Extra-pancreatic manifestations of IgG4-related systemic disease: a single-centre experience of treatment with combined immunosuppression.

BACKGROUND/AIM: IgG4-related systemic disease (IgG4-RSD) is a systemic inflammatory disease distinguished by tissue infiltrates of IgG4(+) plasma cells and elevated serum IgG4 levels. While IgG4-RSD often involves the pancreas, extra-pancreatic organs are also frequently affected. Here, we review the presentation and management of patients with extra-pancreatic IgG4-RSD. METHODS: A retrospective analysis was performed on patients diagnosed with extra-pancreatic IgG4-RSD identified from a single centre. RESULTS: Six patients with extra-pancreatic IgG4-RSD were identified. The median age of the patients was 64 years. The range of involved organs included lymph nodes (three patients), ocular adnexa, lung, kidneys, meninges and exocrine glands. The median delay in diagnosis was 13.5 months (4-60 months). Four patients had elevated serum IgG4 levels at diagnosis. Five symptomatic patients were commenced on combination immunosuppression, which included corticosteroids. Maintenance therapy with azathioprine was used in one patient, methotrexate and mycophenolate were each used in two patients, and cyclophosphamide in one patient. Four treated patients went into remission, while two patients had persistent radiological disease. One patient experienced two relapses. CONCLUSION: IgG4-RSD can manifest in a variety of organs. Lack of awareness regarding this entity may delay diagnosis. Combination treatment of corticosteroids and conventional immunosuppression is effective.

Fc gamma receptor IIIB-NA gene frequencies in patients with systemic lupus erythematosus and healthy individuals of Malay and Chinese ethnicity.

The neutrophil antigen (NA)1 and 2 is coded by two recognized allelic forms of Fc gamma receptor IIIB (FcgammaRIIIB). FcgammaRIIIb is a low affinity receptor and preferentially removes immune complexes from the circulation. Systemic lupus erythematosus (SLE) is an autoimmune and polygenic disorder characterized by accumulation of autoimmune complexes. The majority of SLE patients in our medical center are of Chinese ethnicity, followed by Malay and Indian. Recently, studies have focussed on the Fc receptors in different ethnic groups and their relation to SLE. We chose to study the gene distribution of this receptor in the Chinese and Malays population in Malaysia. We designed a polymerase chain reaction allele specific primers (PCR-ASP) method to distinguish the two allelic forms. Genomic DNA was isolated from the peripheral blood of 183 Chinese and 55 Malays SLE patients as well as 100 Chinese and 50 Malays healthy controls. Genotyping of Chinese SLE patients revealed that the gene frequencies for FcgammaRIIIB-NA1 and FcgammaRIIIB-NA2 were 0.648 and 0.347, while in the ethnically matched healthy controls they were 0.68 and 0.32, respectively. One out of the 183 Chinese SLE patients was identified as a NA-null due to the absence of PCR product for both alleles. The FcgammaRIIIB-NA1 and FcgammaRIIIB-NA2 allele frequencies for both the Malays SLE and healthy controls were 0.62 and 0.38.

Symptomatic choledochoceles in adults. Endoscopic retrograde cholangiopancreatography recognition and management.

During a 2-year interval, we identified 10 patients with symptoms of pancreaticobiliary disorders and small choledochoceles by endoscopic retrograde cholangiopancreatography. Patients ranged from 36 to 89 years of age. Eight were female. Seven presented with recurrent, acute pancreatitis, two presented with biliary colic, and one presented with cholangitis. Dilated common bile ducts were seen in four patients, and no other biliary lesions were demonstrated in any patients. Five patients were shown to have normal gallbladders by ultrasonographic or computed tomographic criteria. Choledochoceles were identified endoscopically as a bulge above or involving the ampulla. Diagnosis was confirmed by cholangiography. All patients underwent successful unroofing of the choledochocele and sphincterotomy of the common bile duct. One pancreatic sphincterotomy was performed for pancreatic ductal obstruction. We encountered no complications. Hospital stays ranged from 1 to 4 days. Follow-up intervals ranged from 2 to 20 months. At this time, no patients have had any recurrence of symptoms, and none has required rehospitalization or surgery.

Combined modality treatment of symptomatic pancreatic ductal lithiasis.

