CASE REPORTS NONTROPICAL SPRUE IN SIBLINGS WITH DISSIMILAR, UNUSUAL, AND SEVERE MANIFESTATIONS. Case Reports

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1 GASTROENTEROLOGY Copyright 1969 by The Williams & Wilkins Co. Vol. 56, No. 1 Printed in U.S.A. CASE REPORTS NONTROPCAL SPRUE N SBLNGS WTH DSSMLAR, UNUSUAL, AND SEVERE MANFESTATONS E. MARVN SOKOL, M.D., GEORGE M. BROWN, M.D., AND HOWARD L. FRUCHT, M.D. Department of Medicine and Section of Orthopedic Surgery, Huntington Hospital, Huntington, New York, and St. Charles Hospital, Port Jefferson, New York The occurrence of nontropical sprue in two brothers is reported. The first presented with severe, deforming, progressive osteomalacia and the second with life-threatening cutaneous and genitourinary bleeding. This report demonstrates the variability of presentation of the disease in relatives as well as its potential severity. The familial occurrence of nontropical sprue (adult celiac disease) has been well recognized. 1 A number of reports have included parents and children,2 siblings,3 and twins. 4 Carter et al. 5 found the risk in the general population to be 0.03% while in siblings and parents of probands the incidence was 2.4%. MacDonald and his associates 6 obtained biopsy specimens from available relatives of a selected series of patients with nontropical sprue and found a 13% incidence of histological disease in siblings and a 19% incidence in children of probands. The complexity of the inheritance of the disease is emphasized by a report of discordance for nontropical sprue in a monozygotic twin. 7 Adult celiac disease can exhibit a variety of manifestations. The majority of familial reports, however, make little comment on the variability of symptoms in the same famly. Rally et al. 8 reported two sisters with different manifestations. n one sister there was long standing iron deficiency anemia and in the other hypocalcemia and hypoprothrombinemia. The present report concerns itself with two brothers, one manifesting as Received May 9, Accepted June 11, Address requests for reprints to: Dr. E. Marvin Sokol, 158 East Main Street, Huntington, New York. 117 crippling osteomalacia and the other as a life-threatening co~gulation defect. Case Reports Case 1. E. D., a 43-year-old man (fig. 1) was first admitted to Huntington Hospital on May 15, 1965, because of abdominal bloating, mild diarrhea, anemia, and bony deformities. His history dates back to age 7 when he was treated for "severe stomach cramps." During the next 20 years the patient was seen at a number of New York City hospitals for bone diseases. At age 11 he developed a knockkneed deformity for which orthopedic surgery was performed. Four years later the patient first noted the onset of persistent pain in the upper and lower extremities as well as a progressive deformity of these regions. At age 20 and 21, because of "abnormal chemistries and bone x-rays," he underwent two separate neck explorations for the possibility of a parathyroid adenoma. None was found. Review of those records revealed a calcium determination of 10.5 mg per 100 ml, a phosphorous of 2.9 mg per 100 ml, and an alkaline phosphatase of 72 King-Armstrong units. A glucose tolerance curve was reported as flat at that time. n June of 1947, a bone biopsy of the right ileum was diagnosed as polyostatic fibrous dysplasia. (More recent review of this biopsy does not confirm the diagnosis.) n 1949, a suspicion of malabsorption was first entertained and the patient was placed on folic

$n 1952 he sustained a fracture of his left knee with apparent good healing. n 1954 and in 1956 X-rays revealed bony cysts (fig. 2).$ The patient became progressively debilitated with weakness, fatique, and persistent bone pain with increasing deformity over the ensuing years (fig. 2). n 1958 the patient referred himself to St.

The patient became progressively debilitated with weakness, fatique, and persistent bone pain with increasing deformity over the ensuing years (fig. 2). n 1958 the patient referred himself to St.

2 118 CASE REPORTS Vol. 56, No.1 FG. 1. Photograph of case 1, in wheel chair, and case 2, standing. acid, calcium, and testosterone. These medications were used only intermittently. n 1952 he sustained a fracture of his left knee with apparent good healing. n 1954 and in 1956 X-rays revealed bony cysts (fig. 2). The patient became progressively debilitated with weakness, fatique, and persistent bone pain with increasing deformity over the ensuing years (fig. 2). n 1958 the patient referred himself to St. Charles Hospital in Port Jefferson, Long sland, for attempted rehabilitation and was followed at that institution until admission to Huntington Hospital. Physical examination in 1958 revealed a dwarfed adult man with marked deformities of all e~tremities and the spine. t was noted that the bones could be indented by external pressure. Laboratory data revealed a hemoglobin of 6 g, persistent hypocalcemia ranging to lows of 6.5 mg per 100 ml accompanied by a phosphorous of 1 to 2.4 mg per 100 ml, and a persistent elevation of the alkaline phosphatase in the range of 25 King-Armstrong units. Radiographic studies of the bones were interpreted as widespread osteomalacia (figs. 2,3). n 1960, because of the above determinations and the clinical status, the diagnosis of osteomalacia secondary to a malabsorption state was entertained. By this time, osteomalacia had progressed to a point where the patient was confined to bed with severe bone

