Background Disorders of coagulation have long been associated with inflammatory bowel disease. Children, as well as adults, with both active and inactive ulcerative colitis have been found to have abnormal coagulation and fibrinolysis. Disseminated intravascular coagulation arises from an overwhelming of the haemostatic regulatory mechanisms leading to an excessive generation of thrombin and a failure of the normal inhibitory pathways to prevent systemic effects of this enzyme. Ulcerative colitis has been associated with disseminated intravascular coagulation in conjunction with septicemia, toxic megacolon and surgery.
Background
Disorders of coagulation have long been associated with inflammatory bowel disease. Children, as well as adults, with both active and inactive ulcerative colitis have been found to have abnormal coagulation and fibrinolysis. Disseminated intravascular coagulation arises from an overwhelming of the haemostatic regulatory mechanisms leading to an excessive generation of thrombin and a failure of the normal inhibitory pathways to prevent systemic effects of this enzyme. Ulcerative colitis has been associated with disseminated intravascular coagulation in conjunction with septicemia, toxic megacolon and surgery.Case presentation A fourteen-year-old boy with a history of poorly controlled ulcerative colitis presented with nonbilious emesis, hematochezia, and hematuria. Laboratory workup revealed disseminated intravascular coagulation. He was placed on triple antibiotics therapy. An infectious workup came back negative. A computerized tomography (CT) scan of the abdomen revealed a marked thickening and irregularity of the bladder wall as well as wall thickening of the rectosigmoid, ascending, transverse, and descending colon. Patient's clinical status remained stable despite a worsening of laboratory values associated with disseminated intravascular coagulation. Patient was begun on high dose intravenous steroids with improvement of the disseminated intravascular coagulation laboratory values within 12 hours and resolution of disseminated intravascular coagulopathy within 4 days. A thorough infectious workup revealed no other causes to his disseminated intravascular coagulation.
Case presentation
A fourteen-year-old boy with a history of poorly controlled ulcerative colitis presented with nonbilious emesis, hematochezia, and hematuria. Laboratory workup revealed disseminated intravascular coagulation. He was placed on triple antibiotics therapy. An infectious workup came back negative. A computerized tomography (CT) scan of the abdomen revealed a marked thickening and irregularity of the bladder wall as well as wall thickening of the rectosigmoid, ascending, transverse, and descending colon. Patient's clinical status remained stable despite a worsening of laboratory values associated with disseminated intravascular coagulation. Patient was begun on high dose intravenous steroids with improvement of the disseminated intravascular coagulation laboratory values within 12 hours and resolution of disseminated intravascular coagulopathy within 4 days. A thorough infectious workup revealed no other causes to his disseminated intravascular coagulation.Conclusions The spectrum of hypercoagulable states associated with ulcerative colitis varies from mild to severe. Although disseminated intravascular coagulation associated with ulcerative colitis is usually related to septicemia, toxic megacolon or surgery, we present a case of an ulcerative colitis flare resulting in disseminated intravascular coagulation and a bladder hematoma.
Conclusions
The spectrum of hypercoagulable states associated with ulcerative colitis varies from mild to severe. Although disseminated intravascular coagulation associated with ulcerative colitis is usually related to septicemia, toxic megacolon or surgery, we present a case of an ulcerative colitis flare resulting in disseminated intravascular coagulation and a bladder hematoma.

Background A wide variety of disorders are associated with the development of disseminated intravascular coagulation (DIC). Initiation usually involves mechanical tissue injury and or endothelial cell activation and injury. DIC arises from an overwhelming of the haemostatic regulatory mechanisms leading to an excessive generation of thrombin and a failure of the normal inhibitory pathways to prevent systemic effects of the enzyme leading to DIC [ 1 ]. Ulcerative colitis has been associated with DIC. In previously reported cases, DIC has arisen from active disease in conjunction with septicemia, toxic megacolon or surgery [ 2 - 5 ]. The authors report a pediatric case of DIC associated with a colitis flare resulting in a bladder hematoma.
