Clinical Focus

  • Anatomic/Clinical Pathology
  • Clinical Chemistry & Immunology

Academic Appointments

Administrative Appointments

  • Member, Editorial Board,, American Association for Clinical Chemistry (2013 - Present)
  • Chair, Division Management Group, American Association for Clinical Chemistry (2012 - Present)
  • Member, Chemistry Resource Committee, College of American Pathologists (2008 - Present)
  • Member, Council for Scientific Affairs, College of American Pathologists (2008 - Present)

Honors & Awards

  • Outstanding Contributions to Clinical Chemistry in Education, AACC, Northern California Section (2008)
  • Outstanding Speaker Award, American Association for Clinical Chemistry (2005 & 2006)
  • Harold van Remortel Service Award, AACC, Northern California Section (2005)
  • Lifetime Achievement Award (Immunology Laboratory Manual), Harvard Medical School (2000)

Professional Education

  • Residency:Massachusetts General Hospital (1980) MA
  • Fellowship:Massachusetts General Hospital (1979) MA
  • Board Certification: Anatomic/Clinical Pathology, American Board of Pathology (1982)
  • Internship:Massachusetts General Hospital (1976) MA
  • Medical Education:Hahnemann University - Medical College of PA (1975) PA
  • MD, Drexel University, Medicine (1975)


2014-15 Courses


Journal Articles

  • Fetal atrioventricular heart block. Clinical chemistry DiMaio, M. A., Faix, J. D. 2014; 60 (9): 1153-1155

    View details for DOI 10.1373/clinchem.2013.212035

    View details for PubMedID 25170164

  • A Progress Report of the IFCC Committee for Standardization of Thyroid Function Tests. European thyroid journal Thienpont, L. M., Van Uytfanghe, K., Van Houcke, S., Das, B., Faix, J. D., MacKenzie, F., Quinn, F. A., Rottmann, M., Van den Bruel, A. 2014; 3 (2): 109-116


    The IFCC Committee for Standardization of Thyroid Function Tests aims at equivalence of laboratory test results for free thyroxine (FT4) and thyrotropin (TSH).This report describes the phase III method comparison study with clinical samples representing a broad spectrum of thyroid disease. The objective was to expand the feasibility work and explore the impact of standardization/harmonization in the clinically relevant concentration range.Two sets of serum samples (74 for FT4, 94 for TSH) were obtained in a clinical setting. Eight manufacturers participated in the study (with 13 FT4 and 14 TSH assays). Targets for FT4 were set by the international conventional reference measurement procedure of the IFCC; those for TSH were based on the all-procedure trimmed mean. The manufacturers recalibrated their assays against these targets.All FT4 assays were negatively biased in the mid- to high concentration range, with a maximum interassay discrepancy of approximately 30%. However, in the low range, the maximum deviation was approximately 90%. For TSH, interassay comparability was reasonable in the mid-concentration range, but worse in the pathophysiological ranges. Recalibration was able to eliminate the interassay differences, so that the remaining dispersion of the data was nearly entirely due to within-assay random error components. The impact of recalibration on the numerical results was particularly high for FT4.Standardization and harmonization of FT4 and TSH measurements is feasible from a technical point of view. Because of the impact on the numerical values, the implementation needs careful preparation with the stakeholders.

    View details for DOI 10.1159/000358270

    View details for PubMedID 25114874

  • Principles and pitfalls of free hormone measurements BEST PRACTICE & RESEARCH CLINICAL ENDOCRINOLOGY & METABOLISM Faix, J. D. 2013; 27 (5): 631-645


    The free hormone hypothesis states that a hormone's physiological effects depend on the free hormone concentration, not the total hormone concentration. Although the in vivo relationship between free hormone and protein-bound hormone is complex, most experts have applied this view to the design of assays used to assess the free hormone concentration in the blood sampled for testing in vitro. The history of the measurement of free thyroxine, probably the most frequently requested free hormone determination, offers a good example of the approaches that have been taken. Methods that require physical separation of the free hormone from the protein-bound hormone must address both the potential disturbance in the equilibrium between the two, as well as the challenge of quantifying small levels of hormone accurately and precisely. The implementation of mass spectrometry in the clinical laboratory has helped to develop proposed reference measurement procedures. These must be utilized to standardize the variety of immunoassay approaches that currently represent options commercially available to the routine clinical laboratory. Practicing endocrinologists should discuss the details of the free hormone assays offered by the clinical laboratory they utilize for patient result reporting, and clinical laboratories should implement the recommendations of published guidelines to ensure that free hormone results using commercially available immunoassays are as accurate and precise as possible.

    View details for DOI 10.1016/j.beem.2013.06.007

    View details for Web of Science ID 000326314500002

    View details for PubMedID 24094635

  • Biomarkers of sepsis CRITICAL REVIEWS IN CLINICAL LABORATORY SCIENCES Faix, J. D. 2013; 50 (1): 23-36


    Sepsis is an unusual systemic reaction to what is sometimes an otherwise ordinary infection, and it probably represents a pattern of response by the immune system to injury. A hyper-inflammatory response is followed by an immunosuppressive phase during which multiple organ dysfunction is present and the patient is susceptible to nosocomial infection. Biomarkers to diagnose sepsis may allow early intervention which, although primarily supportive, can reduce the risk of death. Although lactate is currently the most commonly used biomarker to identify sepsis, other biomarkers may help to enhance lactate's effectiveness; these include markers of the hyper-inflammatory phase of sepsis, such as pro-inflammatory cytokines and chemokines; proteins such as C-reactive protein and procalcitonin which are synthesized in response to infection and inflammation; and markers of neutrophil and monocyte activation. Recently, markers of the immunosuppressive phase of sepsis, such as anti-inflammatory cytokines, and alterations of the cell surface markers of monocytes and lymphocytes have been examined. Combinations of pro- and anti-inflammatory biomarkers in a multi-marker panel may help identify patients who are developing severe sepsis before organ dysfunction has advanced too far. Combined with innovative approaches to treatment that target the immunosuppressive phase, these biomarkers may help to reduce the mortality rate associated with severe sepsis which, despite advances in supportive measures, remains high.

