Gastrointestinal manifestations in Satoyoshi syndrome: a systematic review

Background Satoyoshi syndrome (SS) [OMIM 600705; ORFHA 3130] is a multisystemic disease with a probable autoimmune basis, whose main symptoms are muscle spasms, alopecia, diarrhea and skeletal alterations. Chronic diarrhea may be severe and result in malnutrition, anemia, growth retardation, cachexia, disability and even death. However, to date, no review of the digestive symptoms has been carried out. Methods A search was performed in MEDLINE, Scopus and Web of Science databases. Cases of SS, without language or date restrictions, were recorded. Sixty-seven cases of SS were found up until December 2019. Thirty-nine cases described gastrointestinal manifestations. Results Chronic diarrhea was the main digestive symptom (92.3%). Other symptoms such as abdominal pain (15.4%), nausea (7.7%) and vomiting (7.7%), were less frequent. The D-xylose test was positive in 10 out of 12 patients, and 9 out of 13 cases showed a flattened oral glucose tolerance test suggesting carbohydrate malabsorption. Antinuclear antibodies were detected in 8 out of 16 cases. Antibodies to stomach or duodenum tissue lysates were also detected by Western blot. Histological data revealed predominantly lymphoplasmacytic inflammatory infiltrate that can affect any section of the digestive tract. In 6 out of 10 patients, diarrhea improved with a treatment regimen that included corticosteroids. Other treatments, such as methotrexate, carbohydrate restricted diets or otilonium bromide, improved digestive symptoms in isolated patients. Improvement of symptoms up to three years of follow-up has been described. None of the three patients who died had received corticosteroids or immunosuppressants. Conclusion Chronic diarrhea with malabsorption is one of the most disabling symptoms in SS. The early recognition of this disease is essential for immunosuppressive treatment and a better outcome.


Introduction
Satoyoshi syndrome (SS) [OMIM 600705; ORFHA 3130] is a multisystemic disease, characterized by muscle manifestations in the form of painful spasms or cramps, diarrhea, alopecia, skeletal alterations, growth retardation and menstrual abnormalities [1]. The association of this syndrome with other autoimmune pathologies, the detection of autoantibodies in these patients and their response to immunosuppressive treatment, has led to postulate its autoimmune origin [2,3].
Among the most typical features of the syndrome is diarrhea [4]. Chronic diarrhea and malabsorption can lead to malnutrition, weight loss, growth retardation [2], iron-deficiency anemia [5] or hypoproteinemia [6]. Untreated diarrhea has been described as one of the leading causes of morbidity and mortality in patients with SS [1].Diarrhea with signs of malabsorption, weight loss or growth retardation, and the detection of autoantibodies, are present in SS and other diseases such as celiac disease, tropical sprue or autoimmune enteropathy.
Previous reviews of SS have focused on muscle symptoms and alopecia [7][8][9][10] Our objective in this review is to offer an updated view of the gastrointestinal manifestations and their treatment response in SS.

Material and methods Search
All cases were searched in MEDLINE, using the search strategy: ("Satoyoshi syndrome" [Supplementary Concept] or "Satoyoshi syndrome" [All Fields], or "komuragaeri disease" [All Fields]) or Satoyoshi [TI]). We also searched in Scopus and the Web of Science, using the keywords "Satoyoshi", "Satoyoshi syndrome" or "komuragaeri disease". We included all cases up to December 2019, without limiting year of publication or language. We also explored the references of the OMIM, ORPHA-NET and Rare diseases web pages. The lists of references from the articles found by electronic search were also reviewed to identify additional records. The results of the search are shown in the flow chart in Fig. 1.

Inclusion criteria
The cases were considered to have gastrointestinal manifestations if at least one of the following circumstances was present: -Diarrhea, defined as an increase in the frequency of bowel movements, accompanied by a decrease in their consistency. The presence of abdominal pain was considered when it was not related to the presence of spasms or cramps in the abdominal musculature. -Positive malabsorption test results, including a positive D-xylose test or other evidence of carbohydrate malabsorption. Data compatible with protein or iron absorption deficit have also been considered.
-Histological alterations in any section of the digestive tract. Histological samples were obtained by endoscopy or necropsy. -Endoscopic and radiological data consistent with digestive involvement or malabsorption, such as atrophy or loss of intestinal folds.

Data extraction
The following data were extracted from each of the cases: -Clinical and epidemiological data: age of onset of any of the symptoms pertaining to the syndrome, age of onset of digestive symptoms, sex and country of origin. Presence of diarrhea, number of bowel movements, abdominal pain, bloating, nausea, vomiting, weight loss, short stature or stunted growth, and symptoms of malnutrition or cachexia.