Background
A wide variety of disorders are associated with the development of disseminated intravascular coagulation (DIC). Initiation usually involves mechanical tissue injury and or endothelial cell activation and injury. DIC arises from an overwhelming of the haemostatic regulatory mechanisms leading to an excessive generation of thrombin and a failure of the normal inhibitory pathways to prevent systemic effects of the enzyme leading to DIC [ 1 ]. Ulcerative colitis has been associated with DIC. In previously reported cases, DIC has arisen from active disease in conjunction with septicemia, toxic megacolon or surgery [ 2 - 5 ]. The authors report a pediatric case of DIC associated with a colitis flare resulting in a bladder hematoma.Case presentation A 14-year-old boy with a diagnosis of ulcerative colitis based on colonic histology, serology and a normal barium study of his small bowels was admitted with a five-day history of nonbilious vomiting and bloody diarrhea. Additional symptoms included recent onset hematuria, and low-grade fevers to 100.4 C over the prior four days. He had also sustained a 25 lb weight loss in the last six months, indicating a lack of disease control. As an outpatient, his maintenance therapy included mesalamine (1 gram three times a day), and mercaptopurine (75 mg once per day). In addition, he had been started on prednisone approximately 7 weeks prior for treatment of an ulcerative colitis flare. His current dose of prednisone was 10 mg once a day. Soon after symptoms begun, he had been placed on ciprofloxacin as treatment for a presumptive flare. Physical exam showed he was afebrile, with a heart rate of 130 beats per minute, respiratory 16 breaths per minute and blood pressure 115/67 mmHg. He was alert although with a sallow appearance. Abdominal exam revealed a soft nontender nondistended abdomen. Rectal showed normal external exam with grossly bloody stool. Initial blood work showed hemoglobin of 12.3, a normal white blood cell count, normal differential and normal platelet count with a mildly elevated prothrombin time of 16.2 with an international normalized ratio (INR) of 1.2. Urine analysis showed a specific gravity of 1.035, 3+blood, +ketones and > 100 RBC per high powered field and 0–5 WBC per high power field. Abdominal ultrasound revealed irregular shaped bladder wall. Patient was placed on intravenous fluids (IV) as well as metronidazole (IV). Blood and urine cultures were sent for analysis. Stool was sent for culture and for  Clostridium difficile  toxin analysis. Serial repeat lab works the following day revealed a dropping hemoglobin (7.4 g/dL) and platelet count (64 K/mm 3 ) increasing PT/PTT (21.3/47 seconds) with an INR of 1.8. Blood smear showed moderate amount of elliptocytes, schistocytes, microcytes and fragmented red blood cells. Initial DIC panel revealed an elevated D-dimer of 4.9 mcg/mL with a normal thrombin time and fibrinogen. Thrombin time subsequently increased to > 120 seconds. D-dimers increased to 10.3 mcg/mL. A computerized tomography (CT) scan of the abdomen revealed a marked thickening and irregularity of the bladder wall as well as wall thickening of the rectosigmoid, ascending, transverse, and descending colon (Figure  1 ). Urology was consulted and felt that this represented a submucosal hematoma. Patient was begun on broad-spectrum antibiotics because of concerns regarding possible bacteremia and a worsening DIC laboratory picture. Blood, stool and urine cultures returned negative. Viral cultures and monoclonal antibody staining for adenovirus detection in the urine was negative. Despite a worsening in the DIC panel, the patient remained clinically unchanged. IV steroids were begun approximately 36 hours into patient's hospital stay. Patient had a stabilization of PT/PTT/INR/thrombin time and D-dimer, and a subsequent normalization of labs over the following 4-day period ( Figure  2 ,  3 ,  4 ,  5 ,  6 ,  7 ,  8  ). Patient's diarrhea and hematuria resolved as well. Colonscopy revealed chronic colitis consistent with ulcerative colitis. Cystoscopy revealed a fibrin clot consistent with submucosal hematoma. Patient was discharged from the hospital on a steroid taper, and remains in remission to date.
Case presentation
A 14-year-old boy with a diagnosis of ulcerative colitis based on colonic histology, serology and a normal barium study of his small bowels was admitted with a five-day history of nonbilious vomiting and bloody diarrhea. Additional symptoms included recent onset hematuria, and low-grade fevers to 100.4 C over the prior four days. He had also sustained a 25 lb weight loss in the last six months, indicating a lack of disease control.As an outpatient, his maintenance therapy included mesalamine (1 gram three times a day), and mercaptopurine (75 mg once per day). In addition, he had been started on prednisone approximately 7 weeks prior for treatment of an ulcerative colitis flare. His current dose of prednisone was 10 mg once a day. Soon after symptoms begun, he had been placed on ciprofloxacin as treatment for a presumptive flare.Physical exam showed he was afebrile, with a heart rate of 130 beats per minute, respiratory 16 breaths per minute and blood pressure 115/67 mmHg. He was alert although with a sallow appearance. Abdominal exam revealed a soft nontender nondistended abdomen. Rectal showed normal external exam with grossly bloody stool. Initial blood work showed hemoglobin of 12.3, a normal white blood cell count, normal differential and normal platelet count with a mildly elevated prothrombin time of 16.2 with an international normalized ratio (INR) of 1.2. Urine analysis showed a specific gravity of 1.035, 3+blood, +ketones and > 100 RBC per high powered field and 0–5 WBC per high power field. Abdominal ultrasound revealed irregular shaped bladder wall.Patient was placed on intravenous fluids (IV) as well as metronidazole (IV). Blood and urine cultures were sent for analysis. Stool was sent for culture and for  Clostridium difficile  toxin analysis.Clostridium difficileSerial repeat lab works the following day revealed a dropping hemoglobin (7.4 g/dL) and platelet count (64 K/mm 3 ) increasing PT/PTT (21.3/47 seconds) with an INR of 1.8. Blood smear showed moderate amount of elliptocytes, schistocytes, microcytes and fragmented red blood cells. Initial DIC panel revealed an elevated D-dimer of 4.9 mcg/mL with a normal thrombin time and fibrinogen. Thrombin time subsequently increased to > 120 seconds. D-dimers increased to 10.3 mcg/mL. A computerized tomography (CT) scan of the abdomen revealed a marked thickening and irregularity of the bladder wall as well as wall thickening of the rectosigmoid, ascending, transverse, and descending colon (Figure  1 ). Urology was consulted and felt that this represented a submucosal hematoma.Patient was begun on broad-spectrum antibiotics because of concerns regarding possible bacteremia and a worsening DIC laboratory picture. Blood, stool and urine cultures returned negative. Viral cultures and monoclonal antibody staining for adenovirus detection in the urine was negative. Despite a worsening in the DIC panel, the patient remained clinically unchanged. IV steroids were begun approximately 36 hours into patient's hospital stay. Patient had a stabilization of