    View details for DOI 10.3109/10408363.2013.764490

    View details for Web of Science ID 000316126300002

    View details for PubMedID 23480440

  • Commentary. Clinical chemistry Faix, J. D. 2011; 57 (12): 1649-?

    View details for DOI 10.1373/clinchem.2011.167445

    View details for PubMedID 22125319

  • Established and novel biomarkers of sepsis BIOMARKERS IN MEDICINE Faix, J. D. 2011; 5 (2): 117-130


    The increased incidence of sepsis, a systemic response to infection that occurs in some patients, has stimulated interest in identifying infected patients who are at risk and intervening early. When this condition progresses to severe sepsis (characterized by organ dysfunction), mortality is high. Hospitals that have implemented recommendations of the Surviving Sepsis Campaign have seen a reduction in mortality rate for hospital-acquired severe sepsis. They may reduce this further by focusing on new approaches to diagnosing sepsis, especially at an early stage. Sepsis is a complicated syndrome with many physiological derangements and many emerging laboratory markers of sepsis have been proposed as adjuncts to clinical evaluation. The list includes cytokines, acute phase proteins, neutrophil activation markers, markers of abnormal coagulation and, recently, markers of suppression of both the innate and adaptive immune response. The perfect biomarker would accurately identify patients at risk of developing severe sepsis and then guide targeted therapy.

    View details for DOI 10.2217/BMM.11.21

    View details for Web of Science ID 000290598000003

    View details for PubMedID 21473716

  • Vancomycin plasma concentrations in cardiac surgery with the use of profound hypothermic circulatory arrest EUROPEAN JOURNAL OF CARDIO-THORACIC SURGERY van der Starre, P. J., Kolz, M., Lemmens, H. J., Faix, J. D., Mitchell, S., Miller, C. 2010; 38 (6): 741-744


    This study was undertaken to compare the effect of deep hypothermic circulatory arrest, compared with moderate hypothermia, on the plasma concentrations and pharmacokinetic profile of vancomycin, administered as prophylaxis, in patients undergoing cardiac surgery with cardiopulmonary bypass.Two groups of adult cardiac surgery patients were prospectively studied. One group consisted of 12 patients undergoing valvular surgery with moderate hypothermia, and another group was of 12 patients undergoing surgery with the use of profound hypothermic circulatory arrest. Vancomycin was administered before skin incision, and plasma levels were measured at regular intervals for 24h.The plasma concentrations of vancomycin showed a similar pattern in both groups. The pharmacokinetic profile showed a three-compartment model in both groups.The dosing of vancomycin, if used as antibiotic prophylaxis, does not need to be adjusted in cardiac surgery patients when undergoing profound hypothermic circulatory arrest, since the plasma concentrations and pharmacokinetic profile are similar to patients with moderate hypothermia. The pharmacokinetic profile, consisting of three compartments, was not changed by the differences in temperature.

    View details for DOI 10.1016/j.ejcts.2010.03.029

    View details for Web of Science ID 000285221700018

    View details for PubMedID 20663677

  • Report of the IFCC Working Group for Standardization of Thyroid Function Tests; Part 3: Total Thyroxine and Total Triiodothyronine CLINICAL CHEMISTRY Thienpont, L. M., Van Uytfanghe, K., Beastall, G., Faix, J. D., Ieiri, T., Miller, W. G., Nelson, J. C., Ronin, C., Ross, H. A., Thijssen, J. H., Toussaint, B. 2010; 56 (6): 921-929


    Because total thyroid hormone testing is performed on many automated clinical chemistry instruments, the IFCC Scientific Division commissioned the Working Group for Standardization of Thyroid Function Tests to include total thyroxine (TT4) and total triiodothyronine (TT3) in its standardization efforts.Existing SI-traceable reference measurement procedures (RMPs) were used to assign TT4 and TT3 values to 40 single-donor serum samples for subsequent use in a method comparison study with 11 TT4 and 12 TT3 immunoassays. Data from comparison of each immunoassay with the RMPs provided a basis for mathematical assay recalibration.Seven TT4 assays had a mean bias within 10% of the RMP, but 2 deviated by an average of -12% and another 2 by +17%. All TT3 assays showed positive biases, 4 within and 8 outside 10%, up to 32%. Mathematical recalibration effectively eliminated assay-specific biases, but sample-related effects remained, particularly for TT3. Correlation coefficients with the RMPs ranged from 0.82 to 0.97 for TT4 and from 0.32 to 0.92 for TT3. The within-run and total imprecision ranges for TT4 were 1.4% to 9.1% and 3.0% to 9.4%, respectively, and for TT3 2.1% to 7.8% and 2.8% to 12.7%, respectively. Approximately one-half of the assays matched the internal QC targets within approximately 5%; however, we observed within-run drifts/shifts.The study showed that of the assays we examined, only 4 TT4 but the majority of the TT3 assays needed establishment of calibration traceability to the existing RMPs. Most assays performed well, but some would benefit from improved precision, within-run stability, and between-run consistency.

