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Biomedical subjects

Ali S Alzahrani

Publications and source records attributed to Ali S Alzahrani.

13 recordsLinked to original sources
PubMed2006

Clinical case seminar: metastatic follicular thyroid carcinoma arising from congenital goiter as a result of a novel splice donor site mutation in the thyroglobulin gene.

CONTEXT: Defects in thyroglobulin (Tg) synthesis are one of the causes of thyroid dyshormonogenesis. Only a few mutations in the Tg gene have been described. OBJECTIVES: We describe a novel Tg gene mutation and discuss the mechanisms by which it causes dyshormonogenesis with subsequent malignant transformation. CASES: Two siblings aged 21 and 19 yr presented with recurrent goiters for which they had undergone multiple thyroid surgeries since early childhood. The older sibling was diagnosed with metastatic follicular thyroid carcinoma at age 15 yr. METHODS: The entire coding region and intron-exon boundaries of the Tg gene were amplified and sequenced from the patients. We also sequenced the boundaries of exon 5 and intron 5 from both parents. RT-PCR amplification of a cDNA fragment encompassing exons 4-6 was also performed. RESULTS: A homozygous G to A point mutation at position +1 of the splice donor site of intron 5 (g.IVS5+1G-->A) was detected in both patients, whereas a monoallelic mutation was found in their parents. RT-PCR amplification of a cDNA fragment covering exons 4-6 revealed a 191-bp fragment in the patients and 351- and 191-bp fragments in the parents. Sequence analysis of these two fragments confirmed deletion of exon 5 in the 191-bp fragment. CONCLUSIONS: Aberrant splicing occurred as a result of the g.IVS5+1G-->A mutation, which caused fusion of exons 4 and 6, resulting in the frame shift at codon position 141 and a premature stop codon at position 147 (FS141-->147X). The malignant transformation is likely a result of prolonged TSH stimulation.

Adenocarcinoma, Follicular↗
PubMed2006

Thiamine transporter mutation: an example of monogenic diabetes mellitus.

OBJECTIVE: Thiamine-responsive megaloblastic anemia (TRMA) is a rare syndrome characterized by diabetes mellitus (DM), anemia, and sensorineural deafness. We describe the clinical course and the molecular defect of a young woman who was diagnosed to have this syndrome. CASE: The patient is an 18-year-old girl who was born to non-consanguous parents. She was noted to be deaf-mute in the first year of life. She was diagnosed with DM at the age of 9 months and with severe anemia at the age of 2 years. An extensive work up could not identify the cause. She was treated with blood transfusions every 3-4 weeks for the past 16 years. A diagnosis of TRMA was suspected and the patient was treated with thiamine hydrochloride. Hemoglobin and platelets increased to normal values after a few weeks of thiamine therapy. Diabetic control significantly improved but she had no noticeable changes in the deafness. METHODS: Peripheral blood DNA was extracted from the patient, her mother, aunt, and a healthy sister. Exons and exon-intron boundaries of the thiamine transporter gene SLC19A2 were PCR amplified and directly sequenced. RESULTS: A G515C homozygous mutation was identified in the SLC19A2 gene of the patient. This mutation changes Gly to Arg at codon 172 (G172R). The mother, an aunt, and a sister had a heterozygous G172R mutation. CONCLUSIONS: Mutations in thiamine transporter gene, SLC19A2, causes a rare form of monogenic diabetes, anemia, and sensorineural deafness. Thiamine induces a remarkable hematological response and improvement in the diabetic control but has no effect on deafness.

Adolescent↗
PubMed2005

High frequency of somatic mitochondrial DNA mutations in human thyroid carcinomas and complex I respiratory defect in thyroid cancer cell lines.

Significant progress has been made to elucidate the molecular mechanisms that determine thyroid tumor development and progression. However, most investigations have mainly focused on the genetic alterations of nuclear DNA. The potential role of mitochondrial DNA (mtDNA) mutations in thyroid tumorigenesis is not well defined. In the present study, we investigated the frequency of mtDNA mutations in 24 thyroid tumor specimens (19 primary papillary thyroid carcinomas (PTC), one follicular thyroid carcinoma, and four multinodular hyperplasias) and four thyroid cancer cell lines by sequencing the entire coding regions of mitochondrial genome. Among the 19 PTC samples tested, seven (36.8%) had somatic mutations. Somatic mtDNA mutations were also detected in one of four multinodular hyperplasias examined. All the thyroid tumor cell lines carried sequence variations that change amino acid and have not been reported previously as normal sequence variants. Flow cytometry analysis of mitochondria respiratory function in the thyroid tumor cell lines revealed a severe defect in mitochondrial complex I activity. The majority of the mutations was involved in genes located in the complex I of the mitochondrial genome. The mutations were either A --> G or C --> T transitions, often resulting in a change of a moderately or highly conserved amino acid of their corresponding protein. These data suggest that mtDNA mutations may play an important role in the thyroid tumorigenesis. Given that mtDNA mutation is present in the benign multinodular hyperplasia, it might be involved in the early stage of tumor development.