OBJECTIVE: To assess the efficacy and safety of the removal of pancreatic duct stones by a combined modality approach in patients with pancreatic ductal lithiasis and recurrent abdominal pain. DESIGN: Retrospective review with a mean follow-up of 19 months (range, 1 to 56 months). SETTING: A tertiary care, private community hospital with a university affiliation. PATIENTS: The records of patients who presented to the hospital or who were referred with recurrent abdominal pain and who were demonstrated to have pancreatic ductal lithiasis between 1989 and 1994 were reviewed. Patients were assessed by their clinical response to pancreatic duct stone extraction by a variety of therapeutic interventions. RESULTS: Fifteen patients were included in the study. One patient was excluded from analysis because of a concurrent choledochocele. Two patients required operative decompression and stone extraction for endoscopically inaccessible stones. Six patients were treated with endoscopic management alone, and six were treated with a combination of extracorporeal shock wave lithotripsy and endoscopic stone retrieval. Twelve patients had complete clearance of the pancreatic duct. One patient had a stone that was not removed, but adequate pancreatic ductal decompression was achieved. The remaining patient had incomplete clearance of pancreatic stone fragments following extracorporeal shock wave lithotripsy but had adequate ductal drainage. No patient has required further therapy or hospitalization for abdominal pain. No complications occurred as a result of any intervention in this study. CONCLUSIONS: A multidisciplinary combined modality approach is a safe and effective method for extracting pancreatic duct stones in symptomatic patients. Stone extraction and reestablishment of adequate ductal drainage appear to relieve symptoms in some patients.

Molecular rearrangements of chromosome 22 in chronic myeloid leukemia in a multi-ethnic Malaysian population.

Rearrangements in the DNA of chronic myelogenous leukemia patients of Chinese, Malay and Indian origin were detected in the breakpoint cluster region of chromosome 22 using molecular techniques. The DNA of fifty patients was examined using a 1.2 kb DNA probe. Rearrangements were detected in 46/50 patients. Karyotypic data were available in nine patients, all of whom were Philadelphia chromosome positive and exhibited DNA rearrangement. Detection of the Philadelphia translocation by molecular methods, at this institution, where cytogenetics is not routinely performed, confirms its diagnostic value. The rearrangement data obtained in this study is consistent with molecular features of chronic myelogenous leukemia patients of Western countries.

Analysis of ras gene mutations in acute myeloid leukemia by the polymerase chain reaction and oligonucleotide probes.

In vitro deoxyribonucleic acid (DNA) amplification by the polymerase chain reaction (PCR) followed by hybridization with oligonucleotide probes were used to study ras gene mutations in acute myeloid leukemia (AML). The DNA of 30 AML patients at presentation of the disease at the University of Malaya Hospital, Kuala Lumpur were screened for ras gene mutations in codons 12, 13 and 61 of the N-ras, K-ras and H-ras genes. Four patients (13.3%) had ras gene mutations. They were all below their early thirties in age. Of the four patients with ras gene mutations, three were M3 and one was M4 according to the French American British (FAB) classification of AML.

Tretinoin in pregnancy complicated with acute promyelocytic leukaemia.

Acute promyelocytic leukemia (APL) in pregnancy poses serious danger to both the mother and fetus. Cytotoxic chemotherapy may cause teratogenicity to the fetus. APL is unique because it is usually associated with a coagulopathy that markedly increases the risk for the mother and fetus. A 21 year old lady with APL in her third trimester of pregnancy was treated with oral tretinoin. Tretinoin reversed the coagulopathy and normalised her blood counts without causing cytotoxic damage associated with cancer chemotherapy. Fetal distress occurred at 37 weeks of gestation and an emergency caesarean section was performed without complications and no blood transfusion support was needed as her coagulopathy and thrombocytopenia had resolved. A remission was achieved with only tretinoin induction. She subsequently had consolidation and maintenance chemotherapy. The mother and baby remain well at 4 years from completion of chemotherapy. A total of 10 pregnancies associated with APL have been reported in the current literature. Premature delivery and a fetal arrhythmia were the only complications. Although retinoin is considered teratogenic, its use so far in second and third trimester has been safe.

