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.

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.

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.