Two different forms of homozygous sickle cell disease occur in Saudi Arabia

Haematological, clinical and some molecular genetic features of homozygous sickle cell (SS) disease in Saudi Arabia have been compared in 33 patients from the Eastern Province (Eastern) and 30 from the South Western Province (Western). Eastern patients all had the Asian beta globin haplotype whereas Western patients were more variable but predominantly of the Benin haplotype. Eastern patients had more deletional alpha thalassaemia, higher total haemoglobin and fetal haemoglobin levels, and lower HbA₂, mean cell volume, reticulocytes, and platelet counts. Clinically, Eastern patients had a greater persistence of splenomegaly, a more normal body build and greater subscapular skin fold thickness, and Western patients had more dactylitis and acute chest syndrome. Painful crises and avascular necrosis of the femoral head were common and occurred equally in both groups. The disease in the Eastern province has many mild features consistent with the higher HbF levels and more frequent alpha thalassaemia but bone pathology (painful crises, avascular necrosis of the femoral head, osteomyelitis) remains common. The disease in the West is more severe consistent with the Benin haplotype suggesting an African origin.     

Glycosylated hemoglobin levels in a benign form of sickle cell anemia in Saudi Arabia

Glycosylated hemoglobin was determined by the thiobarbituric acid method in sickle cell anemia patients from the Eastern Province of Saudi Arabia. The level of glycosylated hemoglobin in a Saudi SS sample (4.36%, SD 0.83) is 90% of that of the sample of normals (4.85%, SD 0.51). This is in contrast with the reported value of glycosylated hemoglobin in an American Black SS sample (3.9%, SD 0.6), which is only 60% of that of the sample of normals (6.6%, SD 0.7). The fetal hemoglobin level in Saudi sickle cell patients was 12.03% (SD 4.84), which is significantly different from that of Americans of African origin at p = 0.001. There was no significant correlation (r = 0.236) between the percentages of glycosylated Hb and Hb F at the 10% confidence level. The reported positive relationship between the percentages of glycosylated Hb and Hb F in American Blacks seems to be valid in the Saudi population only up to the level of 10-12% of fetal hemoglobin. Above this threshold of Hb F no further alleviating effect is seen. The 2,3-diphosphoglycerate value in Saudi Hb SS adults was 21.7 mumol/g (SD 7.4) and accordingly only twice as high as that of normal individuals. The benign clinical course exhibited by Saudi sickle cell patients is reflected by the survival of the RBC as indexed by its content of glycosylated Hb and 2,3-diphosphoglycerate. Moreover 10-12% of fetal hemoglobin in the RBC seems sufficient to ameliorate the severity of this disease in patients from the Eastern Province of Saudi Arabia.     

Analysis of hemoglobin F production in Saudi Arabian families with sickle cell anemia

Erythrocytes and progenitor-derived erythroblasts of sickle cell anemia patients from the Eastern Province of Saudi Arabia contain increased fetal hemoglobin and G gamma globin. A distinctive DNA polymorphism haplotype in the beta globin gene cluster (++- +-), tightly coupled to a C----T substitution at position -158 5' to the cap site of the G gamma globin gene, is strongly associated with sickle cell disease in this region. To determine whether the increased fetal hemoglobin production and/or elevated G gamma globin content are tightly linked to this haplotype, we studied 55 members of five Saudi families in which sickle cell disease is present. The results did not suggest a tight linkage of the haplotype to increased fetal hemoglobin production. On the other hand, several sickle trait family members heterozygous for the haplotype had normal fetal hemoglobin production in culture but elevated G gamma to A gamma ratios in peripheral blood. This observation suggests that in this genetic background increased expression of the G gamma globin gene may occur without a measurable increase in total fetal hemoglobin production. The family studies also clearly demonstrate that increased fetal hemoglobin production by erythroid progenitors is dependent on zygosity for the sickle gene in this population. These findings strongly suggest that other factors, such as the products of genes stimulated by hemolytic stress or other genetic determinants associated with the Saudi beta S chromosome, may interact with the -158 C----T substitution and influence gamma globin gene expression in this population.     

