset of the dysphagia . Furthermore the dysphagia was of sudden onset during a relapse of ulcerative colitis when the haemoglobin level fell to 9 .0 gm . per 100 ml ., probably indicating further depletion of the iron stores . There is, therefore, suggestive evidence that iron depletion is the cause of dysphagia in this patient . On the other hand, Wynder and Fryer [5] found that 73 per cent of thirty patients with roentgenologic evidence of the Paterson-Kelly syndrome had a normal serum iron level at the time of investigation of their dysphagia, and Jacobs [ 78] believes AMERICAN JOURNAL OF MEDICINE
Sideropenic Dysphagia-- Wright that mucosal changes in the pharynx may occur in patients with pernicious anaemia who are not iron deficient . It is possible, therefore, that iron deficiency is not essential for the development of pharyngeal webs and that other factors may be responsible in some cases . Until recently histologic studies of pharyngeal webs and the adjacent pharynx and oesophagus have been confined to postmortem or surgery specimens taken from patients with advanced disease [19,20] . Such studies have usually disclosed atrophy and hyperkeratinization of the epithelium with round cell infiltration of the submucosa and atrophy and fibrosis of the musculature. In one case a fibrous tissue core covered on both sides by a layer of epithelium was clearly demonstrated in a biopsy specimen taken at open operation [21] . Biopsy specimens of the oesophagus and pharynx taken at oesophagoscopy may, as in our patient, be normal in appearance [22], but early in the course of the disease it is difficult to be certain that the web itself has been biopsied as the lesion may be small and localised . Cheli and his colleagues [23] found atrophic changes in the oesophagus in seven of sixteen patients with hypochromic anaemia, whereas other workers did not find any histologic abnormality in the oesophagus in this condition [24] . It is uncertain, therefore, whether the lesion in the pharynx early in the course is localised or is part of a more diffuse abnormality . It is of interest that, in the patient described herein, the dysphagia developed at the same time as the fissures at the corners of the mouth ; it is possible that similar fissures may develop in the pharynx under the mechanical stress of swallowing and progress to fibrosis and webs . The view has been held for some time that other epithelial changes associated with hypochromic anaemia such as koilonychia, glossitis and angular stomatitis are the result of the iron deficiency [4,19,25] . Here, too, the evidence is largely based on the improvement which may occur following treatment with iron . A similar explanation is given for the gastritis and gastric atrophy which may occur in hypochromic anaemia [26,27] . However, Lees and Rosenthal [28] have been unable to demonstrate any improvement in the gastric lesion or acid secretion after iron therapy . In the present case there was no evidence of glossitis or koilonychia and the tissue structure of the gastric mucosa was normal . The hypochlorhydria and transient VOL .
38,
FEBRUARY
1965
277
fissures at the corners of the mouth probably represent early signs of epithelial lesions, and the underlying cause of all these lesions may be similar . The basic cellular abnormality is uncertain . It has been suggested that iron depletion may damage the cell as a result of lack of ironcontaining enzymes essential for cell metabolism [29] . An associated deficiency of vitamins or trace elements may be responsible and act in a similar way . An immunologic mechanism is also a possibility and may act in conjunction with one of the factors already mentioned . In long-standing cases the histologic appearance of round cell infiltration with atrophy and fibrosis is compatible with such a mechanism. The incidence of thyroid antibodies is increased in iron deficiency anaemia [30] and a moderately high titre of antibodies to thyroglobulin was found in the present case . The second patient referred to previously had a strong family history of thyroid disease, and Shamma'a and his colleagues [22] have drawn attention to the frequent occurrence of pharyngeal webs and thyroid disease in the same patient . It is possible that this association indicates a disturbance of immunologic response in patients with sideropenic dysphagia and iron deficiency anaemia . SUMMARY
A case of sideropenic dysphagia is described in a patient with ulcerative colitis . Serial specimens of the patient's serum were available for a period of eight months before the onset of the dysphagia . The iron content of these samples was measured and found to be extremely low even when the haemoglobin level was normal . Two other features of the case which are of interest is the family history of upper oesophageal carcinoma and the presence in the patient's serum of a moderately high titre of antibodies to thyroglobulin . The role of iron deficiency in the development of the dysphagia is discussed and it is suggested that an immunologic disturbance may be a factor in the production of the associated tissue changes . Acknowledgment : I am indebted to Dr. S . C. Truelove, Dr . S . T . Callender and Dr . B . R . Beveridge for their advice . Mr . D. L . Williams kindly made the serum iron estimations .