Breakpoint cluster region (BCR) gene rearrangement studies in chronic myeloid and acute lymphoblastic leukemias.

Deoxyribonucleic acid (DNA) of twenty chronic myeloid leukemia (CML) and thirty acute lymphoblastic leukemia (ALL) patients were analysed by Southern hybridization. The DNA was digested with BglII and hybridized with a 4.5-kilobase (kb) ph1/bcr-3 DNA probe. All the 20 CML patients showed gene rearrangement within a 5.8-kb segment (the major breakpoint cluster region, M-bcr) of the breakpoint cluster region (bcr) gene of chromosome 22, indicating the presence of the Philadelphia chromosome. M-bcr rearrangement at the bcr gene of chromosome twenty-two was not detected in all the thirty ALL patients (nine adults and twenty-one children) and two normal controls.

Adult allogeneic bone marrow transplantation: initial experience in the University Hospital, Kuala Lumpur.

Prior to 1993, bone marrow transplantation for adult patients was not available in Malaysia. Adult allogeneic bone marrow transplantation commenced in Malaysia when the first transplant was conducted at the University Hospital, Kuala Lumpur on 2 November 1993. Up till July 1995, 10 adult bone marrow transplants had been conducted at the University Hospital. Five patients had acute myeloid leukaemia in first remission, 4 had chronic myeloid leukaemia and 1 had acute lymphoblastic leukaemia in first partial remission. The age range of patients at the time of transplant is 16-40 years (mean 25.5 years). All patients engrafted successfully and the survival for the first 100 days post-transplant is 90%. One patient demonstrated haematological relapse post-transplant but achieved remission with donor buffy-coat infusion. The mean drug cost incurred was RM28,269 for the first 100 days. Locally available adult allogeneic bone marrow transplantation is safe, affordable and has comparable results with reputable overseas transplant centres.

Anti-lymphocyte globulin therapy in aplastic anaemia--a university hospital experience.

Antilymphocyte globulin (ALG) was given every other day for 5 doses with platelet transfusions immediately following ALG administration in 6 patients with aplastic anaemia. Four patients responded and 3 durable remissions were achieved. One patient relapsed and further treatment with anti-thymocyte globulin and cyclosporin also failed. One patient died of Flavobacterium septicaemia 6 days after completion of ALG. Our data suggests that using an alternate day regimen, a response rate similar to a daily regimen can be obtained.

Acquired haemophilia--a therapeutic challenge.

Acquired haemophilia is a rare clinical condition arising from the spontaneous development of inhibitors to factor VIII. We describe two cases encountered in the University Hospital over the past five years. We also review the literature and discuss the therapeutic difficulties faced in dealing with patients with high levels of inhibitors. In one of these patients we also describe, for the first time in this region, a novel method in managing the acute bleeding episode in acquired haemophilia using recombinant factor VIIa.

Clinical stage of chronic granulocytic leukaemia and BCR breakpoint location in South-East Asian patients.

Forty-six Malaysian patients with chronic granulocytic leukaemia were found to be rearranged in the breakpoint cluster region (BCR) of chromosome 22, molecular evidence of Philadelphia chromosome (t9.22) translocation. Through the use of a 1.2 kb 3' BCR probe and two restriction enzyme digests, patients' breakpoints could be localized either to 5' or 3' regions of the BCR. Breakpoint site localization at the time of DNA sampling did not show any positive statistical association to clinical status defined as chronic phase, chronic phase with less than 6 months to blast crisis, accelerated phase and blast crisis. This was in contrast to earlier reports which indicated that patients with breakpoint at 3' site were at a higher biologic risk for entering blast crisis.

Selective IgA deficiency presenting with hypersplenism.

A young patient presenting with splenomegaly and hypersplenism was inadvertently found to have selective IgA deficiency. There were no symptoms of immunodeficiency and the patient responded well to splenectomy, with return of blood counts to normal without adverse effects. No other cause for the hypersplenism was found. We postulate selective IgA deficiency as a cause of splenomegaly and hypersplenism.

Advantage of induction therapy with all trans retinoic acid in acute promyelocytic leukaemia in a country with limited transfusion resources: a Malaysian experience.

Induction of remission of acute promyelocytic leukaemia (APL) needs intensive blood support (16) to prevent bleeding attributed to disseminated intravascular coagulation. Between 1989 and 1991, at the University Hospital in Kuala Lumpur, Malaysia, the remission rate of APL was only 27% with conventional chemotherapy as a result of inadequate transfusion resources. The use of all trans retinoic acid in induction therapy followed by consolidation and maintenance chemotherapy has improved the situation dramatically. Twelve patients entered the study. Ten patients achieved remission (83%), indicating how ATRA had significantly improved the results (p = 0.003). Blood component transfusions were also significantly reduced (p = 0.003). Two ethnic Chinese patients developed pulmonary leucostasis. Published Chinese (2, 6) and Japanese (11) studies have not reported this serious adverse effect. We can now state that leucostasis is not a phenomenon limited to the Western population. ATRA has proved to be extremely beneficial for patients at this centre. Early analysis also suggests that consolidation and maintenance chemotherapy has prolonged remission duration. ATRA should be made available for the treatment of APL in all countries where there are inadequate transfusion services.

Acute plasma calcium regulation in rats: effect of vitamin D deficiency.

Vitamin D-replete (+D) and vitamin D-deficient (-D) rats received large doses of calcium (2-18 mg) by intraperitoneal injection and their responses to the calcium load was analysed in terms of the instantaneous and time-dependent responses of the plasma calcium concentration, [Cas]. Following an initial expansion, [Cas] returned to the preinjection value in a strictly exponential manner, with t1/2 = 22.5 +/- 2.0 (SE) min in +D and 51 +/- 5.2 min in -D animals. In both groups of animals, these rates were independent of the calcium load. Extraprolation of [Cas] to t = 0, i.e., the time just after administration of the calcium, revealed that the amount of calcium circulating at that moment was only about one-fifth of the amount that would have been found if all of the injected calcium had remained in the plasma. Calculations suggest that in all animals about four-fifths of the injected calcium load became distributed virtually instantaneously in the extracellular water. In both +D and -D groups the fraction of the injected load that left the plasma instantaneously was independent of the calcium load, of [Cas] at t = 0 or of the animals' plasma volume. The ability of rats to disperse some 80% of the load to outside the plasma would seem to constitute a major mechanism of acute plasma calcium regulation. Dilution was insufficient, however, totally to reduce [Cas] to the preinjection level. That occurred exponentially, with most of the calcium presumed to enter the skeleton. This exponential rate was markedly and significantly slower in the vitamin D-deficient animals than in their controls.

Acute myelomonocytic leukaemia complicated by an acute aortic thrombosis.

Acute aortic thrombosis is a rare condition, occurring mainly as a result of trauma or atherosclerosis and occasionally secondary to hypercoagulable states. We report a patient with relapsed acute myeloid leukaemia who developed an unusual complication, acute aortic thrombosis.

Ovarian failure in oral cyclophosphamide treatment for systemic lupus erythematosus.

Ninety-two women with systemic lupus erythematosus treated with oral cyclophosphamide were studied to ascertain the prevalence and the factors associated with ovarian dysfunction. Menstrual disturbance during treatment occurred in 55% of patients: 36% had amenorrhoea and 19% had oligomenorrhoea. Sustained oligomenorrhoea occurred in 12% patients. Permanent amenorrhoea (> 12 months) after cessation of oral cyclophosphamide occurred in 27% of patients. Hormonal studies in these patients were consistent with ovarian failure. Older age at initiation of treatment and high cumulative dose of cyclophosphamide were found to be associated with this outcome. There was a trend towards linear relationship between the age of initiation of cyclophosphamide therapy and frequency of amenorrhoea. A statistically significant association between amenorrhoea and cumulative dose of cyclophosphamide after adjustment for age was found whereas no such association was linked to the duration of treatment. Fourteen of the 23 women who wished to become pregnant after cessation of treatment conceived resulting in 20 live births and two abortions.

Endoscopic management of cystic duct fistulas after laparoscopic cholecystectomy.

Two patients are reported who developed bile ascites as a result of cystic duct fistulas following laparoscopic cholecystectomy. Both patients were successfully treated with endoscopic retrograde cholangiopancreatography, utilizing sphincterotomy and nasobiliary tube placement. Characteristics of this syndrome and advantages of this form of therapy are emphasized.