The pancreas and tuberculosis: a diagnostic challenge.

Pancreatic tuberculosis is often mistaken for malignancy and can pose a diagnostic challenge. A high degree of suspicion is necessary to diagnose this condition which responds well to anti-tuberculosis treatment (ATT). Fine-needle aspiration cytology helps to differentiate malignancy from treatable conditions like tuberculosis. Records of four patients treated for pancreatic tuberculosis between 1997 and 2006 were studied. All patients had a pancreatic mass which was suspected to be malignant at imaging. The diagnosis of tuberculosis was established by FNAC in one case and after laparotomy in one; two had tuberculosis of other systems. All showed good response to ATT which included resolution of the pancreatic mass over mean follow up of 2 years. We suggest that all inoperable masses of the pancreas should be subjected to FNAC to rule out treatable conditions like pancreatic tuberculosis.     

Inhaled corticosteroids stabilize constrictive bronchiolitis after hematopoietic stem cell transplantation

Post transplantation constrictive bronchiolitis (PTCB) is the most common pulmonary complication among long-term survivors of allogeneic hematopoietic stem cell transplantation (HSCT). It is a late manifestation of GVHD. Its treatment with high-dose systemic corticosteroids and other immunosuppressive regimens is associated with multiple side effects. Topical corticosteroids are used for the treatment of other manifestations of GVHD to minimize these side effects. We conducted a retrospective analysis of a series of adult patients to evaluate the efficacy of high-dose inhaled corticosteroids in the treatment of PTCB. Seventeen patients with new-onset airflow obstruction were diagnosed with PTCB. Their forced expiratory volume in 1 s (FEV1) declined from a median of 84% (range, 56-119) before HSCT to 53% (26-82) after HSCT. All patients received inhaled fluticasone propionate 500-940 microg two times daily. Symptoms of airway obstruction improved and FEV1 stabilized 3-6 months after treatment. We conclude that high-dose inhaled corticosteroids may be effective in the treatment of PTCB and propose a plausible mechanism of its action. A prospective evaluation of its efficacy is warranted.     

Maintenance zinc therapy after initial penicillamine chelation to treat symptomatic hepatic Wilson’s disease in resource constrained setting

Background

Experience with zinc in treating symptomatic hepatic Wilson’s disease (WD) is limited.

Aim

To study the efficacy of Penicillamine followed by zinc in treating symptomatic hepatic Wilson’s disease.

Methods

We retrospectively analyzed case records of 31 symptomatic hepatic WD patients for whom disease severity scores (Child’s, model for end-stage liver disease (MELD), Nazer’s, and New Wilson Index (NWI) score) and 24-h urinary copper were compared at 3-time points—baseline at presentation, at transition from penicillamine to zinc and at end of follow up.

Results

Thirty-one patients (median age 11 [5–24] years) with symptomatic hepatic WD were studied; ten had associated neuropsychiatric manifestations of WD. Penicillamine was changed to zinc sulfate either due to financial constraints (28 patients) or due to adverse effects of penicillamine (3 patients). At presentation (baseline), six patients belonged to Child’s class A, five to Child’s B, and 17 to Child’s C. Duration of initial penicillamine chelation therapy was 134 (2–320) weeks, and of subsequent zinc therapy was 363 (35–728) weeks. There was a significant improvement in liver function tests and disease severity scores (Child’s, MELD, Nazer’s, and NWI score) at the transition from penicillamine to zinc compared to baseline. This improvement was maintained until the end of study period with 90% survival at 10 (2–20) years. Fifteen of the 17 Child’s C cirrhotic patients showed significant improvement in disease severity scores from baseline until end of follow up.

Conclusions

Penicillamine followed by zinc may be a safe and effective treatment in resource-constrained setting for symptomatic hepatic WD patients in all grades of baseline disease severity. Some patients with decompensated cirrhosis due to WD may be managed with medical treatment, avoiding liver transplantation.

     

ATP7B mutations in families in a predominantly Southern Indian cohort of Wilson's disease patients.

