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Intestinal Malabsorption: First Manifestation of Amyloidosis in Familial Mediterranean Fever
Vol. 66, No.3
GASTROENTEROLOGY 66:446- 449, 1974 Copyri ght © 1974 by The Williams & Wilkins Co.
Printed in U.S .A.
INTESTINAL MALABSORPTION: FIRST MANIFESTATION OF AMYLOIDOSIS IN FAMILIAL MEDITERRANEAN FEVER Report of two cases MORDECHAI RAVID, M.D ., AND EZRA SOHAR, M.D.
Department of Medicine, The Chaim Sheba Medical Center and Heller Institute of Medical Research. Tel-Aviv University Medical School , Tel-Hashomer , Israel
Proteinuria, progressing to nephrosis , is the first clinical manifestation in virtually all cases of secondary and familial Mediterranean fever amyloidosis. Although malabsorption has been encountered in a few patients, they had all previously suffered from advanced renal involvement. Two patients with familial Mediterranean fever are described, in whom intestinal malabsorption was the presenting symptom of amyloidosis , although there had been no previous evidence of renal involvement. The differential diagnosis of a malabsorption syndrome should, therefore, include amyloidosis also in patients with normal renal functions and without proteinuria. Amyloidosis of familial Mediterranean fever (FMF), although most probably genetic in origin, is clinically and histologically indistinguishable from secondary amyloidosis. 1- 3 The first, outstanding, and fatal manifestation of both secondary and FMF amyloidosis is renal disease: in close to 100 patients in our series with FMF amyloidosis, proteinuria was the first clinical manifestation in all patients, and renal amyloidosis was the cause of death in all but 1. 2 , 4 Of 88 patients with secondary amyloidosis, taken from hospitals in Israel between 1950 and 1960, all presented and died of kidney disease, except for 1 patient who died of liver failure. 5 Intestinal malabsorption has previously been described in patients with secondary amyloidosis, 6-9 but all had previously suffered from advanced renal disease. The 2 patients to be described in this paper are unique in that severe intestinal malabsorption was the Received March 5, 1973. Accepted October 22, 1973. Address requests for reprints to: Dr. Ezra Sohar, Heller Institut e of Medical Research , Tel-Aviv University Medical School , Tel-Hashomer Hospital, TelAviv, Israel.
446
first clinical manifestation of FMF amyloidosis. Case Reports Case 1. The patient was a 20-year-old male, who was born in Lybia. Four cousins were known to have FMF. This patient's illness first became manifest at the age of 4 when he developed pain in the left sacroiliac joint. His illness continued with attacks of synovitis and peritonitis typical of familial Mediterranean fever. Rectal biopsy , performed at the age of 13, showed minute deposits of amyloid in the intima of submucosal blood vessels. At the age of 18, he presented with crampy abdominal pain, the passage of four to five bulky, yellow stools daily, fatigue, and weight loss . The patient was thin (height 6 feet, weight 117 Ib) and pale, but had no edema. Physical examination, chest roentgenograms, and repeated electrocardiograms were within normal limits . The hemoglobin was 8.5 g per 100 ml, and a peripheral blood smear showed hypochromic erythrocytes and occasional macrocytes. Serum albumin was 3.1 g per 100 ml, cholesterol 83 mg per 100 ml, total lipids 383 mg per 100 ml , calcium 8.7 mg per 100 ml , and phosphorus 4 mg per 100 ml ; serum iron was 28 J.lg per 100 ml, rising to 43 J.lg per 100 ml after an oral loading dose . Total iron binding capacity was 205 J.lg per 100 m!. The
March 1974
CASE REPORTS
447
oral glucose tolerance test showed a flat curve: fasting value was 104 mg per 100 ml, 74 mg per 100 ml at 30 min, and 74 mg per 100 ml at 60 min. The stools were bulky, and weighed 600 g daily; the pH was 5. Total fecal fat excretion averaged 30 g daily on a regular hospital diet which contained approximately 70 g of fat per day. Ingestion of 5 g of n-xylose resulted in the urinary excretion of 0.2 g over a 5-hr collection period. Radiological studies revealed slightly distended small bowel loops. There was no evidence of blind loop formation. The mucosal pattern was normal. A small intestinal biopsy from the region of the ligament of Treitz and a rectal biopsy (fixed in formalin, paraffinembedded, and stained with hematoxylin and eosin and Congo red) were examined by light microscopy with regular and polarized light. 10, 11 The appearance of the villi and the epithelial cells was normal. Numerous amyloid deposits were found underneath the surface epithelium around the glands of Lieberkiihn and in the lamina propria. Bands of amyloid were seen in the muscularis mucosae and in
FIG. 2. Case 1, section of jejunal biopsy specimen showing numerous small deposits of amyloid in the mucosa, creating a band of amyloid directly underneath the surface epithelium. The mucosal cells retain a normal appearance. Congo red stain. Polarized light (x 400).