Epidemiological data
The mean age of presentation of SS was 12.8 years (range, from a few months to 52 years), and the mean age of presentation of digestive symptoms was slightly higher (15.08 years, range from a few months to 53 years). Thirty-two patients (82%) were under 18 years of age at onset of disease. In 10 cases, the digestive symptoms were part of the manifestation of disease onset [1,2,7,8,13,15,19,31], together with muscular spasms. Thirty-two of the patients were women (82%). Eighteen of these 39 cases (46.15%) were Japanese patients, although cases have been described worldwide.

Gastrointestinal clinical features
The most common symptom was diarrhea, present in 36 (92.3%) cases [1, 2, 4-8, 11-16, 18-32]. Diarrhea was described as an increase in the number of stools and a decrease in consistency. The diarrhea of patients with SS is of a chronic nature, although not necessarily continuous; in fact, it may present as recurrent episodes [13,22]. The number of daily stools was between 2 [27] and10 [2]. It was reported that foods with high carbohydrate content could trigger an episode of diarrhea [19]. Moreover, low carbohydrate diets were said to improve diarrhea [2]. Mild steatorrhea was also reported in one case [28]. There were no reports of blood, mucus or pus in the stool.
Carbohydrate malabsorption was assessed by oral glucose tolerance in the first cases published, being progressively replaced in more recent studies by the more accurate D-xylose test. The D-xylose test detected carbohydrate malabsorption in ten out of twelve cases [1,2,4,6,11,17,27,28]. In one case with a positive D-xylose test, diarrhea was not reported [17]. Two cases of diarrhea with a negative D-xylose test were also reported [20,24]. In 13 patients, an oral glucose tolerance test with 50 to 100 g of glucose was performed [1,4,8,17,19,24,26,[28][29][30]. One patient was unable to complete the test due to intolerance [19]. The glucose curve showed a flattened morphology in 9 of the remaining 12 cases, as a manifestation of carbohydrate malabsorption [1,4,26,[28][29][30]. In five of these nine patients, both tests (D-xylose test and oral glucose tolerance test) were positive [1,4,28]. There was a case with a negative oral glucose tolerance test and a positive D-xylose test [17]. Protein loss through the gastrointestinal tract, measured by alpha-1 antitrypsin clearance, was also described in one patient [4]. This patient also suffered from carbohydrate malabsorption, as demonstrated by both the Dxylose test and the oral glucose tolerance test. The I-131-triolein test in feces for fat malabsorption yielded pathological results in two patients [1]. Two cases with increased fat in stool [1] and mild steatorrhea [28] were also found.

Radiological features
Abdominal radiological tests were described in 9 cases [1,4,6,13,15,19,27] (Table 1). In only two cases, do the authors comment on simple radiology studies. Nagahama described radiological findings in the small intestine, with loss of Kerckring's folds throughout [4]. Ashalatha described abdominal ultrasound and abdominal CT, without pathological findings in the digestive tract [19]. Aghoram also reported a normal abdominal CT in a 30 year-old man with SS [13].
Five patients underwent oral barium studies [1, 6, 27] and in two cases, had barium enemas [1]. Aver'ianov reported a 13-year old girl who had a normal oral barium study [27]. Satoyoshi reported 3 cases in which oral barium studies were normal in the early stages; however, in later stages, two of these three cases yielded abnormal barium results [1]. This same author reported two more patients with barium enemas that were normal in the early stages, but abnormal in one of the patients at a later stage [1]. Matsuura, with a double contrast oral barium study, found a mild luminal dilatation and a decrease of Kerckring's folds, which can be interpreted as secondary to chronic inflammatory damage. Matsuura et al. also reported a fine granulation of the second portion of the duodenum and "mesh-like" changes in the mucosa at the end of the second and third portions of the duodenum. An unclear contour and flocculation of the barium was also described, suggesting a malabsorption syndrome [6].
Finally, Ishii performed scintigraphy with a 99mTchighsolid anaerobic digestion pool in a patient with Satoyoshi that showed an accumulation of isotopes in the colon and small intestine, suggesting leakage of albumin [16].
In one case, the endoscopy was macroscopically normal, although histological alterations were found [16]. In another patient, the endoscopic abnormal findings were discovered following a second endoscopic study [5]. Endoscopic findings included: atrophy of the stomach mucosa, with multiple ulcer scars mainly in the gastric body together with whitish granules from the first to the second portion of the duodenum [6], gastric or duodenal ulcerations [6,17,20], duodenum leukoplakia [2] and areas of duodenal mucosal infiltration [5]. Colonoscopy findings were: inflammation [13], flattening of mucous folds [15] and ulcerations [4]. Five colonoscopies were normal [5,8,16,17,27]. A characteristic endoscopic finding described by Nagahama et al. was the presence of nodular protrusions similar to submucosal tumors that can affect different parts of the digestive tract, including the cardia, body of the stomach and duodenum [4]. Using endoscopic ultrasonography, these protrusions appeared as cystic lesions in the stomach wall [4] compatible with the lesions of gastritis cystic polyposa, the histology of which is described below.