High fetal hemoglobin production in sickle cell anemia in the eastern province of Saudi Arabia is genetically determined

Homozygous sickle cell disease in the eastern province of Saudi Arabia is clinically mild. Circulating fetal hemoglobin levels of 16.0 +/- 7.4% were found in these anemic patients, but only 1.09 +/- 0.97% in their sickle trait parents. To determine whether these sickle cell anemia patients inherit an increased capacity to synthesize fetal hemoglobin, a radioimmunoassay of fetal and adult hemoglobin was performed on erythroid progenitor (BFU-E)-derived erythroblasts from Saudi Arabian sickle cell patients and their parents. Mean fetal hemoglobin content per BFU-E-derived erythroblast from Saudi Arabian sickle cell patients was 6.2 +/- 2.4 pg/cell or 30.4 +/- 8.6% fetal hemoglobin (normal 1.1 +/- 0.7 pg/cell and 5.1 +/- 1.8%). Linear regression analysis of % HbF in peripheral blood versus % HbF per BFU-E- derived cell showed a positive correlation with an r of 0.65. The variance of the intrinsic capacity to produce HbF may account for almost 40% (r2) of the variance of circulating fetal hemoglobin but other factors, particularly selective survival of F cells, must also contribute significantly. Despite virtually normal HbF levels in sickle trait parents of these Saudi patients, mean fetal hemoglobin production per BFU-E-derived erythroblast in these individuals was elevated to 3.42 +/- 1.79 pg/cell or 16.1 +/- 6.4% fetal hemoglobin, and the magnitude of fetal hemoglobin production found in parents correlated with that of the patients. These data indicate that the high fetal hemoglobin in Saudi sickle cell disease is genetically determined but expressed only during accelerated erythropoiesis. Further evidence of such genetic determination was provided by analysis of DNA polymorphisms within the beta-globin gene cluster on chromosome 11. This revealed a distinctive 5' globin haplotype (+ + - + +) on at least one chromosome 11 in all high F SS and AS tested. The precise relationship of this haplotype to HbF production in this population remains to be defined.     

Zinc and copper status in patients with sickle cell anemia

Plasma zinc and copper concentrations were determined by atomic absorption spectroscopy in 57 patients with sickle cell anemia and in 45 control subjects from the Eastern Province of Saudi Arabia. Plasma zinc and copper levels in patients were found to be close to those of the control subjects. Similarly, there was a difference neither in urinary zinc level nor in the ratio Cu:Zn in patients and control subjects. This is in contrast to the situation which exists in North American Black subjects with sickle cell anemia, who are known to have zinc deficiency as well as a further decrease in zinc level during sickle cell crises. The near-normal levels of zinc and copper found in Saudi sickle cell patients therefore exclude zinc deficiency and confirm that this population exhibits a milder form of sickle cell anemia.     

Hydroxyurea-induced splenic regrowth in an adult patient with severe hemoglobin SC disease

Hydroxyurea has been extensively used in patients with sickle cell anemia and severe sickle cell-hemoglobin C (SC) disease to reduce the severity of their diseases. We report here our experience with an adult patient with severe SC disease who developed symptomatic splenomegaly requiring splenectomy while being treated with hydroxyurea. This case suggests that hydroxyurea might restore some splenic function in functionally asplenic patients with sickle cell anemia or SC disease, but also raises the clinical concern that hydroxyurea may induce splenic regrowth, resulting in symptomatic splenomegaly. With the increasing use of hydroxyurea in the management of SS disease or other hemoglobinopathies, the importance of spleen monitoring must be further emphasized in these patients.     