FIG. 1. Case 1, section from jejunal biopsy specimen showing large deposits of amyloid in muscularis mucosae and in submucosal blood vessels. The mucosal glands are preserved. Congo red stain. Polarized light (x 100).
almost all submucosal blood vessels (figs. 1 and 2). Renal function was normal and blood urea was 22 mg per 100 ml; creatinine clearance was 104 ml per min, and the urine contained less than 150 mg of protein per 24 hr. The patient was treated with oral tetracycline. A repeated 3-day stool collection revealed a mean daily excretion of 26 g of fat. A proteinuria (1 to 1.5 g daily) and ankle edema first appeared 18 months later, Blood urea and creatinine clearance were still normal. Case 2. The patient was a 24-year-old male, who was born in Tunisia. Familial Mediterranean fever had been diagnosed at the age of 10. He had suffered numerous attacks of fever and abdominal or chest pain, which had usually subsided within 48 hr, as well as rare attacks of arthritis of somewhat longer duration. A 17year-old brother and one cousin were similarly affected. During 1971, the patient noted a gradual loss of weight, and the passage of bulky stools, two to three times daily. Physical examination was normal except for a palpable spleen edge. The patient's height was 5 feet, 10 inches, and his weight was 110 lb.
448
Vol. 66.No.3
CASE REPORTS
Chest roentgenograms showed a normal heart size; the electrocardiogram was normal; hemoglobin 11 g per 100 ml; serum albumin 3.2 g per 100 ml; cholesterol 130 mg per 100 ml; total lipids 402 mg per 100 ml; calcium 8.3 mg per 100 ml; serum iron was 43 f.Lg per 100 ml, rising to 52 f.Lg per 100 ml after an oral loading dose. Total iron binding capacity was 185 f.Lg per 100 ml. The oral glucose tolerance test showed a flat curve: fasting value was 92 mg per 100 ml, 100 mg per 100 ml at 30 min, and 94 mg per 100 ml at 60 min. On a diet containing approximately 70 g of fat per day. the fecal fat excretion averaged 23 g daily for 3 days. The 5 g D-xylose test showed a 5-hr urinary excretion of 0.35 g; gastrointestinal X-rays were interpreted as normal. A rectal biopsy showed massive deposits of amyloid in the intima and media of submucosal blood vessels as well as in the muscularis mucosae and mucosa. The mucosal architecture was preserved; renal function was normal; blood urea was 22 mg per 100 ml; creatinine clearance was 98 ml per min; urinalysis was normal; the 24-hr protein excretion was below 150 mg. Treatment with tetracycline, and high protein, low residue diet resulted in some weight gain (to 1171b within 6 weeks), but in no change in the degree of steatorrhea.
Discussion Amyloidosis was, most probably, the sole cause of the intestinal malabsorption in our patients. There was no evidence of partial obstruction or blind loop formation. The few previously described cases of malabsorption, which was due to secondary or FMF amyloidosis, notably the patient who died of malabsorption, described by Shibolet and Gafni,6 all had shown signs of renal disease when the first intestinal symptoms appeared. Our patients are unique in their clinical presentation with severe malabsorption in the absence of manifest renal disease. This should alert the clinician to the possibility of amyloidosis being the cause of malabsorption, even in patients who show no evidence of renal damage. From a more theoretical aspect, our patients highlight the enigma of the concentration of functional impairment to one organ in a systemic disease which attacks all organs of the body. In all cases of death due to amyloid nephropathy, extensive involvement was found in arterioles
throughout the body. Parenchymal deposits were found in several organs, notably the adrenals, the spleen, and the mucosa of the gastrointestinal tract. 3 Yet, no stigmata of adrenal insufficiency have ever been found in patients with FMF amyloidosis, and systematic search for signs of intestinal malabsorption revealed only minor abnormalities of vitamin B12 and iron absorption in a few patients. 12 Furthermore, no direct relationship could be detected between the extent of amyloid deposits in the intestinal wall and the degree of malabsorption. 