Keywords: AA amyloidosis, protein losing enteropathy, diarrhea, octreotide, corticosteroid, ^sup 99m^Tc-diethylene triamine pentaacetic acid human serum albumin scintigraphy
Abbreviations: BUN, blood urea nitrogen; CRP, C reactive protein; ESR, erythrocyte sedimentation rate; GI, gastrointestinal; HSA-D, diethylene triamine pentaacetic acid human serum albumin; RA, rheumatoid arthritis; SAA, serum amyloid A; WBC, white blood cell
Abstract
This report concerns two patients with severe protein losing enteropathy and refractory diarrhea due to AA amyloidosis who were successfully treated with corticosteroid and octreotide. In these patients, biopsied tissues from the gastrointestinal (GI) tract showed extensive deposition of AA amyloid, which was caused by rheumatoid arthritis in one case and was of unidentified etiology in the other. Both patients manifested severe diarrhea unresponsive to conventional treatment with hypoproteinemia, and protein leakage from the small intestine to the ascending colon was confirmed by ^sup 99m^Tc-diethylene triamine pentaacetic acid human serum albumin (HSA-D) scintigraphy. Soon after starting a long-acting somatostatin analogue, octreotide, with co-administration of oral prednisolone, their general status improved in parallel with a rapid decrease in the volume of watery diarrhea and an increase in serum levels of albumin and IgG. Also on ^sup 99m^Tc-HSA-D scintigraphy protein leakage from the GI tract was apparently decreased in both patients. Combination therapy with a somatostatin analogue and corticosteroid may be effective for protein losing enteropathy with intractable diarrhea ascribable to GI amyloidosis. Because of the lack of specific therapies in this serious clinical situation, the described therapy should actively be considered as a therapeutic option not only in AA amyloidosis, but also in other types of systemic amyloidosis.
Introduction
AA amyloidosis usually develops in patients with various inflammatory and infectious diseases [1,2] and commonly affects the gastrointestinal (GI) tract as well as the kidneys, causing clinical symptoms such as anorexia, vomiting and abdominal pain [3,4]. Among these symptoms intractable diarrhea and protein losing enteropathy sometimes become lifethreatening complications unless treated, because hypoproteinemia and dehydration rapidly worsen the general status of the patient [4,5]. Although there are no established treatments for these complications, a long-acting somatostatin analogue, octreotide, has recently been employed and has shown a good therapeutic effect [6-9]. Here, we report two patients with severe protein losing enteropathy with intractable diarrhea and renal insufficiency due to AA amyloidosis who were successfully treated with octreotide and corticosteroid, and focus on the therapeutic efficacy of this combination treatment.
case report
case 1
A 32-year-old Japanese man suddenly manifested vomiting, severe diarrhea, abdominal pain and high fever above 38C with neither precipitating cause nor particular family history in the middle of August 2003. These symptoms gradually worsened, and he was admitted to a neighboring hospital because of an inability to eat. Blood chemistry revealed renal dysfunction, and he was referred to our hospital. On admission body height and weight were 165 cm and 63 kg, respectively. Physical examination showed decreased turgor of the skin and hepatosplenomegaly with neither macroglossia nor neurological abnormalities. Routine laboratory data demonstrated highly positive inflammatory reactions, including white blood cells (WBC, 35,400 /mm^sup 3^) C reactive protein (CRP, 30 mg/dl, normal
Soon after starting antibiotics the high fever disappeared accompanied by a decrease in WBC, but the volume of watery diarrhea gradually increased with abdominal pain and distension, and CRP stayed at 3 to 5 mg/dl. Following methylprednisolone pulse therapy at 1000 mg/day for 3 days oral prednisolone was started at a dose of 60 mg/day. Although abdominal pain and distension immediately improved in conjunction with a decrease in inflammatory reactions, including CRP and SAA, the daily volume of watery diarrhea reached over 1000 ml and his general status and renal dysfunction gradually worsened (Figure 4). To suppress the watery diarrhea, a somatostatin analogue, octreotide, was started at a dose of 100 g/day at the beginning of November. Oral prednisolone was tapered carefully, keeping in mind a possible increase in inflammatory reactions again. Soon after starting octreotide with coadministration of oral prednisolone, the volume of watery diarrhea dramatically decreased, and his general status improved in parallel with an increase in albumin and IgG in serum and a decrease in creatinine and BUN. In January 2004 he became able to restart oral intake of food. On colonoscopy apparent improvement was seen in erosive lesions throughout the colon (Figure 2B), and biopsied specimens showed diminution of inflammatory cell infiltration in the submucosa, but there was no change in the degree of amyloid deposition (Figure 3C). ^sup 99m^Tc-HSA-D scintigraphy demonstrated no apparent protein leakage (Figure IB). Octreotide was tapered off, and the patient was discharged from our hospital with oral prednisolone only, at a dose of 10 mg/day in February 2004. He has since been in good general condition with normoproteinemia and negative inflammatory reactions, although BUN and creatinine in serum remained at 30-50 mg/dl and 3- 4 mg/dl, respectively. He returned to work in April 2004.