-Biopsies from upper gastrointestinal endoscopy:
There was a broad spectrum of histological manifestations, including normal biopsies [19] or unspecific findings [4]. The most frequent finding was an inflammatory infiltrate [2,5,6], predominantly lymphoplasmacytic [2], although eosinophilic infiltrate was also described [5]. Atrophy of chief cells and edematous submucosal tissue in the stomach was found in one case [29]. Findings compatible with chronic gastritis [20] were reported in one patient.  [1], and Nagahama et al. described another one [4]. The average time elapsed between the age of symptom onset and the time of necropsy in these three patients was 18.6 years. In the rest of the patients, the time from onset of symptoms to biopsy was 7.7 years. Autopsy data revealed alterations throughout the gastrointestinal tract. Infiltration of gastric and duodenal mucosa by predominantly lymphoplasmacytic cells was described in all cases [1,4]. This infiltration of the mucosa also affected the small intestine and the colon. Together with the inflammatory infiltrate, fibrosis of the mucosa and thickening of the muscularis mucosa were present. A characteristic finding in all three cases was the appearance of cystic lesions throughout the gastrointestinal tract, corresponding to glandular cystic dilations containing PAS-positive material. Ulcerative lesions were also found, penetrating the muscularis mucosa in the rectum [1].
In 6 patients, diarrhea improved with a treatment regimen that included corticosteroids, alone or in combination [2, 11-13, 16, 18]. In addition to these six patients, two other cases that were "asymptomatic" without express reference to digestive manifestations, had also received corticosteroid therapy [20,25]. Treatment with corticosteroids or immunosuppressants can cause remission of the whole symptomatic spectrum of SS. However, in one of the patients that improved with corticosteroids, diarrhea improved further after including a low-carbohydrate diet in the treatment plan [2]. Another patient improved by adding methotrexate after corticosteroids failed to control diarrhea [17]. Complete remission of diarrhea for at least 3 years was reported with corticosteroid treatment [16].
Four patients died, three of them due to the poor evolution of the disease [1,4]. Two of them had severe malnutrition and uncontrolled diarrhea. They developed calcium and ionic disturbances. Both patients died after an episode of seizures followed by coma [1]. A third patient was treated with intravenous hyperalimentation due to diarrhea and malabsorption to improve her nutritional status. She also had episodes of acute pancreatitis. One year later, she underwent surgery consisting of gastrojejunostomy, percutaneous enterostomy, and percutaneous cholangiostomy. A few months after surgery, the patient died of sepsis with multiple organ failure [4]. The fourth patient committed suicide ten years after the onset of the disease [1]. It is not reported that these patients received corticosteroids or immunosuppressants.