278
Sideropenic Dysphagia- Wright REFERENCES
1 . PATERSON, D . R . A clinical type of dysphagia . J. Larvng. & Otoi ., 34 : 289, 1919 . 2 . KELLY, A. B . Spasm at the entrance to the esophagus . J. Laryng . & Old ., 34 : 285, 1919 . 3. VwsoN, P . P. Hysterical dysphagia . Minnesota .4 led., 5 : 107, 1922 . 4. WALDENSTROM, J . Iron and epithelium . Some clinical observations . Acta med. scandinav., 90 (supp .) : 380, 1938 . 5. WYNDER, E . L. and FRYER, J . H. Etiologic considerations of Plummer-Vinson (Paterson-Kelly) syndrome. Ann. Int . Med., 49 : 1106, 1958 . 6. WALDENSTROM, J . and KJELLBORG, S . R . Roentgenographic diagnosis of sideropenic dysphagia. Acta radiol ., 20 : 618, 1939 . 7 . Bocx, O . A . A., RIctuRns, W . C . D . and WITTS, L . J . The relationship between acid secretion after augmented histamine stimulation and the histology of the gastric mucosa . Gut, 4 : 112, 1963 . 8 . CALLENDER, S . T ., MALLETT, B . J . and SMITH, M. D . Absorption of haemoglobin iron . Brit. J. Haemat ., 3 : 186, 1957 . 9 . TAYLOR, K . B ., ROUT, I . M ., DONIACH, D., COUCHMAN, K . G . and SHAPLAND, C . Autoimmune phenomena in pernicious anaemia : gastric antibodies . Brit. M. J., 2 : 1347, 1962 . 10 . FULTHORPE, A . J ., ROUT, 1 . M ., DONIACH, D . and COUCHMAN, K . G . A stable sheep cell preparation for detecting thyroglobulin auto-antibodies and its clinical applications . J. Clin . Path ., 14 : 654, 1961 . 11 . HOLBOROW, E . J ., BROWN, P . C ., RorTT, I . M . and DONACH, D . Cytoplasmic localization of "complement-fixing" auto-antigen in human thyroid epithelium . Brit. J. Exper . Path., 40 : 583, 1959 . 12 . BALFOUR, B . M., DomAcH, D ., ROUT, 1 . M . Rod COUCHMAN, K . G . Fluorescent antibody studies in human thyroiditis : auto-antibodies to an antigen of the thyroid colloid distinct from thyroglobulin . Brit . J. Exper. Path ., 42 : 307, 1961 . 13 . BEAL, R . W., SKYRING, A . P., MCRAE, J. and PutBEN, B . G. The anemia of ulcerative colitis . Castroenterology, 45 : 589, 1963 . 14 . TRUELOVE, S . C . and EDwARDs, F. C . The course and prognosis of ulcerative colitis. HI. Complications. Cut, in press .