case 2
A 53-year-old Japanese woman with a 13-year history of rheumatoid arthritis (RA) manifested renal dysfunction with mild proteinuria in August 2001. Despite treatment with methotrexate and oral prednisolone at a dose of 6 mg/week and around 10 mg/ day, respectively, at a neighboring hospital, laboratory data persistently demonstrated elevated levels of inflammatory reactions in serum, including CRP and erythrocyte sedimentation rate (ESR), and her renal dysfunction gradually worsened. In November 2002 the biopsied gastric mucosa showed deposition of AA amyloid mainly in the submucosal tissue, and she was referred to our hospital in January 2003. Although cyclophos- phamide was additionally given at a dose of 50 mg/day following an increase in the daily dose of oral prednisolone to 20 mg/day, the patient showed no improvement in either renal indices or inflammatory reactions. Because of sudden- onset watery diarrhea with lower abdominal pain she became unable to eat, and was admitted to our hospital in April 2004.
On admission her body weight and height were 50 kg and 161 cm, respectively. Physical examination showed mild deformity almost symmetrically in the bilateral metacarpophalangeal and proximal interphalangeal joints with pain on movement. In the classification of severity and global functional status of RA, she was considered to belong to stage 3 and class 3, respectively [14,15]. Mild edema was seen in both pretibial regions. Laboratory data demonstrated hypoproteinemia (total protein 4.9 g/a, albumin 2.8 g/dl), hypogammaglobulinemia (IgG 457 mg/dl, normal 800-2000 mg/dl), renal dysfunction (BUN 51 mg/dl, creatinine 3.29 mg/dl, 24 h creatinine clearance 5.5 1/day), and positive inflammatory reactions, including ESR (18 mm/lh), CRP (4.67 mg/dl), and SAA (55.9 g/ml). Rheumatoid factor was strongly positive and anti-nuclear antibody was negative. CH50 activity and concentrations ofC3 and C4 were all within normal limits. Urinalysis showed proteinuria with protein excretion of 0.4 g/day. Both the electrocardiogram and chest X-ray were normal, and allelic variants of SAA isotype showed 1.3/1.3 in SAAl and 2.1/2.2 in SAA2 [10,11]. On ^sup 99m^Tc-HSA-D scintigraphy marked protein leakage was detected in the small intestine (Figure 1C).
Figure 1. ^sup 99m^Tc HSA-D scintigraphy shows massive leakage of the tracer in the intestinal lumen (arrows) on admission (A, case 1; C, case 2 ) but no accumulation after starting octreotide with co- administration of oral prednisolone (B, case 1; D, case 2).
Figure 2. In case 1 colonoscopy demonstrates multiple erosive lesions with hemorrhages and irregularly edematous mucosa throughout the colon on admission (A), but almost normal findings after starting corticosteroid and octreotide (B).
Figure 3. In case 1 histology of the biopsied specimen from the sigmoid colon demonstrates infiltration of mononuclear cells in the submucosa and amyloid deposition (A, Congo red staining, bar= 100 m), which is located mainly in the perivascular area and was confirmed as AA type on immunohistochemistry (B, bar= 100 m). After starting corticosteroid and octreotide infiltration of mononuclear cells apparently diminishes, while amyloid deposition does not change (C, Congo red staining, bar= 100 m).
Figure 4. Clinical course of case 1. The volume of watery diarrhea dramatically decreases after starting octreotide with coadministration of oral prednisolone. The general status of the patient and renal dysfunction improve in parallel with an increase in albumin and IgG in serum. PSL: prednisolone, CRP: C reactive protein, SAA: serum amyloid A.
With a suspected diagnosis of infectious enterocolitis, oral anti- diarrheal agents and antibiotics were started in addition to prednisolone at a dose of 20 mg/day after cessation of cyclophosphamide. In the stool culture, however, no causative agents could be detected, and the watery diarrhea persisted. Her general status rapidly worsened in parallel with an increase in serum levels of BUN and creatinine. Soon after octreotide was started at a dose of 100 g/day at the beginning of May, the volume of diarrhea suddenly decreased and the general status improved with an increase in albumin and IgG in serum. Although octreotide was stopped 16 days later because of leukopenia ascribable to this drug, the watery diarrhea did not appear, and she was able to eat food again at the end of May. A decrease in protein leakage from the GI tract was objectively confirmed on ^sup 99m^Tc-HSA-D scintigraphy (Figure ID).