Carcinoma↗
PubMed2005

Repeated remissions of Cushing's disease due to recurrent infarctions of an ACTH-producing pituitary macroadenoma.

Infarction of prolactin-secreting or growth hormone-secreting pituitary adenomas is not unusual. However, Infarction of ACTH-secreting adenomas has rarely been reported. Cyclical course of Cushing's syndrome alternating with adrenal insufficiency due to recurrent infarction of an ACTH-secreting pituitary adenoma has not been reported. We report here a 20-year-old lady who presented with florid signs of Cushing's syndrome but was found to have adrenal insufficiency on biochemical evaluation. Magnetic resonance imaging (MRI) of the pituitary gland showed that she had infarction of an ACTH-secreting macroadenoma. Over the next 6 years, her disease ran a cyclical course characterized by periods of hypercortisolism alternating with adrenal insufficiency due to repeated episodes of infarctions of the ACTH-secreting pituitary macroadenoma with corresponding changes in the pituitary adenoma on serial MRIs. The case alerts clinicians to this possibility when a patient presents with clinical picture of Cushing's syndrome but has adrenal insufficiency on biochemical testing. It also suggests that silent or subclinical infarction of pituitary adenomas is not uncommon and is probably under diagnosed.

Adenoma↗
PubMed2005

Severe hypertension secondary to renal artery stenosis and Cushing's syndrome.

We present an unusual patient who simultaneously had severe renal artery stenosis RAS and Cushing's syndrome. The case highlights the difficulty of reaching a specific diagnosis of Cushing's syndrome and the possible interaction between Cushing's syndrome and some other concurrent illnesses that this patient had. A 37-year old man presented with severe hypertension HTN and uncontrolled diabetes mellitus DM without clear physical signs of Cushing's syndrome. He was found to have severe osteoporosis, proximal myopathy, several cutaneous warts, tinea versicolor, and chronic viral hepatitis. Captopril-stimulated renal scan and renal artery angiogram revealed severe RAS. Partial balloon dilatation of RAS led to improvement in HTN. Unexpectedly, urine free cortisol 24 hour was found extremely high. Serum adrenocorticotropic hormone ACTH was also elevated and high dose dexamethasone suppression tests were inconclusive. Several imaging studies failed to localize the source of ACTH. Despite normal MRI of the pituitary gland, bilateral inferior petrosal sinus sampling IPSS localized the source of ACTH secretion to the right side of the pituitary gland and right anterior hemihypophysectomy resulted in cure of Cushing's disease, HTN, DM, and tinea versicolor with significant improvement in cutaneous warts, osteoporosis, and chronic hepatitis. In conclusion, RAS and Cushing's syndrome may occur together. Significant hypercortisolemia can occur without clear signs of Cushing's syndrome. Controlling hypercortisolemia is of paramount importance when treating chronic infections in patients with Cushing's syndrome.

Adrenocorticotropic Hormone↗
PubMed2004

Preoperative neck ultrasonographic mapping for persistent/recurrent papillary thyroid cancer.