PT/PTT/INR/thrombin time and D-dimer, and a subsequent normalization of labs over the following 4-day period ( Figure  2 ,  3 ,  4 ,  5 ,  6 ,  7 ,  8  ). Patient's diarrhea and hematuria resolved as well. Colonscopy revealed chronic colitis consistent with ulcerative colitis. Cystoscopy revealed a fibrin clot consistent with submucosal hematoma. Patient was discharged from the hospital on a steroid taper, and remains in remission to date.Conclusions Disorders of coagulation have long been associated with inflammatory bowel disease [ 6 - 11 ]. Children, as well as adults, with both active and inactive ulcerative colitis have been found to have abnormal coagulation and fibrinolysis[ 11 ]. It is unclear whether this is a direct or indirect result of inflammatory bowel disease. Although hypocoagulable states have been noted in the literature, most studies indicate an associated hypercoagulable state. There appears to be an increase in thrombin-anti-thrombin complex and a decrease in antithrombin III activity, which causes an increase in thrombin generation[ 10 , 12 , 13 ]. Other studies have demonstrated an increase in fibrinogen content, increase Factor VIII, and Factor IX activity, platelet count and aggregation rate[ 9 , 12 ]. These hypercoagulable abnormalities return towards normal with therapy in direct correlation with sedimentation rate and clinical disease activity [ 12 ], but can still show mild abnormalities despite clinical remission[ 14 ]. The hypercoagulable state in ulcerative colitis is associated thromboembolic events; although uncommon, deep vein thrombosis, pulmonary embolisms and stroke have been associated with ulcerative colitis[ 6 , 15 - 18 ]. Disseminated intravascular coagulopathy is a rare occurrence in inflammatory bowel disease. When it occurs, it is usually associated with other co-founding problems such as septicemia, toxic megacolon or surgery. Presented is a case of DIC associated solely with an ulcerative colitis flare resulting in a bladder hematoma. We presume that the occurrence of DIC in this patient resulted from an acute flare on top of a chronic unremitting course of ulcerative colitis. A thorough infectious work-up of this patient did not reveal any infectious etiology that would have predisposed him to develop DIC. The presumed cause of the DIC was damage to the endothelial wall of the colonic blood vessels, which exposed blood to excessive amounts of tissue factor. This in turn led to the excessive generation of thrombin and a failure of the normal coagulation inhibitory pathways. By treating the ulcerative colitis flare, we decreased the intestinal inflammation and thereby decreased the endothelial cell damage. This, theoretically, resolved the DIC. Patient's clinical symptoms and laboratory values normalized after treatment with intravenous steroids, completely resolving the disseminated intravascular coagulopathy.
Conclusions
Disorders of coagulation have long been associated with inflammatory bowel disease [ 6 - 11 ]. Children, as well as adults, with both active and inactive ulcerative colitis have been found to have abnormal coagulation and fibrinolysis[ 11 ]. It is unclear whether this is a direct or indirect result of inflammatory bowel disease.Although hypocoagulable states have been noted in the literature, most studies indicate an associated hypercoagulable state. There appears to be an increase in thrombin-anti-thrombin complex and a decrease in antithrombin III activity, which causes an increase in thrombin generation[ 10 , 12 , 13 ]. Other studies have demonstrated an increase in fibrinogen content, increase Factor VIII, and Factor IX activity, platelet count and aggregation rate[ 9 , 12 ]. These hypercoagulable abnormalities return towards normal with therapy in direct correlation with sedimentation rate and clinical disease activity [ 12 ], but can still show mild abnormalities despite clinical remission[ 14 ].The hypercoagulable state in ulcerative colitis is associated thromboembolic events; although uncommon, deep vein thrombosis, pulmonary embolisms and stroke have been associated with ulcerative colitis[ 6 , 15 - 18 ]. Disseminated intravascular coagulopathy is a rare occurrence in inflammatory bowel disease. When it occurs, it is usually associated with other co-founding problems such as septicemia, toxic megacolon or surgery.Presented is a case of DIC associated solely with an ulcerative colitis flare resulting in a bladder hematoma. We presume that the occurrence of DIC in this patient resulted from an acute flare on top of a chronic unremitting course of ulcerative colitis. A thorough infectious work-up of this patient did not reveal any infectious etiology that would have predisposed him to develop DIC. The presumed cause of the DIC was damage to the endothelial wall of the colonic blood vessels, which exposed blood to excessive amounts of tissue factor. This in turn led to the excessive generation of thrombin and a failure of the normal coagulation inhibitory pathways. By treating the ulcerative colitis flare, we decreased the intestinal inflammation and thereby decreased the endothelial cell damage. This, theoretically, resolved the DIC. Patient's clinical symptoms and laboratory values normalized after treatment with intravenous steroids, completely resolving the disseminated intravascular coagulopathy.Competing interests The authors declare that they have no competing interests.
Competing interests
The authors declare that they have no competing interests.Authors' contributions DLS drafted the manuscript. KM and DC participated in the manuscript preparation. All authors approved the final manuscript. Figure 1 Abdominal CT revealing a marked thickening and irregularity of the bladder wall consistent with bladder hematoma. Figure 2 Graphic illustration of C-reactive protein throughout hospitalization: Day 1 (admission date) – Day 9 (day of discharge). Patient received intravenous steroids at approximately 36 hours into hospitalization. Figure 3 Graphic illustration of hemoglobin throughout hospitalization: Day 1 (admission date) – Day 9 (day of discharge). Patient received intravenous steroids at approximately 36 hours into hospitalization. Figure 4 Graphic illustration of platelets throughout hospitalization: Day 1 (admission date) – Day 9 (day of discharge). Patient received intravenous steroids at approximately 36 hours into hospitalization. Figure 5 Graphic illustration of prothrombin time throughout hospitalization: Day 1 (admission date) – Day 9 (day of discharge). Patient received intravenous steroids at approximately 36 hours into hospitalization. Figure 6 Graphic illustration of international normalized ratio throughout hospitalization: Day 1 (admission date) – Day 9 (day of discharge). Patient received intravenous steroids at approximately 36 hours into hospitalization. Figure 7 Graphic illustration of partial thromboplastin time C-reactive protein throughout hospitalization: Day 1 (admission date) – Day 9 (day of discharge). Patient received intravenous steroids at approximately 36 hours into hospitalization. Figure 8 Graphic illustration of D-dimer throughout hospitalization: Day 1 (admission date) – Day 9 (day of discharge). Patient received intravenous steroids at approximately 36 hours into hospitalization.