15 . SIMPSON, R . R. Anaemia with dysphagia : a preCancerous condition? Prac. Roy . Sac . Med., 32 : 1447, 1939 . 16, WITTS, L. J . The syndrome of glossitis, dysphagia and anaemia . Guy's Hosp. Rep ., 81 : 193, 1931 . 17 . JONES, R . F . MCNAE . The Paterson-Brown-Kelly Syndrome . J . Laryng. & Otal ., 75 : 529, 1961 . 18 . JACOBS, A . Post-cricoid carcinoma in patients with pernicious anaemia . Brit . M. J.,2 : 91, 1962 . 19 . SUZMAN, M . M . Syndrome of anemia, glossitis and dysphagia : report of eight cases, with special reference to the observations at autopsy in one instance . Arch . Int . Med., 51 : 1, 1933 . 20 . SAVILAHTI, M. On the pathologic anatomy of the Plummer-Vinson syndrome . Acta med. scandinav ., 125 : 40, 1946 . 21 . Hoovri, W. B . The syndrome of anemia, glossitis and dysphagia : report of cases. New England J. Med., 213 : 394, 1935 . 22 . SHAMMA'A, M . H . and BENEDICT, E . B . Esophageal webs. A report of 58 cases and an attempt at classification . New England J. Med., 259 : 378, 1958 . 23 . CHELI, R., DODERO, M ., CELLE, G . and VASSALOTTI, M. Gastric biopsy and secretory findings in hypochromic anaemias . Acta heamat ., 22 : 1, 1959 . 24 . MCLEAN, B . I ., DODGE, O . G ., PALMER, F . J . and WAwMAN, R . J . The tongue and oesophagus in iron-deficiency anaemia and the effect of iron therapy. J. Clin . Path ., 14 : 603, 1961 . 25 . DARBY, W. J . The oral manifestations of iron deficiency. J.A .M .A ., 130 : 830, 1946. 26 . DAVIDSON, W . M. B . and MARxsoN, J . L . The gastric mucosa in iron-deficiency anaemia, Lancet, 2 : 639, 1955 . 27 . BADENOCH, J., EVANS, J . R . and RICHARDS, W. C . D. The stomach in hypochromic anaemia . Brit . J. Haemat., 3 : 175, 1957. 28 . LEES, F . and ROSENTHAL, F . D . Gastric mucosal lesions before and after treatment in iron deficiency anaemia . Quart . J. Med., 27 : 19, 1958 . 29 . BEUTLER, E . Iron enzymes in iron deficiency . 1 . Cytochrome C . Am . J. M. Sc., 234 : 517, 1957 . 30 . MARxsON, J . L . and MOORE, J. M . Autoimmunity in pernicious anaemia and iron-deficiency anaemia . Lancet, 2 : 1240, 1962 .
AMERICAN JOURNAL OF MEDICINE
Oxford, England
T
HE syndrome of dysphagia, glossitis, koilonychia and iron deficiency anaemia is
had continued . Sigmoidoscopy was repeated and changes typical of mild ulcerative colitis were observed ; these were confirmed histologically . A barium enema (July 16, 1962) showed fine contour irregularities in the rectum and lower sigmoid colon consistent with mild ulcerative colitis . The haemoglobin was 13 .8 gm . per 100 ml . and the erythrocyte sedimentation rate 6 mm . in 1 hour (Westergren) . Two weeks later diarrhoea developed for the first time . The patient was admitted to a "clinical trial" and was treated with 5 mg, of prednisolone given orally every 6 hours, a rectal infusion of 100 mg. of hydrocortisone hemisuccinate given nightly, and a milk-free diet . In the course of the clinical trial, patients are seen at intervals of approximately one month, when the frequency and nature of the stools are recorded, sigmoidoscopy and rectal biopsy performed, haemoglobin and erythrocyte sedimentation rate measured, and serum separated and stored at -20 ° c . in specially prepared containers for subsequent immunological testing. The patient's response to treatment was satisfactory, and both local and systemic corticosteroid therapy was discontinued after two months . The patient was kept under regular observation and remained well on treatment with a milk-free diet and vitamin supplements, although a fragile rectal mucosa was sometimes seen at sigmoidoscopy and she occasionally noticed blood in her stools . Six months later the diarrhoea recurred, with clear-cut changes of ulcerative colitis on sigmoidoscopy and a fall in the haemoglobin level to 9 .5 gm . per 100 ml . A further course of treatment with local and systemic corticosteroids was given and the diarrhoea settled . Six weeks after the onset of the relapse, while still receiving treatment with corticosteroids, the patient experienced acute dysphagia with choking bouts on eating dry solids . When seen at the clinic two weeks later, the haemoglobin was 9 .0 gm . per 100 ml . and a peripheral blood film showed changes of mild iron deficiency of the red cells . The patient's tongue and nails were normal but there were painful fissures at the corners of the mouth . The spleen was not palpable . A diagnosis of sideropenic dysphagia was made ;
