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G B McDonald

Publications and source records attributed to G B McDonald.

At least 19 recordsLinked to original sources
PubMed2006

Review article: management of hepatic disease following haematopoietic cell transplant.

Hepatic diseases are common complications of haematopoietic cell transplant. The causes are multiple: myeloablative conditioning regimens may cause sinusoidal injury; acute and chronic graft-versus-host disease lead to damaged hepatocytes and small bile ducts; microcrystalline deposits in the gall bladder can cause biliary symptoms; drug-induced liver injury is common; and the liver may be infected by viruses and fungi during the period of severe immune suppression that follows transplant. Pre-transplant evaluation and prevention of liver injury are often more useful than treatment of deeply jaundiced patients in improving transplant outcomes. This review covers pre-transplant evaluation, common hepatobiliary problems in the six months following transplant, and hepatic problems in long-term survivors.

Chronic Disease↗
PubMed2006

Efficacy of neodymium:YAG laser therapy for gastric antral vascular ectasia (GAVE) following hematopoietic cell transplant.

We determined the incidence of severe bleeding from gastric antral vascular ectasia (GAVE) after myeloablative hematopoietic cell transplant and the outcomes after treatment with endoscopic neodymium:YAG laser photocoagulation. From 1992 to 2005, the incidence of severe bleeding from GAVE was 6/4491 (0.13%). All patients had received oral busulfan and four had sinusoidal obstruction syndrome. Gastrointestinal bleeding began a median of 53 days after transplant (range 15-2952). After GAVE was diagnosed by endoscopic and histologic findings, a median of three (range 2-7) sessions of laser therapy were required to control the bleeding with a median of 2737 J (range 1117-6160 J) per session. A median of 16 units (range 4-44) had been transfused prior to laser therapy and a median of four additional units (range 0-113) were transfused until bleeding was controlled. All patients were followed for at least 70 days after the last laser therapy session, with no further episodes of bleeding. Complications were mild and included abdominal pain and asymptomatic ulceration; however, one patient required gastrectomy due to gastric necrosis following transarterial embolizations. In summary, severe bleeding from GAVE is rare following hematopoietic cell transplant. Treatment with endoscopic therapy using the Nd:YAG laser is safe and effective.

Adolescent↗
PubMed2003

Lack of cytoprotective effect of amifostine following HLA-identical sibling transplantation for advanced myelodysplastic syndrome (MDS): a pilot study.

The objective of this prospective study was to determine whether amifostine (Ethyol) reduced conditioning-related toxicity following a regimen of busulfan (7 mg/kg) and fractionated total body irradiation (6 x 200 cGy). In all, 12 patients with advanced myelodysplastic syndrome transplanted from HLA-identical siblings were enrolled. Patients received 340 mg/m(2) amifostine i.v. twice daily during conditioning (days -7 through -1). All patients developed oropharyngeal mucositis. Six patients had evidence of sinusoidal obstruction syndrome of the liver. Six patients experienced pulmonary toxicity of grades II-III. A total of 11 patients died, one with relapse and 10 with infectious complications or regimen-related toxicity. Nonrelapse causes of death included invasive aspergillosis in three, multiorgan failure in three, and idiopathic interstitial pneumonitis in two patients. One patient each died of organizing pneumonia and CMV pneumonia. One patient is alive in complete remission 31 months after transplantation. These results were not superior to those in patients conditioned with busulfan plus fractionated total body irradiation and not given amifostine, and suggest that amifostine, as administered here, has no protective effect against toxicity from this myeloablative regimen.

Adult↗
PubMed2002

Portal vein thrombosis after hematopoietic cell transplantation: frequency, treatment and outcome.