    View details for DOI 10.1373/clinchem.2009.140228

    View details for Web of Science ID 000278145000012

    View details for PubMedID 20395622

  • Report of the IFCC Working Group for Standardization of Thyroid Function Tests; Part 2: Free Thyroxine and Free Triiodothyronine CLINICAL CHEMISTRY Thienpont, L. M., Van Uytfanghe, K., Beastall, G., Faix, J. D., Ieiri, T., Miller, W. G., Nelson, J. C., Ronin, C., Ross, H. A., Thijssen, J. H., Toussaint, B. 2010; 56 (6): 912-920


    Free thyroxine (FT4) and free triiodothyronine (FT3) measurements are useful in the diagnosis and treatment of a variety of thyroid disorders. The IFCC Scientific Division established a Working Group to resolve issues of method performance to meet clinical requirements.We compared results for measurement of a panel of single donor sera using clinical laboratory procedures based on equilibrium dialysis-isotope dilution-mass spectrometry (ED-ID-MS) (2 for FT4, 1 for FT3) and immunoassays from 9 manufacturers (15 for FT4, 13 for FT3) to a candidate international conventional reference measurement procedure (cRMP) also based on ED-ID-MS.For FT4 (FT3), the mean bias of 2 (4) assays was within 10% of the cRMP, whereas for 15 (9) assays, negative biases up to -42% (-30%) were seen; 1 FT3 assay was positively biased by +22%. Recalibration to the cRMP eliminated assay-specific biases; however, sample-related effects remained, as judged from difference plots with biologic total error limits. Correlation coefficients to the cRMPs ranged for FT4 (FT3) from 0.92 to 0.78 (0.88 to 0.30). Within-run and total imprecision ranged for FT4 (FT3) from 1.0% to 11.1% (1.8% to 9.4%) and 1.5% to 14.1% (2.4% to 10.0%), respectively. Approximately half of the manufacturers matched the internal QC targets within approximately 5%; however, within-run instability was observed.The study showed that most assays had bias largely correctable by establishing calibration traceability to a cRMP and that the majority performed well. Some assays, however, would benefit from improved precision, within-run stability, and between-run consistency.

    View details for DOI 10.1373/clinchem.2009.140194

    View details for Web of Science ID 000278145000011

    View details for PubMedID 20395623

  • Report of the IFCC Working Group for Standardization of Thyroid Function Tests; Part 1: Thyroid-Stimulating Hormone CLINICAL CHEMISTRY Thienpont, L. M., Van Uytfanghe, K., Beastall, G., Faix, J. D., Ieiri, T., Miller, W. G., Nelson, J. C., Ronin, C., Ross, H. A., Thijssen, J. H., Toussaint, B. 2010; 56 (6): 902-911


    Laboratory testing of serum thyroid-stimulating hormone (TSH) is an essential tool for the diagnosis and management of various thyroid disorders whose collective prevalence lies between 4% and 8%. However, between-assay discrepancies in TSH results limit the application of clinical practice guidelines.We performed a method comparison study with 40 sera to assess the result comparability and performance attributes of 16 immunoassays.Thirteen of 16 assays gave mean results within 10% of the overall mean. The difference between the most extreme means was 39%. Assay-specific biases could be eliminated by recalibration to the overall mean. After recalibration of singlicate results, all assays showed results within the biological total error goal (22.8%), except for 1 result in each of 4 assays. For a sample with a TSH concentration of 0.016 mIU/L, 6 assays either did not report results or demonstrated CVs >20%. Within-run and total imprecision ranged from 1.5% to 5.5% and 2.5% to 7.7%, respectively. Most assays were able to match the internal QC targets within 5%. Within-run drifts and shifts were observed.Harmonization of TSH measurements would be particularly beneficial for 3 of the 16 examined assays. These data demonstrate that harmonization may be accomplished by establishing calibration traceability to the overall mean values for a panel of patient samples. However, the full impact of the approach must be further explored with a wider range of samples. Although a majority of assays showed excellent quality of performance, some would benefit from improved within-run stability.

    View details for DOI 10.1373/clinchem.2009.140178

    View details for Web of Science ID 000278145000010

    View details for PubMedID 20395624

  • Commentary. Clinical chemistry Faix, J. D. 2010; 56 (1): 19-?

    View details for DOI 10.1373/clinchem.2009.136788

    View details for PubMedID 20040625

  • Rapid blood separation is superior to fluoride for preventing in vitro reductions in measured blood glucose concentration JOURNAL OF CLINICAL PATHOLOGY Shi, R. Z., Seeley, E. S., Bowen, R., Faix, J. D. 2009; 62 (8): 752-753


    To determine whether tubes containing sodium fluoride negatively bias blood glucose concentration by directly comparing glucose concentrations in paired blood samples collected in tubes containing lithium heparin (Li-Heparin) and tubes containing sodium fluoride/potassium oxalate (NaF-KOx).Paired blood samples from a group of patients (n = 1040) were collected in tubes containing Li-Heparin and tubes containing NaF-KOx at the same time. All Li-Heparin samples were centrifuged soon after collection and were kept cool in transport along with NaF-KOx samples, which were centrifuged at the receiving location after an average transport time of 4 h, but immediately before analysis. Glucose concentrations in the paired samples were determined simultaneously by an automated oxidase method.The mean glucose concentrations for NaF-KOx samples and Li-Heparin samples were 5.7 mmol/l and 6.1 mmol/l, respectively, with a mean difference of 0.39 mmol/l.Rapid separation of heparinised blood is superior to fluoride alone for abrogating glycolytic effects on blood glucose measurements in the clinical laboratory.