known by several names including the PatersonKelly syndrome [1,2], the Plummer-Vinson syndrome [3) and sideropenic dysphagia [4) . The view is now generally held that a period of iron deficiency precedes the dysphagia although a normal haemoglobin and serum iron level may be present at the time the diagnosis is first made [5] . An oesophageal web can usually be demonstrated roentgenologically [6] and is thought to be the cause of the dysphagia but the mechanism of its formation is uncertain . The present case is reported because serial haemoglobin and serum iron values were available for several months before the development of the dysphagia, and the symptom appeared to have been precipitated by blood loss occurring during an attack of ulcerative colitis . A further point of interest is the family history of upper oesophageal carcinoma . CASE REPORT
A thirty-four year old woman was admitted to the Radcliffe Infirmary on March 21, 1962 ; her chief complaint was urgency of defaecation with blood and mucus in the stools for two months . There were no abnormal findings on general physical examination . A red, rather friable rectal mucosa was seen at sigmoidoscopy, and histologic examination of a biopsy specimen showed some inflammatory cell infiltration of the mucosa and submucosa . Roentgenologic examination of the colon with barium (barium enema) was within normal limits, and examination of the stools for pathogens and parasites was negative . The haemoglobin was 13 .8 gm . per 100 ml . and the peripheral blood film normal . No definite diagnosis was made and the patient was discharged on the twelfth day because her symptoms had diminished without treatment . When seen three months later, the patient was still passing only one stool daily but the rectal bleeding
* From the Nuffield Department of Clinical Medicine, University of Oxford, Oxford, England . Manuscript received February 11, 1964 .
274
AMERICAN JOURNAL OF MEDICINE
Sideropenic Dysphagia-Wright this was confirmed by a roentgenologic examination with barium which showed two pharyngeal webs of moderate size . (Fig . 1 .) These were also demonstrated by means of cineradiography performed by Dr . Gordon M . Ardran . I lie patient was closely questioned to determine whether she had had any symptoms of iron deficiency previously . Apart from pleurisy at the age of sixteen years, she had never had any serious illnesses and no difficulty with swallowing . Her diet was adequate and included meat at least three times a week, Menstrual loss had never been excessive . She had had three pregnancies fifteen, thirteen and eight years before . A sister had died two years previously at the age of thirty-one, of a squamous carcinoma of the upper portion of the oesophagus which was confirmed at postmortem examination . She had been given iron injections and blood transfusions for some time before her death . An oesophagoscopy was performed under general anaesthesia . A small pharyngeal web was seen anteriorly and a biopsy specimen was taken . Biopsy specimens were also obtained from the body of the stomach and the small intestine . Histologic sections of the specimens were examined by Dr . W . C . D . Richards who reported them to be normal in appearance . By a fortunate coincidence this patient had been selected for special study for another purpose and serial specimens of serum were available for a period of eight months preceding the dysphagia . The serum iron content was measured and in Table I and Figure 2 the values are related to the haemoglobin levels and the clinical course of the colitis . It can be seen clearly that the serum iron values were grossly below normal throughout, even when the haemoglobin level was normal or only slightly diminished .
275
Fle_ 1 . Lateral roentgenogram with )arium showing pharyngeal webs. Tests of gastric and small intestinal function were made . An augmented histamine test showed hypochlorhydria with a low volume of gastric juice . The total acid secretion was 1 .07 mEq . hydrochloride in 1 hour after the subcutaneous administration of 1 .5 mg . histamine acid phosphate (normal range 2 .57 to 46 .75 mEq . hydrochloride per hour 7]) . Faecal fat
TABLE I HAEMOGLOBIN AND SERUM IRON VALUES IN RELATION TO TILE CLINICAL COURSE OF THE COI I] IS
Signs of Inflammation No. of Stools Daily
Date
Sigmoidoscopy
Rectal
Haemoglobin (gm . per 100 MI .)
Biopsy
7/6/62 8/3/62 8/18/62 9/8/62 10/13/62 11/10/62 2/9/63 3/16/63 4/19/63 6/28/63
2-3 2-3 2-3
+ + t f t
1-2
+
"Normal value >60 . t Ulcerative colitis in relapse. On treatment with corticosteroids . VOL .
38,
FEBRUARY
1965
+
I 13 .8 11 .7
++ + ++ ++ f ++ ++
Serum Iron* (µg,/100 ml .)