Surgical resection of persistent/recurrent (P/R) papillary thyroid cancer (PTC), when localized to the neck, is generally recommended; however, its impact on the course of the disease is not clear. We introduced a new technique in the form of preoperative neck ultrasonographic mapping (US-M) to improve the outcome of the surgical resection of P/R PTC. A total of 19 patients had undergone regional (central, lateral, or both) neck dissection before introducing the current technique (group 1, or G1), and 26 patients (group 2, or G2) had limited lymph node resection guided by US-M with findings accurately plotted on a standard diagram. All of the operations were performed by a single surgeon. The surgical outcomes of the two groups were compared. The resected lesions were positive for PTC in 17 patients (89.5%) in G1 and in 25 patients (96.2%) in G2. In G2, the intraoperative findings exactly matched the US-M in 23 patients (88.5%). Postoperatively, neck US became negative in 50% in G1 and in 83.3% in G2 (p = 0.02). Thyroglobulin (Tg) became undetectable in 37.5% in G1 and 52.3% in G2 (p = 0.37). Whole-body iodine scans (WBS) became negative in one of six patients (16.7%) in G1, and in three of four patients (75%) in G2, (p = 0.06). After a mean follow-up of 23.8+/-7.1 months in G1 and 9.8+/-4.7 months in G2, 6 patients (31.6%) in G1 and 15 patients (62.5%) in G2 were in remission (p = 0.04), whereas the disease persisted in 13 cases (68.4%) in G1 and 9 (37.5%) in G2 (p = 0.04). In conclusion, US-M improved the surgical outcome, as evidenced by the postoperative US, Tg, and WBS findings and the higher remission rate for the G2 patients than for the G1 patients.

Adult↗
PubMed2002

Frequency and predictive factors of malignancy in residual thyroid tissue and cervical lymph nodes after partial thyroidectomy for differentiated thyroid cancer.

BACKGROUND: The extent of surgery in differentiated thyroid cancer (DTC) has been a controversial issue. Total thyroidectomy potentially carries a higher operative risk, whereas partial thyroidectomy has the risk of leaving significant residual malignancy. The aim of this study was to assess the frequency and potential predictive factors of malignancy in the residual thyroid tissue and the cervical lymph nodes (CLN) in patients with DTC who had partial thyroid surgery and subsequently underwent completion thyroidectomy and/or modified neck dissection. Age, gender, pressure symptoms, duration of symptoms, size of the original tumor, tumor multifocality, perithyroidal tumor extension, soft tissue invasion, and serum thyroglobulin (Tg) level after first surgery were analyzed as potential predictive factors for the presence of malignancy in the thyroid remnant and the CLN. METHODS: We retrospectively reviewed the medical and pathologic data of 101 cases of DTC; 97 had papillary and 4 had follicular thyroid cancer. On the initial surgery, the median tumor size was 2.5 cm (range, 0.5 to 8.5 cm). Tumor multifocality occurred in 28 cases, perithyroidal tumor extension in 26 cases, and soft tissue invasion in 9 cases. Completion thyroidectomy was performed in 100 cases and modified neck dissection in 90 cases. RESULTS: On completion neck surgery, 39 patients had evidence of malignancy in the residual thyroid tissue and 36 patients in the CLN. In 23 (22.7%) cases, malignancy was present in both CLN and residual thyroid tissue. Only tumor multifocality and Tg level greater than 20 ng/mL after first surgery were predictive of the presence of malignancy in the thyroid remnant, whereas age older than 40 years, soft tissue invasion, perithyroidal tumor extension, and Tg level greater than 20 ng/mL were predictive of malignancy in CLN. CONCLUSIONS: Residual malignancy is common after partial thyroid surgery for DTC. Tumor multifocality and Tg level may be predictive of its presence in residual thyroid tissue. Age, perithyroidal tumor extension, soft tissue invasion, and Tg level are predictive of the presence of lymph node metastases.

Adolescent↗
PubMedDate not supplied

Is subclinical hypothyroidism associated with hyperhomocysteinemia?

OBJECTIVE: To evaluate whether subclinical hypothyroidism is associated with hyperhomocysteinemia, in an attempt to determine whether hyperhomocysteinemia may explain the observed increased risk of coronary artery disease in patients with subclinical hypothyroidism, as has been shown in patients with overt hypothyroidism. METHODS: We prospectively enrolled consecutive patients with newly diagnosed subclinical hypothyroidism and a parallel group of euthyroid control subjects in this study. Subclinical hypothyroidism was defined as high thyrotropin and normal free thyroxine levels. Fasting plasma total homocysteine, thyrotropin, and free thyroxine levels were measured in all participants, and persistent subclinical hypothyroidism was confirmed at least once. RESULTS: Forty-seven patients (42 women and 5 men; mean age, 38 +/- 15 years) with subclinical hypothyroidism and 50 control subjects (46 women and 4 men; mean age, 34 +/- 10 years) were enrolled in the study. The manufacturer's reference range for the total homocysteine assay was 5 to 15 micromol/L, and we defined our own reference range as 3.9 to 10.8 micromol/L. The mean values (+/-SE) for total homocysteine in patients and control subjects were 7.44 +/- 0.5 micromol/L and 7.22 +/- 0.2 micromol/L, respectively (P = 0.68). CONCLUSION: In this study, we found no association between subclinical hypothyroidism and hyperhomocysteinemia. Other contributing factors, such as associated hyperlipidemia, may explain the observed increased risk of coronary artery disease in patients with subclinical hypothyroidism.