    View details for DOI 10.1136/jcp.2008.062547

    View details for Web of Science ID 000268399100017

    View details for PubMedID 19638548

  • Using procalcitonin to diagnose sepsis and the potential for improved antibiotic stewardship. MLO: medical laboratory observer Faix, J. D. 2008; 40 (11): 25-26

    View details for PubMedID 19065938

  • Neurotensin increases mortality and mast cells reduce neurotensin levels in a mouse model of sepsis NATURE MEDICINE Piliponsky, A. M., Chen, C., Nishimura, T., Metz, M., Rios, E. J., Dobner, P. R., Wada, E., Wada, K., Zacharias, S., Mohanasundaram, U. M., Faix, J. D., Abrink, M., Pejler, G., Pearl, R. G., Tsai, M., Galli, S. J. 2008; 14 (4): 392-398


    Sepsis is a complex, incompletely understood and often fatal disorder, typically accompanied by hypotension, that is considered to represent a dysregulated host response to infection. Neurotensin (NT) is a 13-amino-acid peptide that, among its multiple effects, induces hypotension. We find that intraperitoneal and plasma concentrations of NT are increased in mice after severe cecal ligation and puncture (CLP), a model of sepsis, and that mice treated with a pharmacological antagonist of NT, or NT-deficient mice, show reduced mortality during severe CLP. In mice, mast cells can degrade NT and reduce NT-induced hypotension and CLP-associated mortality, and optimal expression of these effects requires mast cell expression of neurotensin receptor 1 and neurolysin. These findings show that NT contributes to sepsis-related mortality in mice during severe CLP and that mast cells can lower NT concentrations, and suggest that mast cell-dependent reduction in NT levels contributes to the ability of mast cells to enhance survival after CLP.

    View details for DOI 10.1038/nm1738

    View details for Web of Science ID 000254674100025

    View details for PubMedID 18376408

  • Lymphoplasmacytic lymphoma arising in the setting of hepatitis c and mixed Cryoglobulinemia JOURNAL OF CLINICAL ONCOLOGY Krishnan, C., Cupp, J. S., Arber, D. A., Faix, J. D. 2007; 25 (27): 4312-4314

    View details for DOI 10.1200/JCO.2007.12.8876

    View details for Web of Science ID 000251073200027

    View details for PubMedID 17878484

  • Proposal of a candidate international conventional reference measurement procedure for free thyroxine in serum CLINICAL CHEMISTRY AND LABORATORY MEDICINE Thienpont, L. M., Beastall, G., Christofides, N. D., Faix, J. D., Ieiri, T., Jarrige, V., Miller, W. G., Miller, R., Nelson, J. C., Ronin, C., Ross, H. A., Rottmann, M., Thijssen, J. H., Toussaint, B. 2007; 45 (7): 934-936


    In the present paper the IFCC WG-STFT recommends and provides the rationale to establish metrological traceability of serum free thyroxine (FT4) measurements to a candidate international conventional reference measurement procedure. It is proposed that this procedure be based on equilibrium dialysis combined with determination of thyroxine in the dialysate with a trueness-based reference measurement procedure. The measurand is thus operationally defined as "thyroxine in the dialysate from equilibrium dialysis of serum prepared under defined conditions". With regard to the trueness-based reference measurement procedure, the WG-STFT recommends use of an isotope dilution-liquid chromatography/tandem mass spectrometry (ID-LC/tandem MS) procedure for total thyroxine that has been optimized towards measurement at picomolar concentration levels and that is listed in the database of the Joint Committee for Traceability in Laboratory Medicine (JCTLM). For calibration, the purified thyroxine material IRMM-468 (resulting from a project funded by the European Commission and recently submitted to the JCTLM) is proposed. The WG-STFT stresses that according to this recommendation it is a prerequisite to strictly adhere to the defined equilibrium dialysis procedure, whereas it is permissible to introduce variants in the ID-LC/tandem MS procedure.

    View details for DOI 10.1515/CCLM.2007.155

    View details for Web of Science ID 000248542900026

    View details for PubMedID 17617044

  • Measurement of free thyroxine in laboratory medicine - proposal of measurand definition CLINICAL CHEMISTRY AND LABORATORY MEDICINE Thienpont, L. M., Beastall, G., Christofides, N. D., Faix, J. D., Ieiri, T., Miller, W. G., Miller, R., Nelson, J. C., Ross, H. A., Ronin, C., Rottmann, M., Thijssen, J. H., Toussaint, B. 2007; 45 (4): 563-564

    View details for DOI 10.1515/CCLM.2007.099

    View details for Web of Science ID 000246305100023

    View details for PubMedID 17439341

  • A noninvasive approach for assessing tumor hypoxia in xenografts: Developing a urinary marker for hypoxia CANCER RESEARCH Nelson, D. W., Cao, H. B., Zhu, Y. H., Sunar-Reeder, B., Choi, C. Y., Faix, J. D., Brown, J. M., Koong, A. C., Giaccia, A. J., Le, Q. T. 2005; 65 (14): 6151-6158


    Tumor hypoxia modifies the efficacy of conventional anticancer therapy and promotes malignant tumor progression. Human chorionic gonadotropin (hCG) is a glycoprotein secreted during pregnancy that has been used to monitor tumor burden in xenografts engineered to express this marker. We adapted this approach to use urinary beta-hCG as a secreted reporter protein for tumor hypoxia. We used a hypoxia-inducible promoter containing five tandem repeats of the hypoxia-response element (HRE) ligated upstream of the beta-hCG gene. This construct was stably integrated into two different cancer cell lines, FaDu, a human head and neck squamous cell carcinoma, and RKO, a human colorectal cancer cell line. In vitro studies showed that tumor cells stably transfected with this plasmid construct secrete beta-hCG in response to hypoxia or hypoxia-inducible factor 1alpha (HIF-1alpha) stabilizing agents. The hypoxia responsiveness of this construct can be blocked by treatment with agents that affect the HIF-1alpha pathways, including topotecan, 1-benzyl-3-(5'-hydroxymethyl-2'-furyl)indazole (YC-1), and flavopiridol. Immunofluorescent analysis of tumor sections and quantitative assessment with flow cytometry indicate colocalization between beta-hCG and 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamide (EF5) and beta-hCG and pimonidazole, two extrinsic markers for tumor hypoxia. Secretion of beta-hCG from xenografts that contain these stable constructs is directly responsive to changes in tumor oxygenation, including exposure of the animals to 10% O2 and tumor bed irradiation. Similarly, urinary beta-hCG levels decline after treatment with flavopiridol, an inhibitor of HIF-1 transactivation. This effect was observed only in tumor cells expressing a HRE-regulated reporter gene and not in tumor cells expressing a cytomegalovirus-regulated reporter gene. The 5HRE beta-hCG reporter system described here enables serial, noninvasive monitoring of tumor hypoxia in a mouse model by measuring a urinary reporter protein.