Massive splenic infarction in Saudi patients with sickle cell anemia: a unique manifestation

Splenic infarcts are common in patients with sickle cell anemia (SCA), but these are usually small and repetitive, leading ultimately to autosplenectomy. Massive splenic infarcts on the other hand are extremely rare. This is a report of our experience with 8 (4 males and 4 females) cases of massive splenic infarction in patients with SCA. Their ages ranged from 16 to 36 years (mean 22 years). Three presented with left upper quadrant abdominal pain and massive splenic infarction on admission, while the other 5 developed massive splenic infarction while in hospital. In 5 the precipitating factors were high altitude, postoperative, postpartum, salmonella septicemia, and strenuous exercise in one each, while the remaining 3 had severe generalized vasoocclusive crises. Although both ultrasound and CT scan of the abdomen were of diagnostic value, we found CT scan more accurate in delineating the size of infarction. All our patients were managed conservatively with I.V. fluids, analgesia, and blood transfusion when necessary. Diagnostic aspiration under ultrasound guidance was necessary in two patients to differentiate between massive splenic infarction and splenic abscess. Two patients required splenectomy during the same admission because of suspicion of secondary infection and abscess formation, while a third patient had splenectomy 2 months after the attack because of persistent left upper quadrant abdominal pain. In all the 3 histology of the spleen showed congestive splenomegaly with massive infarction. All of our patients survived. Two patients subsequently developed autosplenectomy while the remaining 3 continue to have persistent but asymptomatic splenomegaly. Massive splenic infarction is a rare and unique complication of SCA in the Eastern Province of Saudi Arabia, and for early diagnosis and treatment, physicians caring for these patients should be aware of such a complication.     

Non-benign sickle cell anaemia in western Saudi Arabia

Seventy-one Saudi and Yemeni Arabs with sickle cell anaemia from western Saudi Arabia aged between 1 1/2 and 42 years were studied. The mean steady state haemoglobin concentration of 8.1 g/dl was lower than that of 10.7 g/dl reported previously for sickle cell anaemia in eastern Saudi Arabia. The patients were divided into an SSLF group with fetal haemoglobin (HbF) of 10.0% or below (44 patients) and an SSHF group having HbF above 10.0% (27 patients). No significant differences were found in the haemoglobin concentrations, haematological indices and incidences of bone changes of the two groups. SSLF patients were significantly more prone to infections (P less than 0.01), however. Also, there was an overall high incidence of hepatomegaly (69.0%) and splenomegaly (54.9%) and hepatomegaly was significantly more common in the SSLF group (P less than 0.02). Many of the patients, even with HbF levels over 10.0%, did not follow a benign course and suffered from severe anaemia, infections of the respiratory and urinary tracts, bone pains and infarcts, or bossing of the skull. Rarer complications included hepatic crisis, chest syndrome, retinal haemorrhage, epistaxis and hemiplegia. It is therefore apparent that Saudi Arabian sickle cell anaemia, even in patients with raised haemoglobin F levels, may be as clinically severe as in African patients.     

Chronic leg ulcer in diseases of the blood

The literature pertaining to the association of chronic leg ulcer with diseases ofthe blood other than sickle cell anemia has been reviewed.

Two patients with this association have been presented. One patient had ahemolytic anemia and the other a pancytopenia (secondary hypersplenism) inassociation with congestive splenomegaly due to cirrhosis of the liver.

It is suggested that the association of leg ulcer with these various diseases of theblood is related in an unknown manner to either splenomegaly or hyperfunction ofthe spleen (hypersplenism).

     

Splenic function in children with sickle cell disease: two different patterns in Saudi Arabia

Splenic function in 35 Saudi children homozygous for sickle cell disease (age range 3-9 years) was studied using radioactive colloid scans. Two different patterns emerged. Splenic dysfunction was demonstrated in more than 80% of children who were originally from the south-western part of the country. They were found to have low HbF levels. In contrast normal or nearly normal splenic function was found in all patients from the Eastern Province in whom HbF levels were high. These different patterns of splenic function may contribute to the severe and mild forms of sickle cell disease seen in Saudi Arabia.     

Fetal hemoglobin in sickle cell anemia: The Arab‐Indian haplotype and new therapeutic agents

Fetal hemoglobin (HbF) has well‐known tempering effects on the symptoms of sickle cell disease and its levels vary among patients with different haplotypes of the sickle hemoglobin gene. Compared with sickle cell anemia haplotypes found in patients of African descent, HbF levels in Saudi and Indian patients with the Arab‐Indian (AI) haplotype exceed that in any other haplotype by nearly twofold. Genetic association studies have identified some loci associated with high HbF in the AI haplotype but these observations require functional confirmation. Saudi patients with the Benin haplotype have HbF levels almost twice as high as African patients with this haplotype but this difference is unexplained. Hydroxyurea is still the only FDA approved drug for HbF induction in sickle cell disease. While most patients treated with hydroxyurea have an increase in HbF and some clinical improvement, 10 to 20% of adults show little response to this agent. We review the genetic basis of HbF regulation focusing on sickle cell anemia in Saudi Arabia and discuss new drugs that can induce increased levels of HbF.     