Adult↗
PubMedDate not supplied

Diagnostic accuracy of high-resolution neck ultrasonography in the follow-up of differentiated thyroid cancer: a prospective study.

OBJECTIVE: To conduct a prospective study of the diagnostic value of features of cervical lymph nodes (large size, central location, abnormal shape, cystic changes, calcifications, and loss of echogenic hilum), assessed by neck ultrasonography (US), in patients scheduled for surgical treatment of persistent or recurrent differentiated thyroid cancer. METHODS: We studied 152 US abnormalities in 42 patients (median age, 38.5 years) who had undergone one or more neck operations, with or without radioiodine therapy, but continued to have persistent or recurrent disease, which was confirmed by fine-needle aspiration. Another surgical procedure was planned for these patients. On the day of operation, patients underwent a detailed US neck examination by an experienced radiologist. US abnormalities were plotted on a standard diagram of the neck and given specific numbers to help track them during surgical intervention and histopathologic examinations. The US features were compared with the final histopathologic diagnosis. RESULTS: Of 152 US abnormalities, 127 involved cervical lymph nodes and 25 involved other types of tissue. In univariate analysis, size, absent echogenic hilum, cystic changes, calcifications, and central location (medial to the sternomastoid muscle) of cervical lymph nodes were significantly associated with the presence of metastatic involvement. In multivariate analysis, only central location (odds ratio, 4.07; 95% confidence interval [CI], 1.64 to 10.10) and size (odds ratio, 5.14; 95% CI, 1.64 to 16.06) remained significant. The receiver operating characteristic curve for the size of lymph nodes showed a large area under the curve of 0.77 (95% CI, 0.68 to 0.85), and a size of 7.5 mm showed the highest sensitivity and specificity. CONCLUSION: Size and central location of cervical lymph nodes assessed by US during follow-up of patients with differentiated thyroid cancer were the most important predictors of presence of metastatic disease.

Adolescent↗
PubMedDate not supplied

Role of [18F]fluorodeoxyglucose positron emission tomography in follow-up of differentiated thyroid cancer.

OBJECTIVE: To assess the diagnostic utility of [(18)F]flu-orodeoxyglucose positron emission tomography (FDG PET) in the follow-up of patients with differentiated thyroid cancer (DTC). METHODS: In this study, we used strict definitions of presence and absence of the disease and performed all FDG PET scans while the patients were not taking levothyroxine (LT4). We report the results of conventional FDG PET scans obtained during the follow-up of 50 nonselected patients with DTC (34 female and 16 male patients; median age, 40.5 years; range, 18 to 68). All FDG PET scans and measurement of thyroglobulin (Tg) levels were performed while the patients were not taking LT4 (thyrotropin>or=25 microIU/mL). Tg antibodies were negative in all patients. The initial surgical procedure was total thyroidectomy in all cases, and 26 patients underwent additional operations (2 to 4 procedures). Radioactive iodine (131I) therapy was given to 48 patients (median dose, 5,550 MBq). In 42 patients, FDG PET was used for evaluation of Tg-positive (Tg>2 ng/mL in the absence of LT4 therapy), scan-negative disease. In 8 patients, Tg was 2 ng/mL without LT4 therapy) for >1 year. Disease was considered absent if Tg was <or=2 ng/mL and at least all the following imaging studies were negative: diagnostic radioiodine whole-body scan, chest radiography or spiral computed tomography of the chest, and high-resolution neck ultrasonography. If all these criteria were present, a positive FDG PET scan was considered a false-positive study. RESULTS: FDG PET scans were positive in 27 patients (54%) and negative in 23 (46%). FDG PET results were true-positive in 26 cases, false-positive in 1, true-negative in 7, and false-negative in 16. The sensitivity, specificity, and positive and negative predictive values were 61.9%, 87.5%, 96.3%, and 30.4%, respectively. CONCLUSION: FDG PET scanning is moderately sensitive and specific for detection of persistent or recurrent DTC.

Adolescent↗