13 • 14 Additional investigation is needed to determine why certain organs are affected more severely and more frequently in a systemic disease, and why, of organs which seem to be histologically affected to the same degree, one is functionally more damaged than the others. REFERENCES 1. Heller H, Missmahl HP, Sohar E, et al: Amyloidosis: its differentiation into perireticulin and pericollagen types. J Pathol Bacteriol 88:15-34. 1964 2. Sohar E, Gafni J, Prass M, et al: Familial mediterranean fever. A survey of 470 cases and review of the literature. Am J Med 43:227-253, 1967 3. Heller H. Gafni J, Sohar E: The inherited systemic amyloidosis, The Metabolic Basis of Inherited Disease. Second edition. Edited by JB Stanbury, JB Wyngaarden, DS Fredrickson. New York, McGraw-Hill, 1966, p 995-1014 4. Gafni J, Ravid M, Sohar E: The role of amyloidosis in familial mediterranean fever. A population study. Isr J Med Sci 4:995-999. 1968 5. Blum A. Sohar E: The diagnosis of amyloidosis: ancillary procedures. Lancet. 1:721-724, 1962 6. Shibolet S, Gafni J: Fatal malabsorption syndrome in FMF amyloidosis. Proc Tel-Hashomer Hosp 3: 117-118, 1964 7. Beddow RM, Tilden IL: Malabsorption syndrome due to amyloidosis of the intestine secondary to lepr.omatous leprosy: a report of a case. Ann Intern Med 53:1017-1027, 1960 8. Herskovic T, Bartholomew LG, Green PA: Amyloidosis and malabsorption syndrome. Arch Intern Med 114:629-633, 1964 9. Babb RA. Alarcon-Segovia D. Dissner GR, et al: Malabsorption in rheumatoid arthritis: an unusual complication caused by amyloidosis. Arthritis Rheum 10:63-70, 1967
March 1974
CASE REPORTS
10. Missmahl HP, Hartwig M: Polarizationoptische untersuchungen an der amyloidsubstanz. Virchows Arch 324:489-508, 1953 11. Gafni J, Sohar E: Rectal biopsy for the diagnosis of amyloidosis. Am J Med Sci 240:332-335, 1960 12. Yoran C, Weber H, Gilat T: Studies of gastrointestinal function in amyloidosis of familial Medi-
449
terranean fever. Scand J GastroenteroI4:275-279, 1969 13. Gilat T, Revach M, Sohar E: Deposition of amyloid in the gastrointestinal tract. Gut 10:98-104, 1969 14. Gilat T, Spiro HM: Amyloidosis and the gut . Am J Dig Dis 13:619-633, 1968
GASTROENTEROLOGY 66:446- 449, 1974 Copyri ght © 1974 by The Williams & Wilkins Co.
Printed in U.S .A.
INTESTINAL MALABSORPTION: FIRST MANIFESTATION OF AMYLOIDOSIS IN FAMILIAL MEDITERRANEAN FEVER Report of two cases MORDECHAI RAVID, M.D ., AND EZRA SOHAR, M.D.
Department of Medicine, The Chaim Sheba Medical Center and Heller Institute of Medical Research. Tel-Aviv University Medical School , Tel-Hashomer , Israel
Proteinuria, progressing to nephrosis , is the first clinical manifestation in virtually all cases of secondary and familial Mediterranean fever amyloidosis. Although malabsorption has been encountered in a few patients, they had all previously suffered from advanced renal involvement. Two patients with familial Mediterranean fever are described, in whom intestinal malabsorption was the presenting symptom of amyloidosis , although there had been no previous evidence of renal involvement. The differential diagnosis of a malabsorption syndrome should, therefore, include amyloidosis also in patients with normal renal functions and without proteinuria. Amyloidosis of familial Mediterranean fever (FMF), although most probably genetic in origin, is clinically and histologically indistinguishable from secondary amyloidosis. 1- 3 The first, outstanding, and fatal manifestation of both secondary and FMF amyloidosis is renal disease: in close to 100 patients in our series with FMF amyloidosis, proteinuria was the first clinical manifestation in all patients, and renal amyloidosis was the cause of death in all but 1. 2 , 4 Of 88 patients with secondary amyloidosis, taken from hospitals in Israel between 1950 and 1960, all presented and died of kidney disease, except for 1 patient who died of liver failure. 5 Intestinal malabsorption has previously been described in patients with secondary amyloidosis, 6-9 but all had previously suffered from advanced renal disease. The 2 patients to be described in this paper are unique in that severe intestinal malabsorption was the Received March 5, 1973. Accepted October 22, 1973. Address requests for reprints to: Dr. Ezra Sohar, Heller Institut e of Medical Research , Tel-Aviv University Medical School , Tel-Hashomer Hospital, TelAviv, Israel.