Discussion
As demonstrated in our review, more than half of the patients described with SS have digestive manifestations, of which the main symptom is diarrhea. The clinical picture of these patients can vary from practically asymptomatic with a positive D-xylose test, to very symptomatic patients with more severe diarrhea and signs of malabsorption, cachexia and dehydration. Diarrhea in SS can lead to significant consequences for the patient, including malnutrition, growth retardation, interference with daily life activities and even death. Diarrhea in SS is usually noninflammatory, without blood or mucus in the stool. The D-xylose test appears to be more accurate in determining carbohydrate malabsorption; therefore it has been replacing the oral glucose tolerance test used mainly in the first published cases.
Most of the radiological tests performed showed nonpathological or non-specific findings. Endoscopic explorations often revealed alterations in the gastrointestinal mucosa, such as infiltrative and granular mucosa or ulcers in stomach, duodenum and colon. Histological data showed a predominantly lymphoplasmacytic inflammatory infiltrate that can involve all sections of the digestive tract. In the 3 patients who underwent autopsy, cystic lesions suggestive of gastritis cystica polyposa were discovered. This variation in lesions, ranging from a mild inflammatory infiltrate in the mucosa to more severe lesions with atrophy, fibrosis and the appearance of cystic lesions, suggests a progressive disease course. Moreover, autopsy patients showed more severe lesions. The time elapsed between the age of symptom onset and necropsy/biopsy was greater (18.6 years) in these patients than for the other subjects (7.7 years).
The combination of diarrhea with muscle spasms, cramps, alopecia and osteoarticular deformities is very specific to SS [1]. However, SS may mimic other diseases with non-inflammatory diarrhea, weight loss, growth retardation and signs and symptoms of malabsorption, including: celiac disease, refractory sprue, tropical sprue, Whipple's disease, drug-induced colitis, autoimmune enteropathy, amyloidosis or inflammatory bowel disease [39,40].
In terms of the differential diagnosis (Table 2) of SS, celiac disease and SS have many overlapping symptoms. For example, they both present manifestations secondary to nutrient malabsorption, with diarrhea, weight loss or iron-deficiency anemia. Both diseases also predominate in women in the first decades of life. Additionally, celiac disease can be associated with other conditions described in SS patients, such as autoimmune thyroid disease or myasthenia gravis [40]; even the rare manifestations of celiac disease, such as infertility, arthralgia, arthropathy or alopecia are part of the clinical spectrum of SS [40]. However, the improvement of symptoms with a gluten-free diet favors a celiac disease diagnosis, although this diet has not been tested in patients with SS. On the other hand, the appearance of muscle cramps points towards the diagnosis of SS. In terms of laboratory analysis, anti-gliadin antibodies present in celiac disease have been detected in one case of SS. Anti-endomysial antibodies also common to celiac disease were assessed in two SS cases, but with negative results. Anti-transglutaminase antibodies have not yet been tested for in SS. Histologically, the inflammatory cells in intestinal biopsies characteristic of celiac disease are also common to SS and may lead to an initial diagnosis of celiac disease in SS patients. In the future, detailed characterization of intraepithelial lymphocytes may provide important distinguishing features for Satoyoshi patients.
As in SS, inflammatory bowel disease can also manifest in young patients with diarrhea and weight loss. However, signs of inflammatory diarrhea, proctitis, bloody diarrhea, tenesmus, perianal fistulas and stenotic or fibrotic alterations do not occur in patients with SS. Arthritis can be present in inflammatory bowel disease, mainly in Crohn's disease in the form of migratory and asymmetric polyarthritis; in SS, however, the most frequent osteoarticular manifestations are bone deformities and alterations in the metaphysis, but not arthritis.
With respect to irritable bowel syndrome, there may be increased frequency of bowel movements, but this syndrome usually involves abdominal pain and distension, which are less frequent in SS. In addition, irritable bowel syndrome does not show signs or symptoms related to the malabsorption, weight loss or malnutrition of SS.
Autoimmune enteropathy, a rare condition that can occur both in children and adults, must also be differentiated from SS. It is characterized by immune-mediated intestinal mucosal atrophy that can affect the esophagus, stomach, small bowel and colon. However, it is the clinical picture of SS, with alopecia, muscle spasms and skeletal alterations that differentiates it from autoimmune enteropathy.
Medications, such as nonsteroidal anti-inflammatory drugs (NSAID) or olmesartan, can also cause diarrhea and duodenitis. NSAID duodenitis presents with histological alterations in the duodenum, reminiscent of those of celiac disease. These lesions consist of a non-specific infiltration of the neutrophil and plasma cells in lamina propria, with intraepithelial lymphocytes and low-grade villous blunting. Furthermore, prolonged use of these anti-inflammatory drugs can cause iron-deficiency anemia. On the other hand, in some patients, olmesartan can induce severe diarrhea associated with duodenal inflammation indistinguishable from other pathologies, such as celiac disease. Improvement after drug withdrawal, as well as the other manifestations of SS, can help in the differential diagnosis. The use of these drugs is not described in the patients included in this review.
The treatment of diarrhea does not differ from that of the other clinical manifestations in SS. Corticosteroids and immunosuppressants remain the treatment of choice for diarrhea in patients with SS. Although there is not much data in the follow-up of these patients, at least one case has been documented in which improvement was maintained throughout 3 years of follow-up [16].
The main limitation of our review is that it is composed of isolated cases. Besides, symptom descriptions lack detail. The authors refer to the presence of diarrhea in the majority of cases; however, this symptom is poorly characterized. On the other hand, the most complete histological data come from autopsies published many years ago and performed on SS patients who were not treated with immunosuppressants.
Findings such as the presence of specific antibodies against brain, stomach and intestinal lysates have been reported by two authors [6,38]. These findings are consistent with the autoimmune character of SS and could be useful in the future as a diagnostic tool. More studies are needed to clarify the role of these antibodies in both the pathogenesis of the syndrome and the diagnostic approach to patients.

Conclusions
Chronic diarrhea with malabsorption is one of the most disabling symptoms in SS. The clinical spectrum of these patients can vary from practically asymptomatic with a positive D-xylose test, to very symptomatic patients with severe diarrhea. Thus, malabsorption testing seems advisable in presumed SS patients, even if digestive symptoms are absent. Corticosteroids and immunosuppressants are still the treatment of choice for diarrhea in these patients. SS shares clinical manifestations with celiac disease and other autoimmune and gastrointestinal inflammatory syndromes, thus differential diagnosis is key. The recognition of SS is essential for early immunosuppressive treatment and for achieving a favorable outcome. In this regard, determining the specific auto-antibody pattern for SS remains a pending issue for future research in this field.