12 .0 12 .3 12 .1 14 .2 11 .0 10 .4 9 .5 9 .0
51 15t 81 12t 13 3 0 3t 4t
276
Sideropenic Dysphagia- Wright CORTCOS :EROIJ TREATMENT
Hb .(gm/100mL)
0 ; HEMOOLORIN
14 0
I RELAPSE OF ULCERATIVE COLITIS
0
SERUM IRON ~
7
3
4
5
9
10
9
0
II
I 12
Month, order ob,,rvorian .
Serial serum iron and haemoglobin values in relation to the clinical course of the colitis and the onset of the dysphagia. A low serum iron value was present throughout the period of observation and preceded the onset of the dysphagia . FIG. 2 .
excretion was 2 .1 gm . in 24 hours based on a four day collection . The absorption of CoRE-labeled vitamin B o was normal . Almost the entire dose of Fesslabeled haemoglobin [8] administered orally appeared in the blood after ten days, indicating greatly increased absorption compatible with severe iron deficiency-In view of the finding of hypochlorhydria, gastric parietal cell antibodies were looked for in the patients' serum using a fluorescent technic [9] . The result was negative . Antibodies to thyroglobulin were detected at a titre of 1/25,000 by means of the tanned erythrocyte haemagglutination technic according to the method of Fulthorpe and associates [10] . Imrnunofluorescent tests for antinuclear factor, thyroid cytoplasmic antibodies [11] and antibodies to the second colloid antigen [72] were negative . The dysphagia disappeared after oesophagoscopy and a course of intramuscular iron injections, although the colitis remained active with some rectal bleeding. Cineradiographic examination of the pharynx and oesophagus was repeated two months later and only slight ridging was observed at the original site of the webs. COMMENTS
Several aspects of the present case are of particular interest and will be commented upon under three separate headings . Sideropenic Dypphagia in Ulcerative Colitis . Iron deficiency as a result of blood loss is the most important cause of anaemia in ulcerative colitis [13] . In a retrospective survey Truelove and Edwards (14] found that 127 (20 .4 per cent) of 624 patients with ulcerative colitis had a haemoglobin level of 9 .0 gm . per 100 ml . or less at some time during the course of their illness . In none of their patients was a diagnosis
of sideropenic dysphagia made and the association is probably rare . The very low serum iron values found in this patient despite a normal haemoglobin level illustrate the limitations of the haemoglobin level as an index of iron depletion in the presence of chronic blood loss . Family History of Pharyngeal Carcinoma . Paterson and Kelly [7,2] first drew attention to the liability of patients with the syndrome of iron deficiency anaemia and dysphagia to the development of postcricoid carcinoma, and Simpson [15] reported the occurrence of the two conditions in different members of the same family . A neoplasm in the upper part of the oesophagus, with the histologic features of a squamous carcinoma, was the cause of death at the age of thirty-one of a sibling of the patient described herein . She had been treated previously for chronic iron deficiency anaemia . One other patient with sideropenic dysphagia seen in this Department had a sister who died of a squamous carcinoma of the pharynx at the early age of twenty-eight years, and it is of interest (aide infra) that there was, in addition, a strong family history of thyrotoxicosis, a sibling and an aunt being affected . The occurrence of upper oesophageal or pharyngeal carcinoma in young siblings of some patients with sideropenic dysphagia supports the view that similar genetic and/or environmental factors may he of importance in their aetiology . The Role of Iron Deficiency in Producing Dysphagia .