OBJECTIVE: To analyze ATP7B mutations in Wilson's disease (WD) patients from the Indian subcontinent and to correlate these with WD phenotype. METHODS: We studied 27 WD patients from 25 unrelated families. Twenty-two families were from three southern Indian states - Tamil Nadu andhra Pradesh and Kerala. We applied conformation- sensitive gel electrophoresis (CSGE) to screen for the mutations in patients and their families. PCR products exhibiting aberrant patterns in CSGE were subjected to direct DNA sequencing. As siblings affected by WD within a family share identical ATP7B genotype, we compared WD phenotype among affected siblings within families. RESULTS: ATP7B mutations were detected in 22 of the 25 probands -13 were homozygotes and 9 were compound heterozygotes. Eleven novel mutations were detected. Only two common mutations were found: G3182A in 4 (16%) and C813A in 3 (12%) probands. 'Hot spots' for ATP7B mutations were exons 18 and 13. Lack of common dominant mutations prevented correlation of individual ATP7B mutations with WD phenotype. Symptomatic WD in a live sibling was not found in any family. In 8 families, a sibling died of presumed WD - in 6 of these, WD phenotype was identical to that in the proband. CONCLUSIONS: We describe the spectrum of ATP7B mutations including 11 novel mutations in Indian WD patients and document lack of a single dominant mutation. Identical WD phenotype among siblings in only 6 of 8 families with >1 child affected by WD suggests that factors other than ATP7B mutations influence WD phenotype.     

DNA damage-induced cell-cycle arrest of hematopoietic cells is overridden by activation of the PI-3 kinase/Akt signaling pathway

Exposure of hematopoietic cells to DNA-damaging agents induces cell-cycle arrest at G1 and G2/M checkpoints. Previously, it was shown that DNA damage-induced growth arrest of hematopoietic cells can be overridden by treatment with cytokine growth factors, such as erythropoietin (EPO) or interleukin-3 (IL-3). Here, the cytokine-activated signaling pathways required to override G1 and G2/M checkpoints induced by gamma-irradiation (gamma-IR) are characterized. Using factor-dependent myeloid cells stably expressing EPO receptor (EPO-R) mutants, it is shown that removal of a minimal domain required for PI-3K signaling abrogated the ability of EPO to override gamma-IR-induced cell-cycle arrest. Similarly, the ability of cytokines to override gamma-IR-induced arrest was abolished by an inhibitor of PI-3K (LY294002) or by overexpression of dominant-negative Akt. Moreover, the ability of EPO to override these checkpoints in cells expressing defective EPO-R mutants could be restored by overexpression of a constitutively active Akt. Thus, activation of a PI-3K/Akt signaling pathway is required for cytokine-dependent suppression of DNA-damage induced checkpoints. Together, these findings suggest a novel role for PI-3K/Akt pathways in the modulation of growth arrest responses to DNA damage in hematopoietic cells. (Blood. 2001;98:834-841)     

Liver histology and immunohistochemical findings in asymptomatic Indians with incidental detection of hepatitis B virus infection.

BACKGROUND AND OBJECTIVES: The relationship between hepatocyte expression of hepatitis B virus (HBV) antigens, liver histology and viral replication in asymptomatic subjects with incidental detection of hepatitis B surface antigen (HBsAg) remains unclear. We evaluated the histological activity index (HAI) and hepatocyte expression of viral antigens with replicative status in asymptomatic chronic HBV infection. METHODS: Asymptomatic subjects with incidental detection of HBsAg and ALT levels less than twice the upper limit of normal were grouped as follows: Group A - negative for HBeAg and HBV DNA (no HBV replication); B - HBeAg negative, HBV DNA positive (low HBV replication or pre-core mutant); C - positive HBeAg and HBV DNA (high viral replication). Liver biopsies were assessed for HAI (Ishak's scoring system). These were also subjected to immunohistochemistry for expression of HBsAg and hepatitis B core antigen (HBcAg); distribution, staining pattern and quantitative measurement of antigen expression were assessed. RESULTS: Median HAI was similar in the three groups (1.0, 2.0 and 2.0 in groups A, B and C, respectively). All subjects in Group C showed discrete cytoplasmic expression of HBsAg, whereas the other two groups showed heterogeneity in distribution and pattern of HBsAg staining. Quantitative measurement of cytoplasmic HBsAg revealed similar results in the three groups. Core antigen (nuclear) was detected in 4 of 5 subjects in Group C and none of those in Groups A and B. Ground-glass hepatocytes were seen in 20 and orcein-positive cells in 26 cases. HBsAg was detected by immunohistochemistry in 37 biopsies. CONCLUSIONS: Among asymptomatic subjects with chronic HBV infection, those with high rate of viral replication had discrete cytoplasmic HBsAg expression and nuclear expression of core antigen; these findings were uncommon in subjects with low or no viral replication.     

Raised plasma levels of H<Subscript>2</Subscript>S and nitrate predict intrapulmonary vascular dilations: A preliminary report in patients with cryptogenic cirrhosis

Background and Aims

The role of vasoactive chemicals in the pathogenesis of hepatopulmonary syndrome (HPS), a disorder characterized by intrapulmonary vascular dilation (IPVD), is only vaguely elucidated. We aimed to study the association between plasma H₂S, nitrate levels, and presence and severity of IPVD and HPS.

Methods

Consecutive adult patients with cryptogenic cirrhosis were evaluated for IPVD (by contrast echocardiography) and for hypoxemia (by arterial blood gas analysis). Plasma H₂S and nitrate levels were measured in these patients.

Results

Fifty-eight patients with cryptogenic cirrhosis (male, 45; median age, range, 45, 16–74 years; Child’s class; A, 30; B, 18; C, 10) were enrolled in this study. Thirty-four of the 58 (59%) patients had IPVD and 13 (22%) had HPS (mild, 4; moderate, 5; severe, 2; very severe, 2). Plasma H₂S levels were significantly higher in patients with IPVD (19.6, 5.7–83 μmol/L) as compared to patients who had no IPVD (12.3, 0–47 μmol/L; p-value 0.03) with an area under receiver operating characteristic curve of 0.68 (95% CI 0.53–0.84). Plasma H₂S levels were higher in patients with IPVD irrespective of liver disease severity. There was a trend for higher plasma nitrate levels in patients with IPVD (47, 15.8–126.4 nmol/mL) as compared to patients who had no IPVD (32.3, 6.9–51.4 nmol/mL; p-value 0.1). Raised plasma H₂S and nitrate levels had an additive effect on the presence of IPVD. Neither plasma H₂S nor plasma nitrate levels correlated with the degree of hypoxemia.

Conclusion

Raised plasma H₂S and nitrate levels predict the presence of IPVD in patients with cryptogenic cirrhosis.

     

Unrelated donor hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis

We report outcomes after unrelated donor hematopoietic cell transplantation (HCT) for 91 patients with hemophagocytic lymphohistiocytosis (HLH) transplanted in the US in 1989-2005. Fifty-one percent were <1 year at HCT and 29% had Lansky performance scores<90%. Most (80%) were conditioned with BU, CY, and etoposide (VP16) with or without anti-thymocyte globulin. Bone marrow was the predominant graft source. Neutrophil recovery was 91% at day-42. The probabilities of grades 2-4 acute GVHD at day-100 and chronic GVHD at 5 years were 41 and 23%, respectively. The overall mortality rate was higher in patients who did not receive BU/CY/VP16-conditioning regimen (RR 1.95, P=0.035). The 5-year probability of overall survival was 53% in patients who received BU/CY/VP16 compared to 24% in those who received other regimens. In the subset of patients with known disease-specific characteristics, only one of five patients with active disease at HCT is alive. For those in clinical remission at HCT (n=46), the 5-year probability of overall survival was 49%. Early mortality rates after HCT were high, 35% at day-100. These data demonstrate that a BU/CY/VP16-conditioning regimen provides cure in approximately 50% of patients and future studies should explore strategies to lower early mortality.