    View details for Web of Science ID 000230633400024

    View details for PubMedID 16024616

  • Iodine sufficiency and measurements of thyroid function in maternal hypothyroidism CLINICAL ENDOCRINOLOGY Mitchell, M. L., Klein, R. Z., SARGENT, J. D., Meter, R. A., Haddow, J. E., Waisbren, S. E., Faix, J. D. 2003; 58 (5): 612-616


    To test the hypothesis that thyroglobulin (Tg) and free T4 (FT4) concentrations more than 2SD from the control mean are not increased in pregnancy in an iodine replete area in the absence of elevated TSH concentrations. The second hypothesis to be tested was that if such abnormalities in FT4 and Tg in the absence of elevated TSH concentrations were to exist they would not be associated with lowered IQs in the progeny.Cross-sectional study in New England comparing TSH, Tg, antibodies to Tg and FT4 in volunteer nonpregnant women 20-40 years old with those in hypothyroid mothers and matched euthyroid control mothers. The results are contrasted with those from similar studies reported from iodine deficient areas.Sera obtained at 17 weeks gestation and stored at -20 degrees C for 8 years were retrieved and analysed from 62 mothers with subclinical hypothyroidism and 124 matched euthyroid mothers. The diagnosis of hypothyroidism was made by finding a TSH concentration > 97.7 percentiile for 25 000 consecutive pregnant women. Sera were also analysed from 53 healthy nonpregnant volunteer women aged 20-40 years.TSH, Tg and Tg antibodies were measured in the sera of the nonpregnant volunteers, and Tg and Tg antibodies in the sera of the pregnant women who had previously been analysed for TSH and FT4. The incidence of FT4 concentrations below the 2.3 percentile of nonpregnant laboratory controls was compared for the euthyroid and hypothyroid mothers and the laboratory normal controls.Thirty-one per cent of the 62 hypothyroid mothers had FT4 concentrations below the 2.3 percentile compared with only one (0.8%) of the euthyroid mothers. Mean Tg concentrations did not differ between the nonpregnant controls and the euthyroid pregnant women, 14 +/- 10 vs. 16 +/- 10 micro g/l. Tg concentration in the hypothyroid mothers was 44 +/- 61, significantly greater than for either of the euthyroid control groups, P < 0.005. Positive antibodies to Tg were found in 9% and 10% of the control groups and 57% of the hypothyroid mothers, P < 0.0005. When TSH is included as an independent variable in multiple linear and logistic regressions, FT4 and Tg no longer correlate significantly with IQs.The incidences of FT4 concentrations more than 2SD below the control mean and of Tg > 2SD above the control mean are significantly increased in hypothyroid mothers in iodlne-sufficient New England. However, in the absence of elevated TSH concentrations, the incidences of such abnormalities in FT4 and TG are negligible. Indeed, concentrations for FT4, Tg and Tg antibodies for nonpregnant and pregnant controls in our iodine-replete area do not differ significantly from each other or from previously reported normative concentrations with the methods used. Thus, pregnancy in New England neither increases Tg nor lowers FT4 concentrations.

    View details for Web of Science ID 000182305900012

    View details for PubMedID 12699443

  • Maternal thyroid deficiency and pregnancy complications: implications for population screening JOURNAL OF MEDICAL SCREENING Allan, W. C., Haddow, J. E., Palomaki, G. E., Williams, J. R., Mitchell, M. L., Hermos, R. J., Faix, J. D., Klein, R. Z. 2000; 7 (3): 127-130


    To examine the relation between certain pregnancy complications and thyroid stimulating hormone (TSH) measurements in a cohort of pregnant women.TSH was measured in sera obtained from women during the second trimester as part of routine prenatal care. Information was then collected about vaginal bleeding, premature delivery, low birthweight, abruptio placentae, pregnancy induced hypertension, need for cesarean section, low Apgar scores, and fetal and neonatal death.Among 9403 women with singleton pregnancies, TSH measurements were 6 mU/l or greater in 209 (2.2%). The rate of fetal death was significantly higher in those pregnancies (3.8%) than in the women with TSH less than 6 mU/l (0.9%, odds ratio 4.4, 95% confidence interval 1.9-9.5). Other pregnancy complications did not occur more frequently.From the second trimester onward, the major adverse obstetrical outcome associated with raised TSH in the general population is an increased rate of fetal death. If thyroid replacement treatment avoided this problem this would be another reason to consider population screening.