The main evidence favouring the possibility that iron deficiency is responsible for producing dysphagia in the Paterson-Kelly syndrome is the fact that the symptom may diminish or disappear when the iron deficiency is corrected [4,16,17] . A unique feature of the present case is that it has been possible to show clearly that the serum iron values were extremely low for at least eight months before the onset of the dysphagia . Furthermore the dysphagia was of sudden onset during a relapse of ulcerative colitis when the haemoglobin level fell to 9 .0 gm . per 100 ml ., probably indicating further depletion of the iron stores . There is, therefore, suggestive evidence that iron depletion is the cause of dysphagia in this patient . On the other hand, Wynder and Fryer [5] found that 73 per cent of thirty patients with roentgenologic evidence of the Paterson-Kelly syndrome had a normal serum iron level at the time of investigation of their dysphagia, and Jacobs [ 78] believes AMERICAN JOURNAL OF MEDICINE
Sideropenic Dysphagia-- Wright that mucosal changes in the pharynx may occur in patients with pernicious anaemia who are not iron deficient . It is possible, therefore, that iron deficiency is not essential for the development of pharyngeal webs and that other factors may be responsible in some cases . Until recently histologic studies of pharyngeal webs and the adjacent pharynx and oesophagus have been confined to postmortem or surgery specimens taken from patients with advanced disease [19,20] . Such studies have usually disclosed atrophy and hyperkeratinization of the epithelium with round cell infiltration of the submucosa and atrophy and fibrosis of the musculature. In one case a fibrous tissue core covered on both sides by a layer of epithelium was clearly demonstrated in a biopsy specimen taken at open operation [21] . Biopsy specimens of the oesophagus and pharynx taken at oesophagoscopy may, as in our patient, be normal in appearance [22], but early in the course of the disease it is difficult to be certain that the web itself has been biopsied as the lesion may be small and localised . Cheli and his colleagues [23] found atrophic changes in the oesophagus in seven of sixteen patients with hypochromic anaemia, whereas other workers did not find any histologic abnormality in the oesophagus in this condition [24] . It is uncertain, therefore, whether the lesion in the pharynx early in the course is localised or is part of a more diffuse abnormality . It is of interest that, in the patient described herein, the dysphagia developed at the same time as the fissures at the corners of the mouth ; it is possible that similar fissures may develop in the pharynx under the mechanical stress of swallowing and progress to fibrosis and webs . The view has been held for some time that other epithelial changes associated with hypochromic anaemia such as koilonychia, glossitis and angular stomatitis are the result of the iron deficiency [4,19,25] . Here, too, the evidence is largely based on the improvement which may occur following treatment with iron . A similar explanation is given for the gastritis and gastric atrophy which may occur in hypochromic anaemia [26,27] . However, Lees and Rosenthal [28] have been unable to demonstrate any improvement in the gastric lesion or acid secretion after iron therapy . In the present case there was no evidence of glossitis or koilonychia and the tissue structure of the gastric mucosa was normal . The hypochlorhydria and transient VOL .
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fissures at the corners of the mouth probably represent early signs of epithelial lesions, and the underlying cause of all these lesions may be similar . The basic cellular abnormality is uncertain . It has been suggested that iron depletion may damage the cell as a result of lack of ironcontaining enzymes essential for cell metabolism [29] . An associated deficiency of vitamins or trace elements may be responsible and act in a similar way . An immunologic mechanism is also a possibility and may act in conjunction with one of the factors already mentioned . In long-standing cases the histologic appearance of round cell infiltration with atrophy and fibrosis is compatible with such a mechanism. The incidence of thyroid antibodies is increased in iron deficiency anaemia [30] and a moderately high titre of antibodies to thyroglobulin was found in the present case . The second patient referred to previously had a strong family history of thyroid disease, and Shamma'a and his colleagues [22] have drawn attention to the frequent occurrence of pharyngeal webs and thyroid disease in the same patient . It is possible that this association indicates a disturbance of immunologic response in patients with sideropenic dysphagia and iron deficiency anaemia . SUMMARY
A case of sideropenic dysphagia is described in a patient with ulcerative colitis . Serial specimens of the patient's serum were available for a period of eight months before the onset of the dysphagia . The iron content of these samples was measured and found to be extremely low even when the haemoglobin level was normal . Two other features of the case which are of interest is the family history of upper oesophageal carcinoma and the presence in the patient's serum of a moderately high titre of antibodies to thyroglobulin . The role of iron deficiency in the development of the dysphagia is discussed and it is suggested that an immunologic disturbance may be a factor in the production of the associated tissue changes . Acknowledgment : I am indebted to Dr. S . C. Truelove, Dr . S . T . Callender and Dr . B . R . Beveridge for their advice . Mr . D. L . Williams kindly made the serum iron estimations .
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Sideropenic Dysphagia- Wright REFERENCES
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