446
first clinical manifestation of FMF amyloidosis. Case Reports Case 1. The patient was a 20-year-old male, who was born in Lybia. Four cousins were known to have FMF. This patient's illness first became manifest at the age of 4 when he developed pain in the left sacroiliac joint. His illness continued with attacks of synovitis and peritonitis typical of familial Mediterranean fever. Rectal biopsy , performed at the age of 13, showed minute deposits of amyloid in the intima of submucosal blood vessels. At the age of 18, he presented with crampy abdominal pain, the passage of four to five bulky, yellow stools daily, fatigue, and weight loss . The patient was thin (height 6 feet, weight 117 Ib) and pale, but had no edema. Physical examination, chest roentgenograms, and repeated electrocardiograms were within normal limits . The hemoglobin was 8.5 g per 100 ml, and a peripheral blood smear showed hypochromic erythrocytes and occasional macrocytes. Serum albumin was 3.1 g per 100 ml, cholesterol 83 mg per 100 ml, total lipids 383 mg per 100 ml , calcium 8.7 mg per 100 ml , and phosphorus 4 mg per 100 ml ; serum iron was 28 J.lg per 100 ml, rising to 43 J.lg per 100 ml after an oral loading dose . Total iron binding capacity was 205 J.lg per 100 m!. The
March 1974
CASE REPORTS
447
oral glucose tolerance test showed a flat curve: fasting value was 104 mg per 100 ml, 74 mg per 100 ml at 30 min, and 74 mg per 100 ml at 60 min. The stools were bulky, and weighed 600 g daily; the pH was 5. Total fecal fat excretion averaged 30 g daily on a regular hospital diet which contained approximately 70 g of fat per day. Ingestion of 5 g of n-xylose resulted in the urinary excretion of 0.2 g over a 5-hr collection period. Radiological studies revealed slightly distended small bowel loops. There was no evidence of blind loop formation. The mucosal pattern was normal. A small intestinal biopsy from the region of the ligament of Treitz and a rectal biopsy (fixed in formalin, paraffinembedded, and stained with hematoxylin and eosin and Congo red) were examined by light microscopy with regular and polarized light. 10, 11 The appearance of the villi and the epithelial cells was normal. Numerous amyloid deposits were found underneath the surface epithelium around the glands of Lieberkiihn and in the lamina propria. Bands of amyloid were seen in the muscularis mucosae and in
FIG. 2. Case 1, section of jejunal biopsy specimen showing numerous small deposits of amyloid in the mucosa, creating a band of amyloid directly underneath the surface epithelium. The mucosal cells retain a normal appearance. Congo red stain. Polarized light (x 400).
FIG. 1. Case 1, section from jejunal biopsy specimen showing large deposits of amyloid in muscularis mucosae and in submucosal blood vessels. The mucosal glands are preserved. Congo red stain. Polarized light (x 100).
almost all submucosal blood vessels (figs. 1 and 2). Renal function was normal and blood urea was 22 mg per 100 ml; creatinine clearance was 104 ml per min, and the urine contained less than 150 mg of protein per 24 hr. The patient was treated with oral tetracycline. A repeated 3-day stool collection revealed a mean daily excretion of 26 g of fat. A proteinuria (1 to 1.5 g daily) and ankle edema first appeared 18 months later, Blood urea and creatinine clearance were still normal. Case 2. The patient was a 24-year-old male, who was born in Tunisia. Familial Mediterranean fever had been diagnosed at the age of 10. He had suffered numerous attacks of fever and abdominal or chest pain, which had usually subsided within 48 hr, as well as rare attacks of arthritis of somewhat longer duration. A 17year-old brother and one cousin were similarly affected. During 1971, the patient noted a gradual loss of weight, and the passage of bulky stools, two to three times daily. Physical examination was normal except for a palpable spleen edge. The patient's height was 5 feet, 10 inches, and his weight was 110 lb.
448
Vol. 66.No.3
CASE REPORTS
Chest roentgenograms showed a normal heart size; the electrocardiogram was normal; hemoglobin 11 g per 100 ml; serum albumin 3.2 g per 100 ml; cholesterol 130 mg per 100 ml; total lipids 402 mg per 100 ml; calcium 8.3 mg per 100 ml; serum iron was 43 f.Lg per 100 ml, rising to 52 f.Lg per 100 ml after an oral loading dose. Total iron binding capacity was 185 f.Lg per 100 ml. The oral glucose tolerance test showed a flat curve: fasting value was 92 mg per 100 ml, 100 mg per 100 ml at 30 min, and 94 mg per 100 ml at 60 min. On a diet containing approximately 70 g of fat per day. the fecal fat excretion averaged 23 g daily for 3 days. The 5 g D-xylose test showed a 5-hr urinary excretion of 0.35 g; gastrointestinal X-rays were interpreted as normal. A rectal biopsy showed massive deposits of amyloid in the intima and media of submucosal blood vessels as well as in the muscularis mucosae and mucosa. The mucosal architecture was preserved; renal function was normal; blood urea was 22 mg per 100 ml; creatinine clearance was 98 ml per min; urinalysis was normal; the 24-hr protein excretion was below 150 mg. Treatment with tetracycline, and high protein, low residue diet resulted in some weight gain (to 1171b within 6 weeks), but in no change in the degree of steatorrhea.
Discussion Amyloidosis was, most probably, the sole cause of the intestinal malabsorption in our patients. There was no evidence of partial obstruction or blind loop formation. The few previously described cases of malabsorption, which was due to secondary or FMF amyloidosis, notably the patient who died of malabsorption, described by Shibolet and Gafni,6 all had shown signs of renal disease when the first intestinal symptoms appeared. Our patients are unique in their clinical presentation with severe malabsorption in the absence of manifest renal disease. This should alert the clinician to the possibility of amyloidosis being the cause of malabsorption, even in patients who show no evidence of renal damage. From a more theoretical aspect, our patients highlight the enigma of the concentration of functional impairment to one organ in a systemic disease which attacks all organs of the body. In all cases of death due to amyloid nephropathy, extensive involvement was found in arterioles
throughout the body. Parenchymal deposits were found in several organs, notably the adrenals, the spleen, and the mucosa of the gastrointestinal tract. 3 Yet, no stigmata of adrenal insufficiency have ever been found in patients with FMF amyloidosis, and systematic search for signs of intestinal malabsorption revealed only minor abnormalities of vitamin B12 and iron absorption in a few patients. 12 Furthermore, no direct relationship could be detected between the extent of amyloid deposits in the intestinal wall and the degree of malabsorption. 13 • 14 Additional investigation is needed to determine why certain organs are affected more severely and more frequently in a systemic disease, and why, of organs which seem to be histologically affected to the same degree, one is functionally more damaged than the others. REFERENCES 1. Heller H, Missmahl HP, Sohar E, et al: Amyloidosis: its differentiation into perireticulin and pericollagen types. J Pathol Bacteriol 88:15-34. 1964 2. Sohar E, Gafni J, Prass M, et al: Familial mediterranean fever. A survey of 470 cases and review of the literature. Am J Med 43:227-253, 1967 3. Heller H. Gafni J, Sohar E: The inherited systemic amyloidosis, The Metabolic Basis of Inherited Disease. Second edition. Edited by JB Stanbury, JB Wyngaarden, DS Fredrickson. New York, McGraw-Hill, 1966, p 995-1014 4. Gafni J, Ravid M, Sohar E: The role of amyloidosis in familial mediterranean fever. A population study. Isr J Med Sci 4:995-999. 1968 5. Blum A. Sohar E: The diagnosis of amyloidosis: ancillary procedures. Lancet. 1:721-724, 1962 6. Shibolet S, Gafni J: Fatal malabsorption syndrome in FMF amyloidosis. Proc Tel-Hashomer Hosp 3: 117-118, 1964 7. Beddow RM, Tilden IL: Malabsorption syndrome due to amyloidosis of the intestine secondary to lepr.omatous leprosy: a report of a case. Ann Intern Med 53:1017-1027, 1960 8. Herskovic T, Bartholomew LG, Green PA: Amyloidosis and malabsorption syndrome. Arch Intern Med 114:629-633, 1964 9. Babb RA. Alarcon-Segovia D. Dissner GR, et al: Malabsorption in rheumatoid arthritis: an unusual complication caused by amyloidosis. Arthritis Rheum 10:63-70, 1967
March 1974
CASE REPORTS
10. Missmahl HP, Hartwig M: Polarizationoptische untersuchungen an der amyloidsubstanz. Virchows Arch 324:489-508, 1953 11. Gafni J, Sohar E: Rectal biopsy for the diagnosis of amyloidosis. Am J Med Sci 240:332-335, 1960 12. Yoran C, Weber H, Gilat T: Studies of gastrointestinal function in amyloidosis of familial Medi-
449
terranean fever. Scand J GastroenteroI4:275-279, 1969 13. Gilat T, Revach M, Sohar E: Deposition of amyloid in the gastrointestinal tract. Gut 10:98-104, 1969 14. Gilat T, Spiro HM: Amyloidosis and the gut . Am J Dig Dis 13:619-633, 1968