    View details for Web of Science ID 000165766900004

    View details for PubMedID 11126160

  • Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child NEW ENGLAND JOURNAL OF MEDICINE Haddow, J. E., Palomaki, G. E., Allan, W. C., Williams, J. R., Knight, G. J., Gagnon, J., O'Heir, C. E., Mitchell, M. L., Hermos, R. J., Waisbren, S. E., Faix, J. D., Klein, R. Z. 1999; 341 (8): 549-555


    When thyroid deficiency occurs simultaneously in a pregnant woman and her fetus, the child's neuropsychological development is adversely affected. Whether developmental problems occur when only the mother has hypothyroidism during pregnancy is not known.In 1996 and 1997, we measured thyrotropin in stored serum samples collected from 25,216 pregnant women between January 1987 and March 1990. We then located 47 women with serum thyrotropin concentrations at or above the 99.7th percentile of the values for all the pregnant women, 15 women with values between the 98th and 99.6th percentiles, inclusive, in combination with low thyroxine levels, and 124 matched women with normal values. Their seven-to-nine-year-old children, none of whom had hypothyroidism as newborns, underwent 15 tests relating to intelligence, attention, language, reading ability, school performance, and visual-motor performance.The children of the 62 women with high serum thyrotropin concentrations performed slightly less well on all 15 tests. Their full-scale IQ scores on the Wechsler Intelligence Scale for Children, third edition, averaged 4 points lower than those of the children of the 124 matched control women (P= 0.06); 15 percent had scores of 85 or less, as compared with 5 percent of the matched control children. Of the 62 women with thyroid deficiency, 48 were not treated for the condition during the pregnancy under study. The full-scale IQ scores of their children averaged 7 points lower than those of the 124 matched control children (P=0.005); 19 percent had scores of 85 or less. Eleven years after the pregnancy under study, 64 percent of the untreated women and 4 percent of the matched control women had confirmed hypothyroidism.Undiagnosed hypothyroidism in pregnant women may adversely affect their fetuses; therefore, screening for thyroid deficiency during pregnancy may be warranted.

    View details for Web of Science ID 000082061500001

    View details for PubMedID 10451459

  • Thyroid function in very low birth weight infants CLINICAL ENDOCRINOLOGY Klein, R. Z., Carlton, E. L., Faix, J. D., Frank, J. E., Hermos, R. J., MULLANEY, D., Nelson, J. C., Rojas, D. A., Mitchell, M. L. 1997; 47 (4): 411-417


    The purpose of this study was to test the hypothesis that low circulating thyroxine concentrations characteristic of very low birth weight (VLBW) neonates (< 1500 g) are the result of decreased protein binding of thyroid hormones and to elucidate the mechanism(s) responsible and possible significance thereof.Cross-sectional comparison of thyroid related measurements in cord blood specimens from VLBW infants and from full term infants. Longitudinal comparison in cord and 2- and 4-week blood specimens from VLBW infants.Cord blood specimens were analysed from 47 VLBW and 45 full term infants weighing > or = 2500 g. Repeat analyses in venous bloods from 32 of the VLBW infants were analysed at 2 weeks of age and again at 4 weeks in 23. The first cohort of patients was studied in 1994 and comprised 28 VLBW and 24 full term infants (Cohort A). The studies were repeated in 1995-96 in 19 VLBW infants and 21 full term infants (Cohort B).T4, free T4 (FT4), T3, thyroxine binding globulin (TBG), and TSH were measured in cord blood and 2- and 4-week venous specimens from VLBW infants and in cord blood specimens of full term infants. Molar ratios of T4/TBG were calculated.(1) Cord blood TBG, T4 and T3 concentrations of VLBW infants were each 60% of those of term infants. TBG concentrations were 397 +/- 111 vs 680 +/- 172 nmol/l (P < 0.0005). T4 concentrations were 76 +/- 22 vs 139 +/- 26 nmol/l (P < 0.0005). FT4 concentrations were in the normal adult range in both neonatal groups. T4/TBG ratios did not differ between the neonatal groups but were significantly less than that of adults (P < 0.001). (2) TSH concentrations in VLBW infants at 2 and 4 weeks were less than 50% of cord blood values. At 2 weeks, TBG concentrations of VLBW infants were unchanged from cord blood concentrations but mean T4 concentration fell by 18% and T4/TBG ratios by 21% (P < 0.005). Mean FT4 rose by 78% (P < 0.02). The changes in mean T4 and FT4 were due largely to FT4 concentrations of 37-113 pmol/l and T4 concentrations of 13-48 nmol/l in 5 infants. These infants also had lower T4/TBG ratios and were smaller and more ill than the remainder of the cohort. The changes disappeared by 4 weeks in 3 of the 4 infants tested.Cord T4/TBG ratios are the same in very low birth weight and term infants and are significantly lower than in adult blood. These are more than compensated for in term infants by a 236% increase in thyroxine binding globulin concentrations. The lower thyroxine binding globulin concentrations in very low birth weight infants explain their much lower T4 concentrations. Cord FT4 concentrations of full term and very low birth weight infants are in the normal adult range. T4 concentrations are further depressed and free T4 concentrations elevated in the most ill very low birth weight infants at 2 weeks of age in a manner analogous to that of the 'sick euthyroid syndrome'.