Authors' contributions
DLS drafted the manuscript. KM and DC participated in the manuscript preparation. All authors approved the final manuscript.Pre-publication history The pre-publication history for this paper can be accessed here:
Pre-publication history
The pre-publication history for this paper can be accessed here:


Background It is believed that the development of gastric cancer (GC) before the age of 50 has a hereditary basis. Blood group A and history of gastric cancer in first-degree relatives have been shown to be risk factors for GC.
Background
It is believed that the development of gastric cancer (GC) before the age of 50 has a hereditary basis. Blood group A and history of gastric cancer in first-degree relatives have been shown to be risk factors for GC.Methods In this case-control study, we enrolled patients with GC who were diagnosed before the age of 50. Patients who were diagnosed as having GC were selected. A total of 534 cases were found; of these, 44 diagnosed before the age of 50 were included in the case group. For the control group, 22 males and 22 females were randomly selected from the remaining subjects, who had diagnoses of GC after the age of 50. All the surviving patients and family members of the dead patients were interviewed about the history of cancer in the family and the age at which other family members developed cancer. The blood group of each subject was also obtained.
Methods
In this case-control study, we enrolled patients with GC who were diagnosed before the age of 50. Patients who were diagnosed as having GC were selected. A total of 534 cases were found; of these, 44 diagnosed before the age of 50 were included in the case group. For the control group, 22 males and 22 females were randomly selected from the remaining subjects, who had diagnoses of GC after the age of 50. All the surviving patients and family members of the dead patients were interviewed about the history of cancer in the family and the age at which other family members developed cancer. The blood group of each subject was also obtained.Results forty-four cases under 50 years old (mean age: 36.2 years) and forty-four controls (mean age: 67.1 years) were enrolled in the study. At the time of the study, 59.1% of the study group and 50% of the control group were alive (P value = NS). In the study group, 68.1%, 13.6%, 13.6% and 4.5% had blood groups O, A, B and AB, respectively. In the control group the corresponding figures were 27.7%, 63.6%, 6.8% and 4.5%. First or second-degree relatives with cancer, including gastric (the most frequent), breast, lung, gynecological and hematological malignancies, were noted in 54.5% of the cases and 11.4% of the controls (p < 0.01). Family histories of cancer were accepted as valid provided that they were based on valid medical documents.
Results
forty-four cases under 50 years old (mean age: 36.2 years) and forty-four controls (mean age: 67.1 years) were enrolled in the study. At the time of the study, 59.1% of the study group and 50% of the control group were alive (P value = NS). In the study group, 68.1%, 13.6%, 13.6% and 4.5% had blood groups O, A, B and AB, respectively. In the control group the corresponding figures were 27.7%, 63.6%, 6.8% and 4.5%. First or second-degree relatives with cancer, including gastric (the most frequent), breast, lung, gynecological and hematological malignancies, were noted in 54.5% of the cases and 11.4% of the controls (p < 0.01). Family histories of cancer were accepted as valid provided that they were based on valid medical documents.Conclusions It seems that the development of GC before the age of 50 is likely to be accompanied by familial susceptibility. Interestingly, our study showed a significant correlation between blood group O and the development of gastric cancer under the age of 50.
Conclusions
It seems that the development of GC before the age of 50 is likely to be accompanied by familial susceptibility. Interestingly, our study showed a significant correlation between blood group O and the development of gastric cancer under the age of 50.

Background Gastric cancer is the second most common cause of cancer-related death in the world [ 1 ]. Its incidence varies considerably worldwide [ 2 ]. In general, it is a larger problem in developing countries than in industrialized nations, and shows a predilection for urban and lower socioeconomic groups [ 3 , 4 ]. The estimated crude rate accounts for approximately 9.9% of cancers worldwide [ 5 ]. Gastric cancer rarely occurs before the age of 40. The incidence rises steadily thereafter, peaking in the seventh decade. Men are nearly twice as susceptible as women. This cancer alone is the cause of more than 750,000 deaths per annum in the world [ 6 ]. Marked variation within countries has also been observed [ 3 , 4 ], particularly in high-risk countries [ 7 ]. In developing countries, the overall incidence of gastric cancer is increasing and projections indicate that the annual number of new cases will increase significantly during the next few decades as a result of adult population growth [ 6 ]. A recent cancer survey by the Iranian Ministry of Health and Medical Education revealed that gastric adenocarcinoma is the most common fatal cancer in Iran, with a wide variation of death rate among different provinces [ 8 ]. According to recent cancer statistics, deaths due to gastric cancer constitute about 39% of all deaths due to cancer each year in some parts of Iran [ 9 ]. The reduced incidence of gastric cancer in western countries reflects a decrease in cancers arising in the distal stomach (body and antrum). In contrast, the incidence of cancer in the proximal stomach and esophagogastric junction has steadily increased, at a rate exceeding that of any other cancer except melanoma and lung cancer [ 10 - 13 ]. In a very recent study, our group showed that cardiac cancer constitutes 49.5% of all sites for gastric cancer in Iran. In contrast, cancers of body and antrum comprise 20.6% and 29.9% respectively [ 9 ]. Unlike cancer of the distal stomach, cancers of the proximal stomach and esophagogastric junction are more common among higher socioeconomic classes [ 6 ]. Overall, these observations suggest that proximal cancers share a similar pathogenesis, which is distinct from that of distal cancers. Zanghieri and La Vecchia found that about 10% of cases show familial clustering. Epidemiological studies have shown that the risk of gastric cancer in first-degree relatives is increased 2- to 3-fold [ 14 - 17 ]. The relative contributions of inherited susceptibility and environmental effects on familial gastric cancer are poorly understood. In general, familial genetic mechanisms do not play as important a role in gastric cancer as they do in e.g. colorectal cancer. Nonetheless, in some regions, a family history of gastric cancer may be a risk factor for the disease, although this might reflect environmental factors shared by members of a family [ 18 ]. Rate collections of familial aggregates of gastric cancer have been reported, but are distinctly unusual. As yet there is no comprehensive hypothesis for the development of gastric cancer. Gastric cancers are associated with chromosomal aberrations and other genetic defects, but none of these is necessary or sufficient for cancer to occur. In a review about genetic predisposition to gastric cancer, Bevan and Houlston (1999) concluded that several genes may be associated with increased risk [ 19 ]. Gastric cancer is a manifestation of several inherited cancer predisposition syndromes including hereditary nonpolyposis colon cancer, familial adenomatous polyposis, Peutz-Jeghers syndrome and Cowden disease. This suggests the presence of predisposing genes with different effects. Many studies have addressed the correlation between ABO antigens and the development of gastric cancer, but most of these have indicated a correlation between sporadic cases of gastric cancer and blood group A. This association further supports the role of genetic factors in the development of gastric cancer [ 21 ]. Blood type A is more strongly associated with the diffuse histopathological type of gastric cancer than the intestinal type [ 21 , 22 ]. To our knowledge, similar studies on the specific category of gastric cancer in younger patients are scanty. This may be one of the first studies on the role of hereditary factors in the development of the gastric cancer in younger patients.
Background
Gastric cancer is the second most common cause of cancer-related death in the world [ 1 ]. Its incidence varies considerably worldwide [ 2 ]. In general, it is a larger problem in developing countries than in industrialized nations, and shows a predilection for urban and lower socioeconomic groups [ 3 , 4 ]. The estimated crude rate accounts for approximately 9.9% of cancers worldwide [ 5 ]. Gastric cancer rarely occurs before the age of 40. The incidence rises steadily thereafter, peaking in the seventh decade. Men are nearly twice as susceptible as women. This cancer alone is the cause of more than 750,000 deaths per annum in the world [ 6 ]. Marked variation within countries has also been observed [ 3 , 4 ], particularly in high-risk countries [ 7 ]. In developing countries, the overall incidence of gastric cancer is increasing and projections indicate that the annual number of new cases will increase significantly during the next few decades as a result of adult population growth [ 6 ]. A recent cancer survey by the Iranian Ministry of Health and Medical Education revealed that gastric adenocarcinoma is the most common fatal cancer in Iran, with a wide variation of death rate among different provinces [ 8 ]. According to recent cancer statistics, deaths due to gastric cancer constitute about 39% of all deaths due to cancer each year in some parts of Iran [ 9 ].The reduced incidence of gastric cancer in western countries reflects a decrease in cancers arising in the distal stomach (body and antrum). In contrast, the incidence of cancer in the proximal stomach and esophagogastric junction has steadily increased, at a rate exceeding that of any other cancer except melanoma and lung cancer [ 10 - 13 ]. In a very recent study, our group showed that cardiac cancer constitutes 49.5% of all sites for gastric cancer in Iran. In contrast, cancers of body and antrum comprise 20.6% and 29.9% respectively [ 9 ]. Unlike cancer of the distal stomach, cancers of the proximal stomach and esophagogastric junction are more common among higher socioeconomic classes [ 6 ]. Overall, these observations suggest that proximal cancers share a similar pathogenesis, which is distinct from that of distal cancers. Zanghieri and La Vecchia found that about 10% of cases show familial clustering. Epidemiological studies have shown that the risk of gastric cancer in first-degree relatives is increased 2- to 3-fold [ 14 - 17 ]. The relative contributions of inherited susceptibility and environmental effects on familial gastric cancer are poorly understood.In general, familial genetic mechanisms do not play as important a role in gastric cancer as they do in e.g. colorectal cancer. Nonetheless, in some regions, a family history of gastric cancer may be a risk factor for the disease, although this might reflect environmental factors shared by members of a family [ 18 ]. Rate collections of familial aggregates of gastric cancer have been reported, but are distinctly unusual. As yet there is no comprehensive hypothesis for the development of gastric cancer. Gastric cancers are associated with chromosomal aberrations and other genetic defects, but none of these is necessary or sufficient for cancer to occur.In a review about genetic predisposition to gastric cancer, Bevan and Houlston (1999) concluded that several genes may be associated with increased risk [ 19 ]. Gastric cancer is a manifestation of several inherited cancer predisposition syndromes including hereditary nonpolyposis colon cancer, familial adenomatous polyposis, Peutz-Jeghers syndrome and Cowden disease. This suggests the presence of predisposing genes with different effects.Many studies have addressed the correlation between ABO antigens and the development of gastric cancer, but most of these have indicated a correlation between sporadic cases of gastric cancer and blood group A. This association further supports the role of genetic factors in the development of gastric cancer [ 21 ]. Blood type A is more strongly associated with the diffuse histopathological type of gastric cancer than the intestinal type [ 21 , 22 ]. To our knowledge, similar studies on the specific category of gastric cancer in younger patients are scanty. This may be one of the first studies on the role of hereditary factors in the development of the gastric cancer in younger patients.Methods The study was designed as a case-control study. We set up an active surveillance to identify patients with gastric cancer. Patients' records in the department of pathology in the main private referral facility in Tehran were scrutinized for gastric cancer cases between 1999 and 2003. Patients are referred here from all regions of the country and from different ethnic backgrounds and they are operated upon in the same hospital, so all the operation and pathology reports were available simultaneously. All the pathology reports were prepared and diagnosed by the same pathologists. The cases were selected from patients who were diagnosed with gastric cancer before the age of fifty. The sex-matched controls were randomly selected and enrolled from patients who were diagnosed over the age of fifty. All the patients and their family were interviewed regarding the history of gastric or other types of cancer over three generations, and the blood groups of affected members were ascertained. Family histories of cancer were accepted as valid provided that they were based on valid medical documents. The transfusion records of the operation were also used to identify the patients' blood groups. Statistical analysis  was performed using the SPSS Statistical Package (version 10.0). The quantitative variables were expressed as means (minimum-maximum) when appropriate. A chi-square test was performed to ascertain the overall effect of blood group on the development of gastric cancer before the age of 50. All statistical tests were two-sided and differences at the 0.01 level were considered statistically significant.
Methods
The study was designed as a case-control study. We set up an active surveillance to identify patients with gastric cancer. Patients' records in the department of pathology in the main private referral facility in Tehran were scrutinized for gastric cancer cases between 1999 and 2003. Patients are referred here from all regions of the country and from different ethnic backgrounds and they are operated upon in the same hospital, so all the operation and pathology reports were available simultaneously. All the pathology reports were prepared and diagnosed by the same pathologists. The cases were selected from patients who were diagnosed with gastric cancer before the age of fifty. The sex-matched controls were randomly selected and enrolled from patients who were diagnosed over the age of fifty. All the patients and their family were interviewed regarding the history of gastric or other types of cancer over three generations, and the blood groups of affected members were ascertained. Family histories of cancer were accepted as valid provided that they were based on valid medical documents. The transfusion records of the operation were also used to identify the patients' blood groups.Statistical analysis  was performed using the SPSS Statistical Package (version 10.0). The quantitative variables were expressed as means (minimum-maximum) when appropriate. A chi-square test was performed to ascertain the overall effect of blood group on the development of gastric cancer before the age of 50. All statistical tests were two-sided and differences at the 0.01 level were considered statistically significant.Statistical analysisResults At the beginning of the study, 44 cases (mean age: 36.2, 18–49; m/f = 1) under 50 years old and 44 sex-matched controls (mean age: 67.1, 50–88) were enrolled. Table  1  shows the pathological characteristics of all 88 subjects. At the time of the study, 59.1% of the case group and 50% of the control group were alive; 53.8% of the case group and 38.6% were living in Tehran, but no information on residence background was available. Data regarding first-degree relatives were complete for both groups. These data comprised information on 383 persons in the case group (average 9.1 for each proband) and 498 in the control group (average 11.6 for each proband). Table  2  shows the distribution of blood groups in the two subject groups. Gastric (22 cases) and other types of cancer were reported in 54.5% of the first-degree relatives of the cases and 11.4% of the first-degree relatives of the controls (p < 0.01). The "other types of cancer" among relatives of the case group comprised colorectal (7 cases), breast (3 cases), lung (3 cases), gynecological (2 cases), hematological (1 case) and bladder (1 case) malignancies. For the control group, the corresponding figures were colorectal (2 cases), breast (1 case), lung (1 case) and prostate (1 case) malignancies. Figures  1 ,  2 ,  3  show three pedigrees of familial connections. Table 1 The pathologic characteristics of the tumor in the case and control group (n = 44 in each group). Pathologic differentiation Pathologic Type Location of the tumor Case group Well differentiated 1.4% Diffuse 0.5% Cardia 13.6% Moderately differentiated 5.0% Body 18.2% Poorly differentiated 1.4% Intestinal 7.3% Distal 68.2% Control group Well differentiated 7.3% Diffuse 5% Cardia 22.7% Moderately differentiated 5.0% Body 29.5% Poorly differentiated 7.7% Intestinal 5% Distal 47.7% P value NS NS NS Table 2 Frequency of the different blood groups in the study population ( n  =  44 ).  The figures in parentheses are the number of the patients . Blood group O A B AB Cases (30) 68.1% (6) 13.6% (6) 13.6% (2) 4.5% Controls (11) 27.3% (28) 63.6% (3) 6.8% (2) 4.5% P value <0.05 <0.01 NS NS Figure 1 A family with aggregation with gastric cancer (GC: Gastric Cancer; Ca: History of gastric cancer but not confirmed by a pathologic reports for the histologic type of cancer). Figure 2 A family with a history of the aggregation with Colorectal cancer (GC: Gastric Cancer; CRC: Colorectal Cancer; PLP: Colorectal Polyps; Numbers in circles: Current age of the persons; CAG: Chronic Active Gastritis). Figure 3 A family with a history of the aggregation with other cancers as well as gastric cancer (GC: Gastric Cancer; Lung: Lung Cancer; Blad: Bladder Carcinoma).
Results
At the beginning of the study, 44 cases (mean age: 36.2, 18–49; m/f = 1) under 50 years old and 44 sex-matched controls (mean age: 67.1, 50–88) were enrolled. Table  1  shows the pathological characteristics of all 88 subjects. At the time of the study, 59.1% of the case group and 50% of the control group were alive; 53.8% of the case group and 38.6% were living in Tehran, but no information on residence background was available. Data regarding first-degree relatives were complete for both groups. These data comprised information on 383 persons in the case group (average 9.1 for each proband) and 498 in the control group (average 11.6 for each proband). Table  2  shows the distribution of blood groups in the two subject groups. Gastric (22 cases) and other types of cancer were reported in 54.5% of the first-degree relatives of the cases and 11.4% of the first-degree relatives of the controls (p < 0.01). The "other types of cancer" among relatives of the case group comprised colorectal (7 cases), breast (3 cases), lung (3 cases), gynecological (2 cases), hematological (1 case) and bladder (1 case) malignancies. For the control group, the corresponding figures were colorectal (2 cases), breast (1 case), lung (1 case) and prostate (1 case) malignancies. Figures  1 ,  2 ,  3  show three pedigrees of familial connections.The pathologic characteristics of the tumor in the case and control group (n = 44 in each group).Well differentiatedDiffuseCardiaModerately differentiatedBodyPoorly differentiatedIntestinalDistalWell differentiatedDiffuseCardiaModerately differentiatedBodyPoorly differentiatedIntestinalDistalFrequency of the different blood groups in the study population ( n  =  44 ).  The figures in parentheses are the number of the patients .n44The figures in parentheses are the number of the patientsDiscussion This case control study demonstrates that hereditary factors, especially familial history of cancer and possession of blood group O, are associated with the development of gastric cancer under the age of fifty. To our knowledge, this may be the first study showing a correlation between blood group O and the development of gastric cancer in a specific category of patients. Risk factors for gastric cancers have been explored in a number of previous studies, including genetic factors such as blood group. Haenszel et al. suggested an association between gastric cancer and blood type A, supporting the view that genetic factors have a role in the development of gastric cancer [ 21 ]. Our study emphasizes the role of genetic factors in one subcategory of patients, those who develop gastric cancer under the age of fifty. Blood group A is more strongly associated with the diffuse histopathological type of gastric cancer than the intestinal type [ 21 , 22 ]. In our study, most of the patients had a diffuse rather than intestinal type, so we could not test this association. A larger sample size would be needed. On the other hand, there might be a higher prevalence of Helicobacter pylori in our community, causing a higher incidence of the diffuse type of gastric cancer. However, there were no significant differences in histological type of gastric cancer between the case and control groups. In a study by Su et al. in 2001, a total of 6685 patients with esophageal carcinoma and 2955 patients with cardiac cancer in the Chaoshan district were retrospectively assessed for their association with ABO blood groups. Su et al. showed that the distribution of ABO blood groups in patients with esophageal carcinoma or cardiac cancer was similar to that in the normal local population, but there was an association between blood group B and the development of cancer of cardia in males [ 23 ]. In our study, approximately 54% of the case group had a familial history of cancer compared to 11% of the control group. This seems compatible with the findings of a population-based case-control study of stomach cancer in Warsaw, Poland. Here, the investigators interviewed 464 cases and 480 controls to evaluate the role of family history and other risk factors. A greater than threefold increase in risk was associated with a history of gastric cancer in a first degree relative (OR = 3.5), but no excess risk was seen for other forms of cancer. The risk associated with familial occurrence was not significantly modified by gender, age or ABO blood type, and did not vary with Lauren histological classification24. Despite the relatively large sample size in the Polish study, younger patients were not evaluated as a separate category. This may explain the difference between their results and ours. Furthermore, they defined "positive family history" as having a first-degree relative with gastric cancer. In contrast, we considered all types of malignancy in first and second-degree relatives; though the familial incidence of other (non-GI) malignancies in our study may reflect their higher frequency in the community rather than any genetic risk factor. The Polish study did not confirm previous results on the correlation between blood group A and gastric cancer. Moreover, another study by Parsonnet et al on 90 cases and 89 controls showed no association between ABO blood group and malignancy [ 25 ]. In a multicentric study in Italy, 1016 patients with gastric cancer and 1623 population controls were interviewed to determine family histories of gastric, esophageal and colorectal cancer. A significant association was found with history of gastric cancer in a sibling or parent (odds ratios 2.6 and 1.7, respectively). Among the adult siblings of controls and cases, the prevalences of gastric cancer reported at interview were 1 and 2.7%, respectively. A further increase was noted in families with at least one affected parent (1.4 and 5.7%). The risk of gastric cancer associated with a positive family history was greater (increased about 2-fold) among residents of low-risk areas. Among the cases, there was no relationship between family history of gastric cancer and blood group A or histological type according to the Lauren classification [ 26 ]. In our study, there was no significant relationship between the histological type of the cancer and positive family history or blood group. However, this does not prove that the two variables do not correlate; an association might become apparent with a larger study. Mecklin et al studied the clinical and histopathological characteristics of gastric carcinoma in young patients (under 40 years old) in Finland in 1988. In 94% of the young patients, the carcinoma was of the diffuse type. They showed a poor prognosis, an equal sex ratio, and a strong association with blood group A in their study group. They also found a highly significant over-representation of gastric cancer in the parents of the index cases (p < 0.001) [ 27 ]. The difference between Mecklin's study and ours in the blood groups identified as risk factors may reflect ethnic differences; both studies confirm a significant correlation between a specific blood group and the development of gastric cancer. Future studies may use linkage analysis to detect genetic abnormalities in chromosomal regions that are located near the genes encoding the ABO antigens. Matching the geographical origins of the cases and controls could have improved the power of our study by excluding ethnic factors from the study population. However, this is very difficult to achieve in such studies because there is a high rate of combinations between races in the country. In addition, the sample size was too small for such effects to be excluded. However, there were no significance differences between the two groups in respect of the origins of the subjects. In conclusion, our results show that familial history of cancer, and hereditary factors including blood group, have a role in the development of gastric cancer in young patients. The role of environmental factors may be more important in older patients and can be considered in future studies.
Discussion
This case control study demonstrates that hereditary factors, especially familial history of cancer and possession of blood group O, are associated with the development of gastric cancer under the age of fifty. To our knowledge, this may be the first study showing a correlation between blood group O and the development of gastric cancer in a specific category of patients.Risk factors for gastric cancers have been explored in a number of previous studies, including genetic factors such as blood group. Haenszel et al. suggested an association between gastric cancer and blood type A, supporting the view that genetic factors have a role in the development of gastric cancer [ 21 ]. Our study emphasizes the role of genetic factors in one subcategory of patients, those who develop gastric cancer under the age of fifty. Blood group A is more strongly associated with the diffuse histopathological type of gastric cancer than the intestinal type [ 21 , 22 ]. In our study, most of the patients had a diffuse rather than intestinal type, so we could not test this association. A larger sample size would be needed. On the other hand, there might be a higher prevalence of Helicobacter pylori in our community, causing a higher incidence of the diffuse type of gastric cancer. However, there were no significant differences in histological type of gastric cancer between the case and control groups. In a study by Su et al. in 2001, a total of 6685 patients with esophageal carcinoma and 2955 patients with cardiac cancer in the Chaoshan district were retrospectively assessed for their association with ABO blood groups. Su et al. showed that the distribution of ABO blood groups in patients with esophageal carcinoma or cardiac cancer was similar to that in the normal local population, but there was an association between blood group B and the development of cancer of cardia in males [ 23 ].In our study, approximately 54% of the case group had a familial history of cancer compared to 11% of the control group. This seems compatible with the findings of a population-based case-control study of stomach cancer in Warsaw, Poland. Here, the investigators interviewed 464 cases and 480 controls to evaluate the role of family history and other risk factors. A greater than threefold increase in risk was associated with a history of gastric cancer in a first degree relative (OR = 3.5), but no excess risk was seen for other forms of cancer. The risk associated with familial occurrence was not significantly modified by gender, age or ABO blood type, and did not vary with Lauren histological classification24. Despite the relatively large sample size in the Polish study, younger patients were not evaluated as a separate category. This may explain the difference between their results and ours. Furthermore, they defined "positive family history" as having a first-degree relative with gastric cancer. In contrast, we considered all types of malignancy in first and second-degree relatives; though the familial incidence of other (non-GI) malignancies in our study may reflect their higher frequency in the community rather than any genetic risk factor. The Polish study did not confirm previous results on the correlation between blood group A and gastric cancer. Moreover, another study by Parsonnet et al on 90 cases and 89 controls showed no association between ABO blood group and malignancy [ 25 ]. In a multicentric study in Italy, 1016 patients with gastric cancer and 1623 population controls were interviewed to determine family histories of gastric, esophageal and colorectal cancer. A significant association was found with history of gastric cancer in a sibling or parent (odds ratios 2.6 and 1.7, respectively). Among the adult siblings of controls and cases, the prevalences of gastric cancer reported at interview were 1 and 2.7%, respectively. A further increase was noted in families with at least one affected parent (1.4 and 5.7%). The risk of gastric cancer associated with a positive family history was greater (increased about 2-fold) among residents of low-risk areas. Among the cases, there was no relationship between family history of gastric cancer and blood group A or histological type according to the Lauren classification [ 26 ]. In our study, there was no significant relationship between the histological type of the cancer and positive family history or blood group. However, this does not prove that the two variables do not correlate; an association might become apparent with a larger study. Mecklin et al studied the clinical and histopathological characteristics of gastric carcinoma in young patients (under 40 years old) in Finland in 1988. In 94% of the young patients, the carcinoma was of the diffuse type. They showed a poor prognosis, an equal sex ratio, and a strong association with blood group A in their study group. They also found a highly significant over-representation of gastric cancer in the parents of the index cases (p < 0.001) [ 27 ]. The difference between Mecklin's study and ours in the blood groups identified as risk factors may reflect ethnic differences; both studies confirm a significant correlation between a specific blood group and the development of gastric cancer. Future studies may use linkage analysis to detect genetic abnormalities in chromosomal regions that are located near the genes encoding the ABO antigens.Matching the geographical origins of the cases and controls could have improved the power of our study by excluding ethnic factors from the study population. However, this is very difficult to achieve in such studies because there is a high rate of combinations between races in the country. In addition, the sample size was too small for such effects to be excluded. However, there were no significance differences between the two groups in respect of the origins of the subjects.In conclusion, our results show that familial history of cancer, and hereditary factors including blood group, have a role in the development of gastric cancer in young patients. The role of environmental factors may be more important in older patients and can be considered in future studies.Competing interests The authors declare that they have no competing interest.
Competing interests
The authors declare that they have no competing interest.Authors' contributions MY designed and assisted in the conduction of the study, analyzing of the data and draft the manuscript. NR, FS, RB and YJ assisted in the conducting and designing the study and interview with the study cases as well as drafting manuscript. AM and MA assisted in analyzing of the study and conducting interviews. AA and MH reviewed and approved the pathology reports of the patients and case collecting. RM supervised the study scientifically and executively and assisted in drafting the manuscript. All authors read and approved the final manuscript.
Authors' contributions
MY designed and assisted in the conduction of the study, analyzing of the data and draft the manuscript.NR, FS, RB and YJ assisted in the conducting and designing the study and interview with the study cases as well as drafting manuscript.AM and MA assisted in analyzing of the study and conducting interviews.AA and MH reviewed and approved the pathology reports of the patients and case collecting.RM supervised the study scientifically and executively and assisted in drafting the manuscript.All authors read and approved the final manuscript.Pre-publication history The pre-publication history for this paper can be accessed here:
Pre-publication history
The pre-publication history for this paper can be accessed here: