Hyperammonemia Secondary to 5-Fluorouracil.

5-fluorouracil (5-FU) is one of the most common adjuvant antineoplastic agents used in the treatment of localized and metastatic colon cancer. Frequent side effects of 5-FU include myelosuppression, mucositis, nausea, vomiting, and diarrhea. However, hyperammonemic encephalopathy is a rare neurologic toxicity that can occur after 5-FU chemotherapy administration. Patients with 5-FU-induced hyperammonemic encephalopathy often exhibit symptoms of altered mental status with no radiologic abnormalities or laboratory abnormalities except for significantly elevated ammonia levels with occasional lactic acidosis and respiratory alkalosis. We report a case of a patient with stage IV colon adenocarcinoma who experienced altered state of consciousness due to hyperammonemia during the administration of palliative chemotherapy with 5-FU, bevacizumab, and leucovorin. On cycle 1 day 2 of chemotherapy, the patient became drowsy and confused at home, prompting a visit to the emergency department and ultimately hospital admission. Laboratory tests revealed an elevated blood ammonia level (838 µg/dL). After an extensive negative workup, his altered state of consciousness was thought to be secondary to 5-FU-induced hyperammonemia. Upon admission, 5-FU was immediately discontinued and the patient was treated with lactulose enemas, intravenous fluids, rifaximin, and continuous renal replacement therapy with gradual recovery to baseline mental status. It is crucial for advanced practitioners to be aware of this rare side effect to ensure prompt diagnosis and maximize treatment effectiveness.

Are tuberculosis patients in a tertiary care hospital in Hyderabad, India being managed according to national guidelines?

SETTING: A tertiary health care facility (Government General and Chest hospital) in Hyderabad, India. OBJECTIVES: To assess a) the extent of compliance of specialists to standardized national (RNTCP) tuberculosis management guidelines and b) if patients on discharge from hospital were being appropriately linked up with peripheral health facilities for continuation of anti-Tuberculosis (TB) treatment. METHODS: A descriptive study using routine programme data and involving all TB patients admitted to inpatient care from 1(st) January to 30(th) June, 2010. RESULTS AND CONCLUSIONS: There were a total of 3120 patients admitted of whom, 1218 (39%) required anti-TB treatment. Of these 1104 (98%) were treated with one of the RNTCP recommended regimens, while 28 (2%) were treated with non-RNTCP regimens. The latter included individually tailored MDR-TB treatment regimens for 19 patients and adhoc regimens for nine patients. A total of 957 (86%) patients were eventually discharged from the hospital of whom 921 (96%) had a referral form filled for continuing treatment at a peripheral health facility. Formal feedback from peripheral health facilities on continuation of TB treatment was received for 682 (74%) patients. In a tertiary health facility with specialists the great majority of TB patients are managed in line with national guidelines. However a number of short-comings were revealed and measures to rectify these are discussed.

Operational challenges in diagnosing multi-drug resistant TB and initiating treatment in Andhra Pradesh, India.

BACKGROUND: Revised National TB Control Programme (RNTCP), Andhra Pradesh, India. There is limited information on whether MDR-TB suspects are identified, undergo diagnostic assessment and are initiated on treatment according to the programme guidelines. OBJECTIVES: To assess i) using the programme definition, the number and proportion of MDR-TB suspects in a large cohort of TB patients on first-line treatment under RNTCP ii) the proportion of these MDR-TB suspects who underwent diagnosis for MDR-TB and iii) the number and proportion of those diagnosed as MDR-TB who were successfully initiated on treatment. METHODS: A retrospective cohort analysis, by reviewing RNTCP records and reports, was conducted in four districts of Andhra Pradesh, India, among patients registered for first line treatment during October 2008 to December 2009. RESULTS: Among 23,999 TB patients registered for treatment there were 559 (2%) MDR-TB suspects (according to programme definition) of which 307 (55%) underwent diagnosis and amongst these 169 (55%) were found to be MDR-TB. Of the MDR-TB patients, 112 (66%) were successfully initiated on treatment. Amongst those eligible for MDR-TB services, significant proportions are lost during the diagnostic and treatment initiation pathway due to a variety of operational challenges. The programme needs to urgently address these challenges for effective delivery and utilisation of the MDR-TB services.

Three kinships with ALAS2 P520L (c. 1559 C --> T) mutation, two in association with severe iron overload, and one with sideroblastic anemia and severe iron overload.

Mutations in aminolevulinate synthase 2 (ALAS2) are usually associated with sideroblastic anemia and iron overload. The objective of this study was to determine if "mild" mutations in ALAS2 might increase the severity of primary iron overload. Direct sequencing of the ALAS2 gene was performed on 24 subjects with primary hemochromatosis and one subject with sideroblastic anemia with severe iron overload. We identified a novel mutation P520L (c. 1559 C --> T) in ALAS2 in three subjects. Two had severe iron overload and no anemia: one also had HFE C282Y homozygosity, and the other was wildtype for HFE and other iron-related genes. The third subject had sideroblastic anemia with iron overload, and was hemizygous for both P520L and R560H (c. 1679 G --> A) mutations in ALAS2. The P520L mutation was found at a frequency of 0.0013 (741 alleles) in white control subjects, but was not found in 158 alleles from black control subjects. The proline in this position is highly conserved across species from humans to zebrafish. However, genotype/phenotype studies of the families demonstrate that the P520L mutation alone has no iron-associated phenotype, but it may act as a modifier of iron overload in the presence of mutations in HFE or other uncharacterized hemochromatosis genes. Thus, ALAS2 mutations might contribute to more severe iron loading in persons with primary hemochromatosis.

Genetic abnormalities and juvenile hemochromatosis: mutations of the HJV gene encoding hemojuvelin.

Juvenile hemochromatosis is an early-onset form of iron storage disease characterized by hypogonadotrophic hypogonadism and cardiomyopathy. Recently, the putative causative gene (LOC148738) encoding a protein designated hemojuvelin was cloned. The previously proposed designation of this gene as HFE2 is contrary to established convention, because it is not a member of the HFE family. We suggest that it be designated HJV. We sequenced this gene in members of 2 previously reported kinships that manifest typical juvenile hemochromatosis. In one kinship, 2 previously undescribed mutations of HJV were identified, c.238T>C (C80R) and c.302T>C (L101P). In the second kinship, 2 previously identified mutations, G320V and I222N, were found. These studies confirm that mutations in HJV cause juvenile hemochromatosis.

Quantitative real-time RT-PCR analysis of PML-RAR alpha mRNA in acute promyelocytic leukemia: assessment of prognostic significance in adult patients from intergroup protocol 0129.

The potential prognostic value of quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR [qrtPCR]) measurements of PML-RAR alpha mRNA in acute promyelocytic leukemia was retrospectively assessed before treatment and at 3 posttreatment intervals in 123 patients on intergroup protocol 0129. The primary measure was the PML-RAR alpha(GAPDH) normalized quotient (NQ), that is, PML-RAR alpha mRNA copies divided by glyceraldehyde-3'-phosphate dehydrogenase (GAPDH) mRNA copies. Only samples with more than 2.5 x 10(5) copies of the housekeeping gene GAPDH mRNA (detection sensitivity exceeding 10(4)) were considered NQ evaluable. With RNA from low-density selected cells, paired peripheral blood (PB) and bone marrow samples (n = 140) had comparable NQs (P <.001). Before treatment, high NQ was associated with short-form PML-RAR alpha (P <.001), but not with white blood cell count or clinical outcome. Following treatment, NQ was lower in all-trans retinoic acid-induced complete remission (CR) than chemotherapy-induced CR (P =.018) and at first test after consolidation chemotherapy (P =.037). After consolidation chemotherapy, patients with NQ exceeding 10(-5) had 4.1-fold increased relapse risk (P =.008); however, 73% of patients who experienced relapse had NQ lower than 10(-5). In the follow-up period (FUP), any NQ exceeding 10(-5) and 10(-6) had 17.5-fold and 7.6-fold increased relapse risk, respectively (P <.001), while no gradation of relapse risk (approximately 18%) could be identified at NQ lower than 10(-6), including NQ(-). These results indicate that qrtPCR monitoring of PML-RAR alpha NQ can identify patients at high risk of relapse and suggest that clinically practical PB NQ monitoring at more frequent FUP intervals may improve predictive accuracy for relapse or continuing CR in patients with persistent, fluctuating minimal residual disease levels.

Juvenile hemochromatosis in the southeastern United States: a report of seven cases in two kinships.

We report clinical and genetic characteristics of seven juvenile hemochromatosis (JH) patients (six females, one male) in two unrelated kinships from the southeastern U.S. All had severe iron overload. Mean age at diagnosis was 20 +/- 5 years (range 8-23 years). In six patients, the mean age at onset of signs and symptoms attributable to iron overload was 15 +/- 2 years (12-18 years); an 8-year-old girl had no symptoms. Six of the seven patients had hypogonadotrophic hypogonadism, two had severe cardiomyopathy, seven had hepatomegaly, two had hepatic cirrhosis, and five had hyperpigmentation. Two of four siblings with JH also had Hashimoto thyroiditis. One patient with severe cardiomyopathy improved with therapeutic phlebotomy, medical therapy for congestive heart failure, and a permanent pacemaker; the other died before phlebotomy was initiated. Estimates of average daily iron absorption before phlebotomy-induced iron depletion were 2.3, 3.1, and 1.7 mg in a male and two females, respectively. Both parents of four siblings with JH were heterozygous at two Ch1q loci (D1S1156, D1S2344); each of the four affected siblings was homozygous at both loci. An unaffected sib was heterozygous at D1S1156. One patient was heterozygous for HFE H63D, five others did not have HFE C282Y or H63D, and one was unavailable for testing. We conclude that JH occurs in the southeastern U.S. It is likely that JH allele(s) in at least one of the present kinships occur(s) on Ch1q, and presumably this represents a mutation(s) of the same gene localized to Ch1q in Italian and Greek JH kindreds. The present cases do not have HFE genotypes typical of hemochromatosis diagnosed in adults. Hashimoto thyroiditis, linked to Ch6p in many kinships, did not segregate with JH alleles on Ch1q in the present kinship.