Discussion
On the basis of immunohistochemical findings in biopsied tissues from the GI tract both patients were diagnosed as having systemic AA amyloidosis. On admission a systemic survey demonstrated advanced involvement of multiple organs, including the heart, the GI tract and/or kidneys, and amyloid deposition was considered to have silently developed over a long period. Considering that administration of antibiotics was partly effective in reducing inflammatory reactions in case 2, bacterial infection may have contributed to the acute onset of GI tract symptoms. Systemic AA amyloidosis is, in principle, caused either by chronic inflammatory disorders, including RA, tuberculosis, leprosy and Mediterranean fever, or by malignant tumors such as mesothelioma and Hodgkin’s disease [I]. In case 2 amyloidosis was considered to be ascribable to RA, while case 1 showed neither physical findings nor laboratory data suggestive of these causative disorders. Although colonoscopy in the latter case did demonstrate multiple erosive lesions throughout the colon, the histopathology of biopsied specimens was nondiagnostic for either Crohn’s disease or ulcerative colitis, which can also cause AA amyloidosis [16,17]. According to a recent report, no underlying disease is found in approximately 5% of patients with AA amyloidosis [2]. Since, in case 1, neither chronic inflammatory diseases nor malignant tumors were identified despite an intensive systemic survey, the AA amyloidosis was regarded as idiopathic.
GI amyloidosis usually shows various clinical manifestations, including mucosal erosions and ulceration, malabsorption, hemorrhages, protein losing enteropathy and intractable diarrhea, irrespective of the different precursor proteins of amyloid, and is sometimes the direct cause of death [4]. In our patients ^sup 99m^Tc- HSA-D scintigraphy demonstrated massive leakage of serum albumin into the intestinal lumen, mainly from the small intestine, leading to the diagnosis of protein losing enteropathy [18]. This manifestation is often seen in the advanced stage of GI amyloidosis as in both our patients. Although the precise mechanism of the protein losing enteropathy remains unclear, autonomie neuropathy and/ or involvement of blood vessels and lymphatics in the submucosa are thought to be central to the pathogenesis [5]. Considering that urinary protein excretion was relatively low in both patients, hypoproteinemia was mainly ascribable to protein losing enteropathy as well as intractable diarrhea.
There are no established treatments for protein losing enteropathy associated with AA amyloidosis. To suppress production of serum amyloid A, which is the precursor protein of this disease, corticosteroid is often used for treatment of the amyloidosis, and this drug sometimes also ameliorates protein losing enteropathy through its reduction of submucosal edema and inflammation in the GI tract [9]. In case 1, the methylprednisolone pulse therapy followed by oral prednisolone was effective for abdominal pain and distension but not for watery diarrhea. Recently, a long-acting somatostatin analogue, octreotide, has been used in the treatment of severe diarrhea ascribable to amyloidosis [6-9]. This drug is considered to act against refractory diarrhea by suppressing excretion of GI hormones, including gastrin, vasoactive intestinal peptide, pancreatic polypeptide and serotonin, all of which increase vascular permeability and bowel motility [19,2O]. The metabolic pathway of cyclic adenosine monophosphate is also inhibited by this drug, resulting in retention of electrolytes [21,22]. According to a few case reports, octreotide immediately improved protein losing enteropathy as well as intractable diarrhea in patients with AA amyloidosis at a dose of 100300 g/day with coadministration of prednisolone [8,9]. In our patients also, octreotide was employed at a dose of 100 g/day with coadministration of oral prednisolone, and the general status of the patients immediately improved in parallel with a decrease in the volume of diarrhea and an increase in serum albumin and IgG. Improvement of protein losing enteropathy was demonstrated on ^sup 99m^Tc-HSA-D scintigraphy in both patients, and biopsied specimens from the colon after treatment histopathologically reflected the therapeutic efficacy of this combination therapy in terms of a reduction in inflammatory cells in the mucosa in case 1. There were no adverse effects due to octreotide other than leukopenia during and after the treatment. These results suggest that combination therapy with octreotide and corticosteroid may be very effective for both protein losing enteropathy and refractory diarrhea ascribable to GI amyloidosis. When abdominal symptoms, particularly diarrhea, are unresponsive or resistant to conventional treatments in patients with amyloidosis, this combination therapy should actively be considered as a therapeutic option irrespective of the precursor protein of amyloid.
Acknowledgments
The authors are grateful to Drs Y. Hoshii and T. Ishihara, Department of Pathology, Yamaguchi University School of Medicine, for their help with immunohistochemical staining of the biopsy specimens. This work was supported by a grant from the Intractable Disease Division, the Ministry of Health and Welfare, Amyloidosis Research Committee, Japan.
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TOMOHISA FUSHIMI1, YASUHUMI TAKAHASHI1, YUICHIRO KASHIMA1, KAZUHIRO FUKUSHIMA1, WATARU ISHII1, KAZUMA KANEKO1, MASAHIDE YAZAKI1, AKINORI NAKAMURA1, TAKAHIKO TOKUDA1, MASAYUKI MATSUDA1, RYO FURUYA2, & SHU-ICHI IKEDA1
1 Third Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan, and 2 Department of Internal Medicine, Yamanashi Prefectural Central Hospital, Japan
Correspondence: Dr Masayuki Matsuda, Third Department of Medicine, Shinshu University School of Medicine, Matsumoto 390- 8621, Japan. Tel: 81 263 372673. Fax: 81 263 373427. E-mail: [email protected]
Copyright CRC Press Mar 2005
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