3 January 1969 CASE REPORTS 119 FG. 2. Serial roentgenograms of right radius and ulna in case 1. A, 1948, rarefaction of bone in mid- and distal ulna. B, 1956, loss of trabecular pattern, thinning of cortices, and bowing of both bones. C, 1959, and D, 1965, further progression of bony demineralization and deformity. FG. 3. Roentgenogram in case 1 of deformed pelvis and femurs showing marked demineralization and cyst formation. There are bilateral pathological mid-shaft femoral fractures.

determination. The patient reached a status of well being, free of pain, but with episodes of hypocalcemic tetany and anemia.

4 120 CASE REPORTS Vol. 56, No.1 pain. Treatment consisted of calcium lactate, vitamin D, folic acid, multivitamins, iron, and vitamin B12 On this regimen, there was gradual improvement both by clinical observation and biochemical determination. The patient reached a status of well being, free of pain, but with episodes of hypocalcemic tetany and anemia. He was limited to a wheelchair, however, because of the deformities of the hips and lower extremities (fig. 3). After some years, he discontinued his medications. n May of 1965 the patient developed diarrhea for the first time. This was accompanied by weight loss, abdominal pain, low grade fever, and recurrence of bone pain. A small bowel X-ray series (fig. 4) revealed dilation, segmentation, and flocculation of the barium column compatible with the malabsorption syndrome. Attempts at small bowel biopsy on three separate occasions were unsuccessful as the biopsy capsule would not pass into the duodenum. This was probably due to the spinal deformity. The laboratory findings are shown in table 1. The patient was treated with a gluten-free diet. On this regimen, there was marked and rapid improvement in the diarrhea, abdominal distention, and flatulence, as well as disappearance of bone pain. Biochemical determinations returned to normal and have remained persistently normal without the use of supplemental vitamins, minerals, or hematinic agents over the ensuing 2 V2 years. The small bowel X-ray pattern has also reverted toward normal (fig. 4). n 1967 the patient was re-admitted to Huntington Hospital for corrective orthopedic surgery of the deformities of the lower extremities so as to make ambulation possible. These deformities had resulted from positions of comfort assumed during years of enforced confinement. Bilateral tibial osteotomies were performed and the resulting surgical specimens were compatible with end-stage osteomalacia. Postoperatively, the patient was fitted with high heel corrective shoes so that for the first time in 10 years he became ambulatory. He has compensated for the upper extremity deformities and no further orthopedic surgery is anticipated. FG. 4. Small intestinal roentgenogram in case 1 before treatment in 1965 (1) showing widening of the lumen, segmentation, and loss of mucosal markings. Two years after gluten withdrawal (2) there has been improvement in the small intestinal pattern. Note spinal deformity.

5 January 1969 CASE REPORTS 121 TAB LE 1. Laboratory determinations Test Hemoglobin Serum Fe Serum Ca Serum PO. Alkaline PO. Cholesterol Albumen Carotene Prothrombin time D-xylose Schilling test Fecal fat a K-A, King-Armstrong units. b N.P.; not performed. Norma] 13 g mg per 100 ml 9-11 mg per 100 ml mg per 100 ml K-A units" 250 mg per 100 ml 3-4 g per 100 ml mg per 100 ml 10- l4 sec >4-5 g excretion >8% excretion Up to 6 g per 24 hr Case 2. J. D., age 45, (fig. 1) is the 2- year-older sibling of case 1 with whom he resided. He considered himself in general good health until July 1, 1967, when he noted the onset of painless, but massive hematuria which continued until the time of admission to Huntington Hospital 4 days later. During this interval, the patient also developed a large, spreading ecchymotic area involving his left thigh and left lower torso. There was no antecedent history of trauma, drug ingestion, bleeding tendencies, or anemia. The patient had been evaluated elsewhere approximately 1 year prior to admission for fatigability and mild weight loss. His hemoglobin at that time was noted to be 13.5 g. The patient was given an injection of vitamin B12 following which there was some improvement in his fatigability but no significant weight gain. He denied infantile or adult diarrhea but on close questioning did recall a number of episodes of loose bowels usually associated with upper respiratory infections. The last such episode was approximately 5 months prior to admission. There was no history of bone pain or deformity but he had always been underweight. Physical examination revealed a blood pressure of 110/80, a height of 5 ft 7 1/ 2 inches, and a weight of 117 lbs. The patient was pale and there were large ecchymotic areas involving the entire left thigh, the left lower abdominal wall, the left palm, and right foot. There was no evidence of nasal, oral, or retinal hemorrhage. The abdomen was slightly distended but not tender. There were no abnormal organs Case 1 Case 2 Pre-Rx Post-Rx Pre-Rx Post-Rx l l N.p.b N. P. l For fat -For fat 25 -For fat or masses felt. The heart and lungs were normal. The neurological examination was intact. There was no peripheral lymph node enlargement. The patient's admitting hemoglobin determination was 5.8 g per 100 ml and the urine was grossly bloody. A Lee-White clotting time revealed no clotting after 20 min. A prothrombin time and a thromboplastin generation test also failed to produce any clotting. A plasma fibrinogen, fibrinolysin, and platelet count were all normal. These studies were interpreted as showing a marked prothrombin deficiency; the patient was, therefore, treated with 75 mg of intramuscular vitamin K analogue and transfusion of 4 units of fresh whole blood. Twenty-four hours later the prothrombin time was 13 sec and the hemoglobin level 11 g per 100 ml. No further evidence of skin bleeding was noted and there was gradual clearing of blood from the urine. Laboratory determinations, which are listed in table 1, indicated the presence of a severe malabsorption syndrome. Radiological studies of the small intestine showed dilation, segmentation, and flocculation of the barium column. An intravenous pyelogram was normal, as were a bone survey and a barium enema. A peroral small intestinal biopsy was obtained, under fluoroscopic control, from the proximal jejunum. The mucosa showed villus atrophy and inflammation in the lamina propria (fig. 5). Following completion of these studies, the patient was placed on a gluten-free diet. He tolerated it well and gained 10 lbs in 1 month.

Biochemical studies have also revealed a return to normal without supplemental treatment, aside from dietary restriction of gluten. A family study was made following recognition of case 2.

6 122 CASE REPORTS Vol. 56, No.1 FG. 5. Small intestinal biopsy in case 2 showing shortened, thickened villi and deep crypts. There are many lymphocytes and plasma cells in the lamina propria (H & E, X 200). To date there has been no further evidence of bleeding or diarrhea. Biochemical studies have also revealed a return to normal without supplemental treatment, aside from dietary restriction of gluten. A family study was made following recognition of case 2. The mother and father were unrelated. The father was reported to have died at age 43 with pneumonia and the mother succumbed to a heart attack in 1961 at age 76. There were six siblings in the family. One female sibling died at age 6 months with pneumonia. The eldest male brother died at age 53 in September of 1967 with an acute coronary thrombosis. The middle two brothers, now aged 48 and 49, have no clinical evidence of malabsorption. Laboratory investigation of these two brothers has shown normal complete blood count, prothrombin time, calcium, phosphorus, alkaline phosphatase, albumin, carotene, cholesterol, and o-xylose absorption. Discussion A reasonably certain diagnosis of nontropical sprue can be made in these two brothers despite the lack of histological confirmation n case 1. Biochemical, radiological, and absorption studies in both confirm the presence of malabsorption. The typical histological changes seen in the elder brother and the response to gluten elimination in both confirm the diagnosis of gluten-sensitive adult celiac disease. Hypocalcemia is seen in 66 and 79% of cases in large series of nontropical sprue, while concomitant hypophosphatemia and elevation of alkaline phosphatase determinations are not unusual. Tentany has been reported in 25 to 50%,9.10 but the incidence of bone pain is somewhat less, being 10 to 20%. Cook et al. reported 27 of 37 patients to have radiographical evidence of bone demineralization. Mineral loss from the bone must approach 50% for roentgen changes to appear in osteomalacia. True fractures occur with little or no trauma and usually are of the neck of the femur and compression fractures of the spine. Osteomalacia also produces pseudofractures, small breaks in the bone, followed by

7 January 1969 CASE REPORTS 123 the laying down of noncalcified osteoid tissue, which occurs in the cortices of long bones, the scapulae, and pelvis.12, 13 Evidence of both osteoporosis and osteomalacia is seen on bone biopsyl3 in the bone disease of malabsorption. Alteration in normal calcium absorption and metabolism is thought to be on multiple basis. 13 There is a primary malabsorption of the exogenous and endogenous calcium ion because of the mucosal lesion as well as malabsorption of the fat soluble vitamin D. Vitamin D is necessary for calcium absorption from the intestinal tract and its skeletal utilization. 14 The degree of calcium malabsorption need not parallel the amount of steatorrhea. 15 Secondary hyperparathyroidism also contributes to the biochemical abnormalities and the bone disease.13, 16 The severity of the osteomalacia and resulting widespread bony deformities seen in the first case is most unusual. 16 Hypoprothrombinemia resulting from malabsorption of fat soluble vitamin K is present in 70% of nontropical sprue patients, with bleeding occurring in 10 to 27%.3,9, 10 Depletion of factors V, X, and X, the other vitamin K-dependent coagulation factors, also contributes to the hemorrhagic tendencies. Purpura is the most frequent manifestation of the coagulation defect but epistaxis, hematuria, hemarthrosis, hematemesis, melena, menorrhagia, and intracranial and retroperitoneal hemorrhage may also occur. Rapid response to parenteral vitamin K is to be expected since there is usually no associated liver disease. Despite the numerous case reports and reviews of nontropical sprue occurring in families, there has been little comment on the variability of expression of the disease in various relatives. Familial cases are most often discovered because of the similarity of their symptoms, the most usual one being diarrhea. Diarrhea may not be a prominent feature in 5 to 20% of patients,3, 9, 10 and its lack in these siblings contributed to the delay in diagnosis as did the unusual and severe mode of presentation. REFERENCES 1. Thompson, M. W Heredity, maternal age, birth order in etiology of celiac disease. Amer. J. Hum. Genet. 3: Norris, T. Stm Three familial cases of adult idiopathic steatorrhea. Proc. Roy. Soc. Med.59: Cooke, W. T., A. L. P. Peeney, and C. F. Hawkins Symptoms, signs, and diagnostic features of idiopathic steatorrhea. Quart. J. Med. 22: Ebbs, J. H Celiac disease. Canad. Med. Assn. J. 75: Carter, C., W. Sheldon, and C. Walker The inheritance of celiac disease. Ann. Hum. Genet. 23: MacDonald, W. C., W. O. Dobbins, and C. E. Rubin Studies on the familial nature of celiac sprue using biopsy of the small intestine. New Eng. J. Med. 272: Hoffman, H. N., E. E. Wollaeger, and E. Greenberg Discordance for nontropical sprue (adult celiac disease) in a monozygotic pair. Gastroenterology 51: Rally, C. R, D: S. Munroe, and A. Bogoch diopathic steatorrhea presenting with different manifestations in sisters. Canad. Med. Assn. J. 90: Green, P. A., and E. E. Wollaeger Clinical behavior of sprue in the United States. Gastroenterology 38: Bossack, E. T., C.. Wang, and D. Adlersberg Clinical aspects of the malabsorption syndrome, p n D. Adlersberg led), The malabsorption syndrome. Grune & Stratton, New York. 11. Cooke, W. T., D. J. Fone, E. V. Cox, M. J. Meynell, and R Gaddie Adult celiac disease. Gut 4: Juergens, J. L., D. A. Sholtz, and E. E. Wollaeger Severe osteomalacia associated with occult steatorrhea due to nontropical sprue. Arch. ntern. Med. (Chicago) 98: Arnstein, A. R, B. Frame, and H. M. Frost Recent progress in osteomalacia and rickets. Ann. ntern. Med. 67: Nordin, B. E. C Measurement and meaning of calcium absorption. Gastroenterology 54: Moss, A. J., C. Waterhouse, and R. Terry Gluten-sensitive enteropathy with osteomalacia but without steatorrhea. New Eng. J. Med. 272: Burkholder, P. K., E. A. BuBoff, and E. V. Filmanowicz Nontropical sprue with secondary hyperparathyroidism. Amer. J. Dig. Dis. 10:

LYMPHOMA PRESENTING AS MALABSORPTION

GASTROENTEROLOGY Copyright 1968 by The Williams & Wilkins Co. Vol. 54, No.3 Pnnted in U.S.A. LYMPHOMA PRESENTING AS MALABSORPTION HORACIO JINICH, M.D., EDMUNDO ROJAS, M.D., JOHN A. WEBB, M.D., AND JOHN