On the nature of sickle cell disease in the south-western province of Saudi Arabia

Sickle cell disease (SCD) occurs at a high prevalence in different parts of Saudi Arabia. Several reports indicate that the disease follows a mild clinical course in the Saudi population of the eastern province of Saudi Arabia, while little is known about the disease in other parts of the country. This study was conducted on 53 children from the Saudi Arabian south-western province with sickle cell disease and 53 age- and sex-matched normal controls (haemoglobin AA phenotype). A statistically significant difference was encountered in the haematological parameters investigated in the two groups. The SCD patients were divided into subgroups with high and low Hb F levels, alpha- and beta-thalassaemia and glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. The haematological parameters were then compared in the different sub-groups. No significant difference could be demonstrated in the haematological parameters in patients with a high or low Hb F level. In patients without thalassaemia, the red cell count, total haemoglobin and haematocrit were significantly lower, while MCV, MCH and MCHC were higher. G-6 PD deficiency existed in association with thalassaemias, and apart from a reduction in MCV and MCH, no other statistically significant difference could be demonstrated. Clinical examination revealed a severe disease with several cases suffering from the hand and foot syndrome.     

Homozygous sickle cell disease and priapism in the eastern province of Saudi Arabia

Two adult sickle cell homozygotes from the eastern oases of the Kingdom of Saudi Arabia presented with severe persistent priapism. Each patient had a high Hb F of 24%, and their red cells were neither hypochromic nor microcytic. Priapism probably occurs more frequently in homozygous sickle cell disease than reported previously from this region. It would appear that a high fetal haemoglobin alone without hypochromia and microcytosis--features suggestive of co-existing alpha-thalassaemia--does not protect against this agonizing vaso-occlusive event.     

Spleen irradiation in chronic lymphocytic leukemia (CLL): palliation in patients unfit for splenectomy

In 22 patients with CLL given 30 courses of spleen irradiation, 23 responses were observed (77%, 95% confidence limits, 58-90%). Response was defined as reduction in palpable spleen size accompanied by relief of symptoms (pain, abdominal discomfort, and sweating) or improvement in hypersequestration or hemolytic anemia. Reduction in leukocyte count alone was not regarded as response. All responses were partial. The median response duration was 1 year. Subsequently, three patients underwent splenectomy. The median survival from the beginning of spleen irradiation was 2.5 years (range: 1 month-greater than 5 years). Only six patients had minor side effects from the gastrointestinal tract. The hematologic effect was most pronounced on the white blood cell count, but also the platelet count was affected. It is concluded that spleen irradiation is a gentle and effective alternative in CLL patients suffering from splenomegaly (pain and hypersplenism), refractory to chemotherapy and glucocorticosteroids and unfit for splenectomy. Splenic irradiation may also be used with benefit preoperatively before splenectomy in patients with excessive splenomegaly and hypersplenism.     

Glycosylated hemoglobin levels in Sudanese sickle cell anemia patients

Glycosylated hemoglobin was measured, by a colorimetric method, in 49 patients with sickle cell anemia attending Khartoum Teaching Hospital. The level obtained (4.9%, SD 1.3) was significantly lower than the control value (5.6%, SD 0.2; p less than 0.0025). Expressed as percentage of the control value, the glycosylated hemoglobin level in these patients was 81%. This falls midway between the 90% reported in a benign form of sickle cell anemia in Saudi Arabia and the 58% reported in a severe form in an American Black group, which gives support to the observed heterogeneity of sickle cell anemia. Alternatively, glycosylated hemoglobin level in 27 subjects with sickle cell trait (5.6%, SD 0.2) was identical to that of the controls. The state of hemolysis in the sickle cell anemia patients, as indicated by bilirubin levels, did not correlate with the glycosylated hemoglobin values. Although glycosylated hemoglobin measurement is affected by red cell survival, it does not reflect the state of ongoing hemolysis.     

Heterogeneity and variation of clinical and haematological expression of haemoglobin S in Saudi Arabs.

Sickle cell haemoglobin (Hb S) occurs at a high frequency in the Eastern (EP), South-Western (SWP) and North-Western (NWP) Provinces of Saudi Arabia and the presentation of the Hb S is believed to exhibit clinical diversity in the different regions. Three areas of Saudi Arabia were screened to determine the frequency of Hb S and alpha- and beta-thalassaemias and glucose-6-phosphate dehydrogenase deficiency genes. Furthermore, in an attempt to investigate and compare the clinical and haematological presentation of sickle cell disease (SCD) in the different regions of Saudi Arabia, the individuals identified as Hb S homozygotes were investigated further. The patients were further classified on the basis of whether there was associated alpha- or beta-thalassaemia. A severity index (SI) was calculated for each patient and the clinical presentations and laboratory findings were compared. The results showed significantly variable severity of SCD in patients from different regions. The patients from the EP generally had a mild clinical presentation, while in the SWP and NWP majority of the patients suffered from a severe disease as judged by the SI. No correlation could be established between Hb F level and SI, though the WBC level correlated positively with the SI. The lowest SI values were encountered in patients with associated alpha-thalassaemia who also had the lowest WBC count and MCV and the highest RBC count and packed cell volume.     

区域性门静脉高压症的临床分析

目的 探讨区域性门静脉高压症(RPH)的病因、临床特点和诊治方法.方法 回顾性分析2005年1月至2010年6月收治的26例RPH患者临床资料.分析26例患者的临床首发症状、血常规、肝功能、乙型和丙型肝炎标志物、肿瘤标志物、腹部超声、腹部增强CT、胃镜检查结果,以及16例行腹部CT血管造影(CTA)者的检查结果.结果 胰源性疾病(18例)是RPH主要病因.临床表现为脾肿大26例,无规律性上腹痛14例,上消化道出血10例.内镜检查示孤立性胃底静脉曲张25例,同时合并食管下段静脉曲张1例.4例行内镜下胃底曲张静脉组织胶注射止血,4例行脾脏切除术,2例行脾脏切除+贲门血管离断术,2例行脾脏切除+胰尾切除+脾肾静脉分流术,3例行脾脏栓塞治疗.结论 RPH常伴胰腺疾病,表现为脾肿大、脾功能亢进,但肝功能正常、无肝硬化,孤立性胃底静脉曲张是其特征性表现.良性病因所致的RPH可治愈.伴消化道出血者脾脏切除的疗效优于单纯内镜下止血治疗.

Abstract：

Objective To investigate the etiology, clinical features, diagnosis and treatment of regional portal hypertension (RPH).Methods The clinical data of 26 patients with RPH treated in Beijing Chaoyang Hospital Affiliated to Capital Medical University between January 2005 and June 2010 were analyzed with retrospective analysis.The first symptom, routine analysis of blood, liver function test, hepatitis B and C markers, tumor markers, abdominal ultrasound, abdominal enhanced CT, endoscopy findings of 26 patients and the results of abdominal CT angiography (CTA) of 16cases were analyzed.Results Pancreatic disease (18 cases) was the leading cause of RPH.The main clinical manifestations of splenomegaly in 26 cases, irregularly abdominal pain in 14 cases, and upper gastrointestinal bleeding in 10 cases.Isolated gastric varices were revealed by endoscopy in 25 cases,complicated with lower esophageal varices in 1 case.4 cases with endoscopic tissue glue injection in gastric variceal bleeding, splenectomy in 4 cases, 2 cases with splenectomy and pericardialdevascularization, 2 cases with splenectomy, pancreatic tail resection and spleno-renal shunt, 3 cases with splenic embolization treatment.Conclusions RPH often accompanied by pancreatic disease,manifested as splenomegaly, hypersplenism, but normal liver function, absence of liver cirrhosis.Isolated gastric varices is the characteristic features of RPH.RPH caused by benign diseases is curable.Splenectomy is more effective than simple endoscopic hemostasis in RPH associated with gastrointestinal bleeding.     

Hematological profile of sickle cell disease in central India

Hematological profile of homozygous sickle cell disease patients attending RHDMC from Central India is presented. Central India has a huge population of sickle cell disease patients. Though predicted SS in the region is 22–44 %, 81 homozygous of sickle cell patients reported during study period of Jan 2003–Dec 2005. The clinical course of these patients is characterized in most of the cases by relatively long period without any symptoms punctuated by acute clinical events. Hematological profile of these 81 patients with age ranging from 6 month to 64 years is presented. There are 44 males and 37 females with an average age of 14.55yrs in males and 18.13 yrs females. Males out number females in pediatric age group where as females with SCD are attending hospital more in reproductive age group. Very few patients are reported after the age of 30 yrs. Average hemoglobin in males is 7.11 ± 2.13 gms/dl and in females 6.75 ± 1.85 gms/dl with parallel low RBC count.Hemoglobin rise is seen after 14 years of age in males and females. Age related rise in MCV is more noted in females after the age of 5 as compared to males. No age or sex related difference was seen in MCHC values. Hb A₂ levels for males is 2.13 ± 0.95% and for females 2.04 ± 0.91 %.Hb F in males is 19.58 + 5.86% and in females is 20.99 + 4.9%. There is no age and sex related difference in Hb F levels. Moderate to severe anemia with high Hb F dominate Central Indian sickle cell disease patient’s hematological profile. The hematological profile in Central India is similar to the profile in other parts of India and Saudi Arabia but different from Jamaica and Africa.     

Splenectomy in patients with malignant non-Hodgkin's lymphoma

Splenectomy in patients with non-Hodgkin's lymphoma (NHL) is performed for either diagnostic or therapeutic reasons. We report on a series of 29 patients with NHL and splenomegaly who underwent splenectomy during the years 1979-1998 in our hospital. According to the indication for splenectomy our patients were categorized in three groups. Group A: In 20 patients splenectomy was performed for diagnostic reasons. Group B: Three patients were splenectomized for autoimmune haemolytic anaemia (AIHA). Group C: Six patients underwent splenectomy because of hypersplenism. A definitive histopathological diagnosis of NHL was obtained in all patients of group A. Hypersplenism and AIHA were resolved in all patients after splenectomy. One (3.5%) patient died postoperatively because of septicemia complicated by disseminated intravascular coagulation. Six postoperative complications were observed in 4 (14%) patients. Splenectomy, with an acceptable surgical risk, has the potential to establish the diagnosis of NHL in patients with splenomegaly without lymphadenopathy and negative bone marrow findings. Moreover, splenectomy has the capacity to modify the disease course in patients with NHL complicated by AIHA or hypersplenism.     

Splenomegaly in sarcoidosis: clinical features and outcome. Analysis of 17 cases

PURPOSE: To describe the clinical features, biological datas and outcome of patients with systemic sarcoidosis and splenomegaly. METHODS: A retrospective analysis of 17 patients presenting splenomegaly and sarcoidosis with histological proof. RESULTS: Splenomegaly was clinically perceptible in 13 patients, with a spleen size that extended 4 cm or more below the costal margin in 11 patients. It was painful in five cases. The more frequent clinical features are constitutional symptom (fever in 9 cases) and hepatomegaly (N =7). Chest X-ray showed bilateral hilar lymphadenopathy in nine patients and no abnormality in five cases. Serum angiotensin converting enzyme levels were elevated in 81% of cases. Thrombopenia (N =5) and hypersplenism (N =5) were also observed. Corticosteroid were given to 88% with a good clinical and biological response including a decrease in the spleen volume. Corticotherapy and splenectomy (performed in two patients to rule out lymphoma) didn't change outcome of disease. Sarcoidosis is often chronical (82%) and extensive. CONCLUSION: Splenomegaly may be present in sarcoidosis. Management is not standardized. Corticosteroid is indicated for symptomatic or massive splenomegaly. Splenomegaly is frequently in chronic and extensive sarcoidosis.