Patients who develop veno-occlusive disease (VOD) of the liver may have low plasma levels of the natural anticoagulants protein C and antithrombin III, but large vessel thromboses are not commonly reported in these patients. We reviewed the records of 1847 consecutive patients for evidence of portal vein thrombosis. Eight patients (0.4%) developed portal vein thrombosis (PVT) at a median of day +28 (range 3-58). All patients had clinical evidence of VOD with ascites, a median total serum bilirubin 11.9 mg/dl, and median weight gain from baseline of 7.9%. Median plasma levels of antithrombin III and protein C were low (36% and 21%, respectively). Four patients with PVT died of severe VOD and multi-organ failure, but PVT did not contribute to death. We conclude that PVT is a rare complication of hematopoietic cell transplant and is associated with hepatic VOD. We speculate that PVT resulted from diminished portal venous flow (related to hepatic sinusoidal obstruction to blood flow) and a hypercoagulable state (related to low circulating antithrombin III and protein C levels). Prognosis depended on the severity of the underlying VOD and not PVT per se, suggesting that treatments directed solely toward dissolution of portal vein thrombi should be used with caution in this setting.

Adult↗
PubMed2001

The relationship between hemodynamics and inflammatory activation in women at risk for preeclampsia.

OBJECTIVE: This study evaluated: 1) whether women with risk factors for preeclampsia had a hyperdynamic circulation and increased markers of endothelial and inflammatory activation; and 2) whether hemodynamically directed therapy was associated with a change in markers. METHODS: A controlled experimental study was performed for two groups: 1) women at risk for preeclampsia (high risk); and 2) women at low risk (controls). Tumor necrosis factor-alpha (TNF-alpha), TNF-alpha receptors 1 and 2, vascular cell adhesion molecule-1, cellular fibronectin, and cardiac output were measured at or before 24 weeks' gestation and at 6-8 week intervals. High-risk subjects with cardiac output greater than 7.4 L/minute were treated with atenolol. Atenolol therapy was not randomized. Therefore, the longitudinal data were descriptive. Data were analyzed by the t test, Wilcoxon rank sum test, chi(2) test, multivariable linear regression, and the standard two-stage test. RESULTS: There were 46 high-risk subjects and 25 controls. Maternal age, gestational age, and parity did not differ between the groups. Cardiac output (P <.001) and vascular cell adhesion molecule-1 (P =.02) at baseline were significantly increased in the high-risk group. A total of 42 women in the high-risk group received atenolol for high cardiac output. There was a slower rise in TNF-alpha receptor 1 in the treated group compared with the controls (P <.001). CONCLUSION: Women with risk factors for preeclampsia had a hyperdynamic circulation and endothelial activation. Hemodynamically directed therapy in women at risk was associated with a slower rise in TNF-alpha receptor 1 compared with low-risk women who were not treated, suggesting a relationship between hemodynamics and inflammatory activation.

Adult↗
PubMed2001

Serum hyaluronic acid in patients with veno-occlusive disease following bone marrow transplantation.

The development of hepatic veno-occlusive disease following bone marrow transplantation is associated with high-dose combination cytoreductive therapy. Experimental models have suggested that drug-induced injury to hepatic sinusoidal endothelial cells is involved in the pathogenesis of this syndrome. Hyaluronic acid is a polysaccharide that is metabolized, almost exclusively, by hepatic sinusoidal endothelial cells. The aim of the present study was to evaluate serum hyaluronic acid as a marker for endothelial cell injury in patients with veno-occlusive disease following bone marrow transplantation. Hyaluronic acid was measured in sera from patients with and without veno-occlusive disease using an enzyme-linked protein binding assay. Mean peak serum hyaluronic acid levels were significantly greater in patients who had a diagnosis of VOD compared to those transplant patients who did not, 1173.4 +/- 982.9 vs 444.9 +/- 735.6 ng/ml (P = 0.01). Serial serum samples obtained from a separate cohort of patients also demonstrated that serum hyaluronic acid levels were higher in patients with moderate or severe veno-occlusive disease compared to those with none or mild disease at days 7, 17 and 25 following transplantation (greatest difference at day 25: 366 +/- 327 vs 126 +/- 151, P = 0.01). Serum hyaluronic acid levels are increased in veno-occlusive disease and increase over time in patients with severe disease. Further studies are required to determine if elevated serum hyaluronic acid levels are due to decreased clearance by injured hepatic sinusoidal endothelial cells or increased production from early hepatic fibrogenesis associated with the acute liver injury.

Adult↗
PubMed2001

Severe gastrointestinal bleeding after hematopoietic cell transplantation, 1987-1997: incidence, causes, and outcome.

OBJECTIVE: Severe GI bleeding after hematopoietic cell transplantation is commonly due to lesions that are unusual in nontransplant patients. The frequency of GI bleeding appears to have decreased over the last decade, but the reasons have not been readily apparent. We sought to determine the incidence of severe bleeding during two time periods, to describe the causes and outcomes of bleeding, and to analyze the reasons behind an apparent decline in severe bleeding over the decade covered. METHODS: During 1986-1987 and 1996-1997, we followed all patients with and without severe bleeding at our institution, a marrow transplant center. RESULTS: Over this decade, the incidence of severe bleeding declined from 50/467 (10.7%) to 15/635 (2.4%) (p < 0.0001). Overall mortality from intestinal bleeding declined from 3.6% to 0.9% (p = 0.002), but mortality in those with bleeding remained high (34% vs 40%). The onset (day 42 vs 47) and platelet counts (35,994 vs 37,600/microl) were similar, but the sites and causes of bleeding were different. During 1986-1987, 27/50 patients bled from multiple GI sites, viral and fungal ulcers, or graft-versus-host disease (GVHD). Over the decade, bleeding from GVHD had decreased 80% (p < 0.0001), and bleeding from viral (p < 0.0001) and fungal (p = 0.023) ulcers almost disappeared. CONCLUSIONS: The incidence of severe GI bleeding has declined significantly over the last decade because of prevention of viral and fungal infections and severe acute GVHD. However, severe bleeding after transplant remains a highly morbid event, particularly among patients with GVHD.

Adult↗
PubMed2000

Chronic graft-versus-host disease of the liver: presentation as an acute hepatitis.

Chronic graft-versus-host disease (GVHD) of the liver usually presents as an indolent cholestatic disease in patients with skin, mouth, and eye involvement. We observed 14 patients in whom chronic GVHD of the liver presented with marked elevations of serum aminotransferases, clinically resembling acute viral hepatitis. Onset of liver dysfunction was at 294 days (range, 74-747 days) after allogeneic hematopoietic cell transplantation and coincided with a recent cessation or taper of immunosuppressive drugs. Median peak serum alanine transaminase (ALT) was 1,640 U/L (698-2,565 U/L), and median bilirubin was 12.3 mg/dL (0.9-55.9 mg/dL). All biopsies showed characteristic features of GVHD with damaged and degenerative small bile ducts. Other features included a marked lobular hepatitis, moderate to marked amounts of hepatocyte unrest, sinusoidal inflammation with perivenular necroinflammatory foci, and many acidophilic bodies scattered throughout the lobule. When high-dose immunosuppressive therapy was instituted soon after presentation, progressive improvement and eventual normalization of liver enzymes and bilirubin levels were observed. However, in cases in which the diagnosis was not made and therapy was delayed, a progressive cholestatic picture emerged with histologic evidence of loss of small bile ducts and portal fibrosis. We conclude that a distinct syndrome of chronic liver GVHD presenting as an acute hepatitis can be recognized in a patient at risk who is receiving no, or minimal, immunosuppressive medications. Liver biopsy is necessary to exclude viral causes of liver dysfunction and to confirm characteristic abnormalities of small bile ducts. Institution of high-dose immunosuppression can prevent progressive bile duct destruction and effect resolution of jaundice if given early.

Acute Disease↗
PubMed2000

Bile duct apoptosis and cholestasis resembling acute graft-versus-host disease after autologous hematopoietic cell transplantation.

BACKGROUND: Acute graft-versus-host disease (GVHD) of the liver is a frequent complication of allogeneic hematopoietic cell transplantation. This report describes hepatic GVHD following autologous transplantation. METHODS: We reviewed 116 consecutive autologous transplant recipients. A diagnosis of GVHD was based on histology (segmental to subtotal destruction of bile ductal epithelial cells with apoptosis and lymphocytic infiltrates), clinical criteria (elevated serum alkaline phosphatase), a response to immunosuppressive therapy, and finding no other cause for cholestatic liver disease. RESULTS: Two patients developed cholestatic liver disease (alkaline phosphatase levels over five times the normal upper limit) and had liver biopsies showing apoptotic and dysmorphic ductular epithelial cells typical of GVHD. Three additional patients developed cholestasis and intestinal symptoms but had gastric biopsies only, showing apoptotic crypt epithelial cells and crypt cell drop-out typical of GVHD. CONCLUSION: Two recipients of autologous hematopoietic cells developed histologic abnormalities of small bile ducts and cholestatic liver disease resembling GVHD of the liver after allogeneic transplant. The mechanisms of bile duct damage in this setting may involve immune dysregulation related to reconstitution of immunity with peripheral blood stem cells.

Acute Disease↗
PubMed1999

Cirrhosis of the liver in long-term marrow transplant survivors.

Patients who survive hematopoietic cell transplantation (HCT) have multiple risk factors for chronic liver disease, including hepatitis virus infection, iron overload, and chronic graft-versus-host disease (GVHD). We studied 3,721 patients who had survived 1 or more years after HCT at a single center and identified patients with histologic or clinical evidence of cirrhosis. Risk factors for the development of cirrhosis were evaluated and compared with a group of matched control subjects. Cirrhosis was identified in 31 of 3,721 patients surviving 1 or more years after HCT, 23 of 1,850 patients surviving 5 or more years, and in 19 of 860 patients surviving 10 or more years. Cumulative incidence after 10 years was estimated to be 0.6% and after 20 years was 3.8%. The median time from HCT to the diagnosis of cirrhosis was 10.1 years (range, 1.2 to 24.9 years). Twenty-three patients presented with complications of portal hypertension, and 1 presented with hepatocellular carcinoma. Thirteen patients have died from complications of liver disease, and 2 died of other causes. Three patients have undergone orthotopic liver transplantation. Hepatitis C virus infection was present in 25 of 31 (81%) of patients with cirrhosis and in 14 of 31 (45%) of controls (P =.01). Cirrhosis was attibutable to hepatitis C infection in 15 of 16 patients presenting more than 10 years after HCT. There was no difference in the prevalence of acute or chronic GVHD, duration of posttransplant immunosuppression, or posttransplant marrow iron stores between cases and controls. Cirrhosis is an important late complication of hematopoietic cell transplantation and in most cases is due to chronic hepatitis C. Long-term survivors should be evaluated for the presence of abnormal liver function and hepatitis virus infection.

Adolescent↗
PubMed1999

Hepatitis C virus infection and bone marrow transplantation: a cohort study with 10-year follow-up.

Before the introduction of routine blood donor screening in 1991, marrow transplant recipients were at significant transfusion-associated risk for infection with hepatitis C virus (HCV). We followed a cohort of 355 patients undergoing transplant in Seattle during 1987 to 1988 to determine (1) the impact of pretransplant HCV infection on the occurrence and severity of venocclusive disease (VOD); (2) the impact of HCV infection on liver dysfunction, other than VOD, occurring between 21 and 60 days after transplantation; and (3) the natural history of post-transplant HCV liver disease with a 10-year follow-up. HCV-RNA status was determined on serum stored before transplant and at day 100 post-transplant. Sixty-two (17%) patients were HCV-RNA positive before transplant, and 113 (32%) were HCV-RNA positive by day 100 post-transplant (or before death). Severe VOD developed in 22 of 46 (48%) evaluable patients with pretransplant HCV infection and in 150 of 229 (14%) evaluable patients without HCV (P <.0001). In multivariable analysis of risk factors for developing VOD, pretransplant HCV infection associated with elevated serum aspartate transaminase (AST) levels predicted the development of severe VOD (relative risk, 9.6; P =.0001). The presence of HCV with normal AST levels before transplant was not a risk factor for severe VOD. Between 21 and 60 days after transplant, HCV-RNA positive-patients had higher AST levels (median 101 U/L), but similar alkaline phosphatase and total bilirubin levels compared with HCV-negative patients, suggesting that cholestatic liver disease (particularly graft-versus-host disease [GVHD]) was not related to HCV infection. An acute flare of hepatitis (AST >10 times the upper limit of normal) developed at a mean of 136 +/- 58 days in 31% of HCV-positive patients; no patients developed fulminant hepatitis. Between 5 and 10 years after transplant, 57% of HCV-positive and 6% of HCV-negative patients had mild to moderate elevations of AST (P <. 0001), but HCV infection was not associated with excess mortality between 3 and 10 years after bone marrow transplantation. In summary, HCV infection with elevated AST levels is a significant risk factor for severe VOD after marrow transplant. However, the decision to proceed to transplantation in HCV-positive patients must balance the absolute risk of death from VOD against the risks of the underlying disease. In long-term survivors, HCV infection is not associated with excess mortality over 10 years of follow-up.

Adult↗
PubMed1999

Autoantibodies in human chronic graft-versus-host disease after hematopoietic cell transplantation.

Primary biliary cirrhosis (PBC) and graft-versus-host disease (GVHD) are thought to have common immunopathologic features and previous studies have reported that 5.2 to 81% of patients with chronic GVHD after allogeneic hematopoietic cell transplant have antimitochondrial antibodies (AMA). We studied a total of 89 patients with chronic GVHD and 60 controls for AMA reactivity by ELISA and immunoblotting using recombinant PDC-E2, BCOADC-E2, and OGDC-E2, immunoblotting of beef heart mitochondrial proteins, and reactivity to nuclei, smooth muscle (ASMA), ribonucleoprotein JO-1, extractable nuclear antigen, nuclear proteins SSA/ SSB, ribonucleic P proteinase III, cardiolipin (ACA), liver kidney microsomal, thyroid microsomal, myeloperoxidase, and the reactivity of rheumatoid factor. A subset of 60 chronic GVHD sera were tested for reactivity to gp210 and LBR. Finally, liver tissue from patients with chronic GVHD and PBC was studied by immunohistochemistry to determine whether there was comparable abnormal apical staining of biliary epithelial cells using PDC-E2-specific monoclonal antibodies. Surprisingly, there were no AMA found in the sera from the 89 patients with chronic GVHD. Review of published data on AMA in GVHD suggests that previous results were primarily false positives. In contrast, sera from the patients with GVHD did have a variety of other autoantibodies and, in particular, 20/89 (22.4%) positive ANA, 23/89 (25.8%) positive ASMA, and 9/89 (10.1%) positive ACA. The other autoantibodies assayed were not statistically different from controls. Finally, abnormal biliary epithelial luminal staining of bile ducts was found, as expected, in liver tissue of patients with PBC but was absent in chronic GVHD.

Adult↗
PubMed1999

Endoscopic and histologic diagnosis of intestinal graft-versus-host disease after marrow transplantation.

BACKGROUND: Gastrointestinal graft-versus-host disease after allogeneic hematopoietic cell transplantation presents a range of upper gastrointestinal endoscopic and histologic abnormalities. Recognition of these sometimes subtle abnormalities is critical for directing specific therapy. METHODS: Endoscopic and histologic abnormalities in 10 patients with gastrointestinal graft-versus-host disease are reviewed to detail the spectrum of findings. RESULTS: The endoscopic appearance of the stomach and duodenum varies from subtle mucosal erythema and edema to frank ulceration and mucosal slough. Histologic findings include crypt epithelial cell apoptosis and dropout, crypt destruction, and variable lymphocytic infiltration of the epithelium and lamina propria. The involvement may vary from diffuse and uniform to focal, with either the stomach or the duodenum appearing much more involved. CONCLUSIONS: Endoscopic evaluation of the stomach and duodenum and histologic evaluation of biopsies of the gastric antrum can be used to diagnose gastrointestinal graft-versus-host disease. The gross appearance of the mucosa and the histology of gastric biopsies are mutually complementary. However, both the endoscopic evaluation and the histology of the upper gut can underestimate the severity of acute graft-versus-host disease elsewhere in the intestine unless extensive mucosal sloughing is seen.

Acute Disease↗