    View details for Web of Science ID A1997YB77800003

    View details for PubMedID 9404437

  • Strong expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in ovarian borderline and malignant neoplasms LABORATORY INVESTIGATION ABUJAWDEH, G. M., Faix, J. D., Niloff, J., Tognazzi, K., MANSEAU, E., Dvorak, H. F., BROWN, L. F. 1996; 74 (6): 1105-1115


    Angiogenesis is a critical factor in the growth, progression, and metastatic spread of solid tumors. Furthermore, angiogenesis has been correlated with prognosis in patients with ovarian cancer. The pathogenesis of the angiogenic events in ovarian cancer, however, are not well defined. Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) is a multifunctional cytokine that has been shown to be an important regulator of tumor angiogenesis. The purpose of the present study was to define the expression of VPF/VEGF and its receptors flt-1 and KDR in ovarian tumors. Four specimens of normal ovarian cortex and 41 specimens of benign (4), borderline (8), and malignant (29) ovarian tumors were studied by in situ hybridization, and in some cases by immunohistochemical analysis. VPF/VEGF protein was also determined by an immunofluorometric assay in cyst fluids obtained from 11 patients, including 7 benign, 2 borderline, and 2 malignant tumors. VPF/VEGF mRNA and protein were expressed by the neoplastic cells in all of the malignant tumors evaluated, with the majority of tumors (28 of 29) showing strong expression of mRNA. Serous borderline tumors had variable VPF/VEGF mRNA expression, with two of six cases showing focal strong expression and four showing low-level expression. No definite expression of VPF/VEGF was seen in two cases of mucinous borderline tumors. No strong expression of VPF/VEGF mRNA was observed in normal ovarian cortex, including surface epithelium, or benign tumors. Substantially higher VPF protein concentrations were detected in cyst fluids of the two malignant (60, 440 pM) and two borderline tumors (210, 590 pM) than in the seven benign serous cysts (mean, 10 +/- 3 pM). In addition, microvascular endothelial cells strongly expressed mRNA of the VPF/VEGF receptors flt-1 and KDR and immunostained for VPF/VEGF protein in the majority of malignant and borderline tumors examined. These findings suggest that VPF/VEGF plays an important role in the angiogenesis associated with ovarian neoplasms.

    View details for Web of Science ID A1996UQ73800012

    View details for PubMedID 8667614

  • Thyroid function in very low birth weight infants: Effects on neonatal hypothyroidism screening JOURNAL OF PEDIATRICS Frank, J. E., Faix, J. E., Hermos, R. J., Mullaney, D. M., Rojan, D. A., Mitchell, M. L., Klein, R. Z. 1996; 128 (4): 548-554


    To supply normative data for screening thyroxine (T4) and thyrotropin concentrations correlated with birth weight and age at screening of infants with birth weights ranging from 400 to 5500 gm, and to document the effects of screening of very low birth weight (VLBW) infants, because VLBW infants comprise 0.86% of surviving newborn infants and have very low total T4 concentrations with normal or elevated free T4 concentrations as a result of deficient protein binding of thyroid hormones.Both retrospective and prospective studies were used. We conducted retrospective analyses of screening of T4 and thyrotropin concentrations in 9,324 term, 18,946 low birth weight, and 3,450 VLBW infants in Massachusetts, and a prospective study of T4 and thyrotropin concentrations in 48 VLBW infants at 2 weeks of age. Forty of the infants also had hormone measurements at 4 weeks, 29 at 8 weeks of age, and 24 had analysis of cord blood samples.Median T4 concentrations for each weight group (in 250 gm increments) increased progressively and significantly up to 2500 gm. Of the surviving VLBW infants, 1.5% had screening T4 concentrations that were unmeasurably low (<3.9 nmol/L (0.3 microgram/dl)). The mean T4 concentration varied with age at screening, increasing from cord blood concentrations to a peak at 1 to 3 days of age and thereafter decreasing to a nadir at about 2 weeks in both low birth weight and VLBW infants. In VLBW infants the mean concentrations return to the level of 1 to 3 days by 4 to 8 weeks of age. The incidence of screening thyrotropin concentrations > or = 40 mU/L correlates inversely with weight. The incidence of early, transient hypothyroidism in VLBW infants defined by this thyrotropin concentration was eight times that in term infants. Two infants had late-onset, transient hypothyroidism at 2 and 7 weeks, respectively.The normative data related to birth weight and age at screening allow proper interpretation of VLBW results for primary T4 and primary thyrotropin screening programs. Screening of the concentrations of T4 and thyrotropin in VLBW increases the number of secondary measurements of T4 in a primary thyrotropin screening program and the number of secondary thyrotropin measurements in a primary T4 screening program by 6% and 9%, respectively. We recommend screening analyses for VLBW infants in the latter part of the first week of life and again at 2 and 4 to 6 weeks of age. This protocol would increase the number of screening analyses by 1.6%.

    View details for Web of Science ID A1996UF24400016

    View details for PubMedID 8618191



    There are many alternative ways of estimating free thyroxine (T4) when thyrotropin screening results are abnormal. In addition to free T4 immunoassays, the menu of most automated immunoassay instruments includes a nonisotopic version of the original triiodothyronine (T3)-uptake assay called "T-uptake." We evaluated the ability of five such assays (Access, ES-300, IMx, Magnum Opus, and Stratus) to accurately estimate the free thyroxine index (FTI) in euthyroid, hyperthyroid, and hypothyroid patients with abnormal concentrations of thyroid hormone-binding proteins, and in patients with nonthyroidal illness. For comparison, we calculated a similar FTI, using either T3-uptake or direct measurement of thyroxine-binding globulin (TBG). Euthyroid reference ranges were comparable. Of euthyroid patients with increased TBG, 12-32% and 5-20% had increased or suppressed FTI, respectively, depending on the T-uptake method used. Except for IMx, 6-35% of hypothyroid patients with increased TBG had inappropriately increased FTI. Patients with nonthyroidal illness had comparable results regardless of the method used, and T-uptake methods were variably affected by known inhibitors of thyroid hormone binding. The most reliable T-uptake method appeared to be the IMx, which, despite claims that it measures all thyroid hormone-binding proteins, correlated best with TBG concentrations.

    View details for Web of Science ID A1995QA21200009

    View details for PubMedID 7813079



    Patients with severe nonthyroidal illness may have low serum levels of thyroid hormone and thyroid-stimulating hormone (TSH) indistinguishable from levels in patients with pituitary insufficiency. It is often difficult prospectively to rule out pituitary insufficiency in these patients. Our hypothesis was that patients sufficiently ill to have low free thyroxine index (FT4I) and TSH from nonthyroidal illness (euthyroid sick syndrome, or ESS) would have serum cortisol levels high enough to make pituitary insufficiency unlikely. Serum samples from all patients admitted to the Intensive Care Unit during 2 months were screened for low FT4I, and cortisol levels were measured on those samples. Five of five patients with a diagnosis of ESS had unequivocal elevations of serum cortisol (> 525 nmol/l), arguing against a diagnosis of pituitary insufficiency. Secondary hypothyroidism due to pituitary insufficiency can often be ruled out in patients with severe ESS by documenting appropriate elevated levels of serum cortisol.

    View details for Web of Science ID A1994PP77000003

    View details for PubMedID 7960686



    A clinically euthyroid 53-year-old woman with an IgA-lambda-secreting multiple myeloma presented with increased serum concentrations of thyroid hormones. Laboratory studies revealed increased total thyroxine (T4) and triiodothyronine (T3) concentrations, a high-normal free T4 concentration, and a normal basal thyrotropin (TSH) concentration with a normal response to thyroliberin (TRH). Her serum concentration of IgA was 11,040 mg/L (normal range 900-4500 mg/L) and immunoelectrophoresis revealed it to be monoclonal. This monoclonal IgA bound both T4 and T3, as determined by serum immunoelectrophoresis and direct binding studies. Immunoelectrophoresis in the presence of [125I]T4 or [125I]T3 localized the radiolabeled iodothyronines to a band corresponding exactly to the precipitin arc of the monoclonal IgA. We performed direct binding studies with IgA purified by affinity chromatography with the lectin jacalin. Purified IgA (50 micrograms) bound both [125I]T4 (12.3%) and [125I]T3 (2.7%) specifically and in a dose-dependent manner. Scatchard analysis of competitive-binding data utilizing [125I]T4 and unlabeled T4 revealed a Kd of 2.2 x 10(-7) mol/L. The binding capacity for T4 was approximately 7 mumol/L. Thus, in this case of IgA-secreting myeloma, the monoclonal IgA acts as an additional thyroid hormone-binding protein in serum that interferes in the T4 and T3 RIAs. This is the first report of a monoclonal IgA producing an apparent euthyroid hyperthyroxinemia.

    View details for Web of Science ID A1993LT22800034

    View details for PubMedID 8353966



    We describe a two-site time-resolved immunofluorometric assay for guinea pig vascular permeability factor (VPF) for quantifying VPF in different biological fluids. Antibody against the carboxy terminus (C-IgG) is immobilized on microtiter wells, and antibody against the amino terminus (N-IgG) is labeled with Eu(3+)-chelate. Line 10 tumor culture medium, known to be rich in VPF, is assayed in a two-step incubation. Bound Eu3+ is then quantified by dissociation into a fluorescent enhancement solution, with measurement of the time-resolved fluorescence. The analytical sensitivity is 0.35 VPF unit, and the intra-assay CV is about 20%. The assay is specific for VPF, because pre-treatment with the appropriate C- or N-peptide, or pre-extraction of VPF, greatly decreases fluorescence. The VPF immunoassay is highly correlated (r2 = 0.94) with the Miles permeability assay, the classical bioassay of VPF. In addition, the immunofluorometric assay is about 30-fold more sensitive than the Miles assay.

    View details for Web of Science ID A1992HB64600013

    View details for PubMedID 1733610

  • PREVALENCE OF THYROID-DEFICIENCY IN PREGNANT-WOMEN CLINICAL ENDOCRINOLOGY Klein, R. Z., Haddow, J. E., Faix, J. D., Brown, R. S., Hermos, R. J., Pulkkinen, A., Mitchell, M. L. 1991; 35 (1): 41-46


    The present study was designed to determine the current prevalence of gestational hypothyroidism, since maternal thyroxine deficiency is associated with poor obstetric outcomes and mental retardation in the surviving offspring.TSH concentrations were measured in the sera of women at 15-18 weeks of gestation. Those sera with TSH concentrations above 6 mU/l and the two sera closest in order with TSH concentrations below 6 mU/l were further analysed for T4, FT4, TBG, and antithyroid antibodies. Study criteria for hypothyroidism were sera with elevated concentrations of TSH plus both a free T4 concentration and a total T4 concentration and/or T4/TBG ratio more than two standard deviations below the mean for the control pregnant women.The sera were from 2000 consecutive women in Maine being tested for alpha-fetoprotein concentration at 15-18 weeks of gestation.TSH concentrations above 6 mU/l were found in the sera of 49 women, 2.5% of the pregnant women. Six women with elevated TSH concentrations (range 6.9-54 mU/l) had both a FT4 concentration and a T4/TBG ratio and/or a T4 concentration more than two standard deviations below the respective control means, meeting the study criteria for thyroid deficiency, and thus giving a prevalence of 0.3%. The remaining 43 women with elevated TSH concentrations were classified as having compensated thyroid disease although some may have been hypothyroid. Fifty-eight per cent of women with TSH concentrations above 6 mU/l and 90% of the women with elevated TSH concentrations and at least one thyroxine index more than two standard deviations below the control means had positive titres of antithyroid antibodies as opposed to 11% of the controls.Although it is not known what severity of maternal thyroid deficiency is necessary to cause fetal brain damage, the present data indicate a sufficiently high prevalence of thyroid dysfunction to demand investigation of the mental development of the offspring of women with thyroid dysfunction and of the effect of replacement therapy.

    View details for Web of Science ID A1991FV01400007

    View details for PubMedID 1889138

Stanford Medicine Resources: