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Karl E Anderson - Top 30 Publications

Reply (to LTE HEP-17-1594).

Porphyria.

Hepatitis C Treatment in Patients With Porphyria Cutanea Tarda.

Hepatitis C virus (HCV) infection is a common susceptibility factor for porphyria cutanea tarda (PCT). Experience on HCV treatment in patients with PCT is limited. Recently, HCV treatment has improved with direct-acting antivirals (DAA). We review our experience on HCV treatment in patients with PCT with older and newer regimens.

Clinical, Biochemical, and Genetic Characterization of North American Patients With Erythropoietic Protoporphyria and X-linked Protoporphyria.

Autosomal recessive erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare photodermatoses presenting with variable degrees of painful phototoxicity that markedly affects quality of life. The clinical variability, determinants of severity, and genotype/phenotype correlations of these diseases are not well characterized.

Acute hepatic porphyrias: Recommendations for evaluation and long-term management.

The acute hepatic porphyrias are a group of four inherited disorders, each resulting from a deficiency in the activity of a specific enzyme in the heme biosynthetic pathway. These disorders present clinically with acute neurovisceral symptoms which may be sporadic or recurrent and, when severe, can be life-threatening. The diagnosis is often missed or delayed as the clinical features resemble other more common medical conditions. There are four major subgroups: symptomatic patients with sporadic attacks (<4 attacks/year) or recurrent acute attacks (≥4 attacks/year), asymptomatic high porphyrin precursor excretors, and asymptomatic latent patients without symptoms or porphyrin precursor elevations. Given their clinical heterogeneity and potential for significant morbidity with suboptimal management, comprehensive clinical guidelines for initial evaluation, follow-up, and long-term management are needed, particularly because no guidelines exist for monitoring disease progression or response to treatment. The Porphyrias Consortium of the National Institutes of Health's Rare Diseases Clinical Research Network, which consists of expert centers in the clinical management of these disorders, has formulated these recommendations. These recommendations are based on the literature, ongoing natural history studies, and extensive clinical experience. Initial assessments should include diagnostic confirmation by biochemical testing, subsequent genetic testing to determine the specific acute hepatic porphyria, and a complete medical history and physical examination. Newly diagnosed patients should be counseled about avoiding known precipitating factors. The frequency of follow-up depends on the clinical subgroup, with close monitoring of patients with recurrent attacks who may require treatment modifications as well as those with clinical complications. Comprehensive care should include subspecialist referrals when needed. Annual assessments include biochemical testing and monitoring for long-term complications. These guidelines provide a framework for monitoring patients with acute hepatic porphyrias to ensure optimal outcomes. (Hepatology 2017;66:1314-1322).

Riboflavin as an independent and accurate biomarker for adherence in a randomized double-blind and placebo-controlled clinical trial.

Medication adherence is critical for success of clinical trials.

Protoporphyrin IX: the Good, the Bad, and the Ugly.

Protoporphyrin IX (PPIX) is ubiquitously present in all living cells in small amounts as a precursor of heme. PPIX has some biologic functions of its own, and PPIX-based strategies have been used for cancer diagnosis and treatment (the good). PPIX serves as the substrate for ferrochelatase, the final enzyme in heme biosynthesis, and its homeostasis is tightly regulated during heme synthesis. Accumulation of PPIX in human porphyrias can cause skin photosensitivity, biliary stones, hepatobiliary damage, and even liver failure (the bad and the ugly). In this work, we review the mechanisms that are associated with the broad aspects of PPIX. Because PPIX is a hydrophobic molecule, its disposition is by hepatic rather than renal excretion. Large amounts of PPIX are toxic to the liver and can cause cholestatic liver injury. Application of PPIX in cancer diagnosis and treatment is based on its photodynamic effects.

Mentoring in Clinical-Translational Research: A Study of Participants in Master's Degree Programs.

Research projects in translational science are increasingly complex and require interdisciplinary collaborations. In the context of training translational researchers, this suggests that multiple mentors may be needed in different content areas. This study explored mentoring structure as it relates to perceived mentoring effectiveness and other characteristics of master's-level trainees in clinical-translational research training programs. A cross-sectional online survey of recent graduates of clinical research master's program was conducted. Of 73 surveys distributed, 56.2% (n = 41) complete responses were analyzed. Trainees were overwhelmingly positive about participation in their master's programs and the impact it had on their professional development. Overall the majority (≥75%) of trainees perceived they had effective mentoring in terms of developing skills needed for conducting clinical-translational research. Fewer trainees perceived effective mentoring in career development and work-life balance. In all 15 areas of mentoring effectiveness assessed, higher rates of perceived mentor effectiveness was seen among trainees with ≥2 mentors compared to those with solo mentoring (SM). In addition, trainees with ≥2 mentors perceived having effective mentoring in more mentoring aspects (median: 14.0; IQR: 12.0-15.0) than trainees with SM (median: 10.5; IQR: 8.0-14.5). Results from this survey suggest having ≥2 mentors may be beneficial in fulfilling trainee expectations for mentoring in clinical-translational training.

Pitfalls in Erythrocyte Protoporphyrin Measurement for Diagnosis and Monitoring of Protoporphyrias.

Laboratory diagnosis of erythropoietic protoporphyria (EPP) requires a marked increase in total erythrocyte protoporphyrin (300-5000 μg/dL erythrocytes, reference interval <80 μg/dL) and a predominance (85%-100%) of metal-free protoporphyrin [normal, mostly zinc protoporphyrin (reference intervals for the zinc protoporphyrin proportion have not been established)]; plasma porphyrins are not always increased. X-linked protoporphyria (XLP) causes a similar increase in total erythrocyte protoporphyrin with a lower fraction of metal-free protoporphyrin (50%-85% of the total).

Afamelanotide for Erythropoietic Protoporphyria.

Erythropoietic protoporphyria is a severe photodermatosis that is associated with acute phototoxicity. Patients with this condition have excruciating pain and a markedly reduced quality of life. We evaluated the safety and efficacy of an α-melanocyte-stimulating hormone analogue, afamelanotide, to decrease pain and improve quality of life.

Liver Transplantation for Acute Intermittent Porphyria: Biochemical and Pathologic Studies of the Explanted Liver.

Acute intermittent porphyria (AIP) is an autosomal-dominant hepatic disorder caused by the half-normal activity of hydroxymethylbilane (HMB) synthase. Symptomatic individuals experience life-threatening acute neurovisceral attacks that are precipitated by factors that induce the hepatic expression of 5-aminolevulinic acid synthase 1 (ALAS1), resulting in the marked accumulation of the putative neurotoxic porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). Here, we provide the first detailed description of the biochemical and pathologic alterations in the explanted liver of an AIP patient who underwent orthotopic liver transplantation (OLT) due to untreatable and debilitating chronic attacks. After OLT, the recipient's plasma and urinary ALA and PBG rapidly normalized, and her attacks immediately stopped. In the explanted liver, (a) ALAS1 mRNA and activity were elevated approximately ~3- and 5-fold, and ALA and PBG concentrations were increased ~3- and 1,760-fold, respectively; (b) uroporphyrin III concentration was elevated; (c) microsomal heme content was sufficient, and representative cytochrome P450 activities were essentially normal; (d) HMB synthase activity was approximately half-normal (~42%); (e) iron concentration was slightly elevated; and (f) heme oxygenase I mRNA was increased approximately three-fold. Notable pathologic findings included nodular regenerative hyperplasia, previously not reported in AIP livers, and minimal iron deposition, despite the large number of hemin infusions received before OLT. These findings suggest that the neurovisceral symptoms of AIP are not associated with generalized hepatic heme deficiency and support the neurotoxicity of ALA and/or PBG. Additionally, they indicate that substrate inhibition of hepatic HMB synthase activity by PBG is not a pathogenic mechanism in acute attacks.

The Multidisciplinary Translational Team (MTT) Model for Training and Development of Translational Research Investigators.

Multiinstitutional research collaborations now form the most rapid and productive project execution structures in the health sciences. Effective adoption of a multidisciplinary team research approach is widely accepted as one mechanism enabling rapid translation of new discoveries into interventions in human health. Although the impact of successful team-based approaches facilitating innovation has been well-documented, its utility for training a new generation of scientists has not been thoroughly investigated. We describe the characteristics of how multidisciplinary translational teams (MTTs) promote career development of translational research scholars through competency building, interprofessional integration, and team-based mentoring approaches. Exploratory longitudinal and outcome assessments from our experience show that MTT membership had a positive effect on the development of translational research competencies, as determined by a self-report survey of 32 scholars. We also observed that all trainees produced a large number of collaborative publications that appeared to be associated with their CTSA association and participation with MTTs. We conclude that the MTT model provides a unique training environment for translational and team-based learning activities, for investigators at early stages of career development.

Similarity of fibroglandular breast tissue content measured from magnetic resonance and mammographic images and by a mathematical algorithm.

Women with high breast density (BD) have a 4- to 6-fold greater risk for breast cancer than women with low BD. We found that BD can be easily computed from a mathematical algorithm using routine mammographic imaging data or by a curve-fitting algorithm using fat and nonfat suppression magnetic resonance imaging (MRI) data. These BD measures in a strictly defined group of premenopausal women providing both mammographic and breast MRI images were predicted as well by the same set of strong predictor variables as were measures from a published laborious histogram segmentation method and a full field digital mammographic unit in multivariate regression models. We also found that the number of completed pregnancies, C-reactive protein, aspartate aminotransferase, and progesterone were more strongly associated with amounts of glandular tissue than adipose tissue, while fat body mass, alanine aminotransferase, and insulin like growth factor-II appear to be more associated with the amount of breast adipose tissue. Our results show that methods of breast imaging and modalities for estimating the amount of glandular tissue have no effects on the strength of these predictors of BD. Thus, the more convenient mathematical algorithm and the safer MRI protocols may facilitate prospective measurements of BD.

Acute porphyrias in the USA: features of 108 subjects from porphyrias consortium.

Recent descriptions of the clinical and laboratory features of subjects with acute porphyrias in the US are lacking. Our aim was to describe clinical, biochemical, and genetic features of 108 subjects.

Management practices of hepatitis C virus infected alcoholic hepatitis patients: A survey of physicians.

To survey gastroenterologists and hepatologists regarding their current views on treating hepatitis C virus (HCV) infected alcoholic hepatitis (AH) patients.

The CTSA as an exemplar framework for developing multidisciplinary translational teams.

Translational science requires that scientists from multiple disciplines work together to improve the prevention, diagnosis, and treatment of human disease. Although a literature exists on the design and management of multidisciplinary teams, little has been written on multidisciplinary translational teams (MTTs). MTTs are distinct hybrid entities, with goals taken from both industry and academic models. We identified 30 design factors in 10 domains from a literature survey relevant to our MTT model: specific goals, structures, and processes. These dimensions were adapted to our own institutional environment in the selection and management of 11 MTTs that exploited resources of University of Texas Medical Branch (UTMB) Clinical and Translational Sciences Awards (CTSA). Case illustrations of two specific MTTs illustrate some of the challenges encountered and opportunities realized in terms of education and scientific advances. Network depiction of disciplinarity indicated that CTSA KRs and CTSA leadership contributed to discipline diversity especially in small (or nascent) MTTs. A separate depiction of MTT-KR utilization indicated that data analysis, translational technologies, and novel methods were heavily utilized by MTTs, whereas other KRs contributed significant effort to infrastructure development. We conclude that the CTSA can provide a rich infrastructural framework and scientific environment for the development of successful MTTs.

Loss-of-function ferrochelatase and gain-of-function erythroid-specific 5-aminolevulinate synthase mutations causing erythropoietic protoporphyria and x-linked protoporphyria in North American patients reveal novel mutations and a high prevalence of X-linked protoporphyria.

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are inborn errors of heme biosynthesis with the same phenotype but resulting from autosomal recessive loss-of-function mutations in the ferrochelatase (FECH) gene and gain-of-function mutations in the X-linked erythroid-specific 5-aminolevulinate synthase (ALAS2) gene, respectively. The EPP phenotype is characterized by acute, painful, cutaneous photosensitivity and elevated erythrocyte protoporphyrin levels. We report the FECH and ALAS2 mutations in 155 unrelated North American patients with the EPP phenotype. FECH sequencing and dosage analyses identified 140 patients with EPP: 134 with one loss-of-function allele and the common IVS3-48T>C low expression allele, three with two loss-of-function mutations and three with one loss-of-function mutation and two low expression alleles. There were 48 previously reported and 23 novel FECH mutations. The remaining 15 probands had ALAS2 gain-of-function mutations causing XLP: 13 with the previously reported deletion, c.1706_1709delAGTG, and two with novel mutations, c.1734delG and c.1642C>T(p.Q548X). Notably, XLP represented ~10% of EPP phenotype patients in North America, two to five times more than in Western Europe. XLP males had twofold higher erythrocyte protoporphyrin levels than EPP patients, predisposing to more severe photosensitivity and liver disease. Identification of XLP patients permits accurate diagnosis and counseling of at-risk relatives and asymptomatic heterozygotes.

Low-dose hydroxychloroquine is as effective as phlebotomy in treatment of patients with porphyria cutanea tarda.

Porphyria cutanea tarda (PCT) is an iron-related disorder caused by reduced activity of hepatic uroporphyrinogen decarboxylase; it can be treated by phlebotomy or low doses of hydroxychloroquine. We performed a prospective pilot study to compare the efficacy and safety of these therapies.

Riboflavin as an oral tracer for monitoring compliance in clinical research.

We studied urinary riboflavin as an objective biomarker of compliance in clinical research using a simplified method amenable to high throughput analysis. Six healthy women not taking vitamin supplements ingested a study pill containing riboflavin (32 mg) as an inactive tracer and the soy isoflavones daidzin (0.243 mmole) and genistin (0.222 mmole) as active ingredients once daily for four days. Riboflavin and metabolites of the isoflavones were measured in urine samples obtained before and after each pill. Urinary excretion of riboflavin and metabolites of both isoflavones peaked within 8 hrs and remained higher than baseline for 24 hrs. Urinary excretion of riboflavin was also measured in 152 additional women with unrestricted dietary supplement intakes. Mean and median urinary riboflavin concentrations in these women were 0.42 and 0.31 μg/mL, respectively, compared to 0.2 μg/mL during a riboflavin-restricted diet. Receiver operating characteristics (ROC) curves indicated that urinary riboflavin within 24 hrs after a 32 mg dose would perform well as a measure of compliance (all areas under the ROC curves ≥0.84. Samples collected during the initial 8 hrs after pill ingestion performed better as a compliance measure than later collections. In summary, compliance in a clinical study can be monitored in real time by incorporating 32 mg of riboflavin into study pills, with compliance indicated by urinary riboflavin levels increasing over individual baselines or to ≥1.0 μg/mL, with a false positive rate of being classified as compliant at <5%.

A career in patient-oriented research on human leukemia: The 2010 E. H. Ahrens, Jr. Award to Emil J Freireich, M.D.

CYP1A2*1F and GSTM1 alleles are associated with susceptibility to porphyria cutanea tarda.

Porphyria cutanea tarda (PCT) is a cutaneous porphyria with sporadic (type 1) and familial (type 2) subtypes, both resulting from decreased hepatic uroporphyrinogen decarboxylase (UROD) activity. Environmental and genetic factors are involved in the development of PCT, and genetic variants in the cytochrome P450 (CYP ) genes, CYP1A1 and CYP1A2, have been implicated. We investigated the association between PCT and variants in CYP1A1, CYP1A2 and CYP2E1, and the glutathione-S-transferase (GST ) genes, GSTM1 and GSTT1. PCT diagnosis was based on urinary or plasma porphyrin profiles. Patients were classified as type 1 or 2 PCT based on UROD mutation analysis. The CYP1A2*1F promoter A allele frequency was significantly higher (P < 0.022) and the A/A genotype frequency marginally higher in PCT patients overall (P < 0.057), with the A/A genotype significantly more common in type 1 PCT (P < 0.043). The presence of the wild-type GSTM1 allele also was associated significantly with PCT (P < 0.019). Neither hemochromatosis (HFE) mutations, tobacco smoking, hepatitis C and HIV infection, ethanol consumption, nor estrogen use were associated with these allelic variants. Age at onset was significantly lower in type 2 PCT patients (P < 0.001), as observed previously. Thus, positive associations between PCT and the CYP1A2*1F promoter A allele and A/A genotype and the wild-type GSTM1 allele indicates that these functional hepatic biotransformation enzymes are risk factors for the development of this disease.

Alkaline phosphatase and percentage body fat predict circulating C-reactive protein in premenopausal women.

C-reactive protein (CRP) is considered a marker of inflammation, which is a risk factor for many chronic diseases. However, determinants of CRP remain unclear and were studied in a strictly defined cohort of healthy premenopausal women (n=233) using multiple regression models. Independent predictors of serum CRP (model R(2)=0.59) were percentage body fat, serum alkaline phosphatase (ALP), sex hormone-binding globulin and white blood cell count. The close association between CRP and ALP suggests that enzymatic activity of ALP may be important for the anti-inflammatory effects of CRP, which should be confirmed with additional studies.

What can be done to protect the translational investigator? : The environment for investigator-initiated clinical research is changing.

Defining translational research: implications for training.

Because translational research is not clearly defined, developers of translational research programs are struggling to articulate specific program objectives, delineate the knowledge and skills (competencies) that trainees are expected to develop, create an appropriate curriculum, and track outcomes to assess whether program objectives and competency requirements are being met. Members of the Evaluation Committee of the Association for Clinical Research Training (ACRT) reviewed current definitions of translational research and proposed an operational definition to use in the educational framework. In this article, the authors posit that translational research fosters the multidirectional and multidisciplinary integration of basic research, patient-oriented research, and population-based research, with the long-term aim of improving the health of the public. The authors argue that the approach to designing and evaluating the success of translational training programs must therefore be flexible enough to accommodate the needs of individual institutions and individual trainees within the institutions but that it must also be rigorous enough to document that the program is meeting its short-, intermediate-, and long-term objectives and that its trainees are meeting preestablished competency requirements. A logic model is proposed for the evaluation of translational research programs.

Associations among behavior-related susceptibility factors in porphyria cutanea tarda.

Porphyria cutanea tarda (PCT) is the most common of the human porphyrias and results from an acquired deficiency of hepatic uroporphyrinogen decarboxylase (UROD). Some susceptibility factors have been identified; we examined associations among multiple factors in a large cohort of patients.

Severe radiation therapy-related soft tissue toxicity in a patient with porphyria cutanea tarda: a literature review.

Some porphyrias are associated with cutaneous phototoxicity due to photoactivation of porphyrins, but whether ionizing radiation can have an additive effect is not clear. We report a case of severe radiation therapy-related toxicity in a patient with porphyria cutanea tarda and review the literature.

Dietary beta-tocopherol and linoleic acid, serum insulin, and waist circumference predict circulating sex hormone-binding globulin in premenopausal women.

Reduced levels of circulating sex hormone-binding globulin (SHBG) are implicated in the etiology of sex steroid-related pathologies and the metabolic syndrome. Dietary correlates of serum SHBG remain unclear and were studied in a convenient cross-sectional sample of healthy 30- to 40-y-old women (n = 255). By univariate analyses, serum SHBG correlated negatively with several indices of the metabolic syndrome, such as BMI, waist circumference, hip circumference (r = -0.36 to -0.44; P < 0.0001), fasting serum insulin (r = -0.41; P < 0.0001), serum triglycerides (r = -0.27; P < 0.0001), serum glucose (r = -0.23; P < 0.001), and plasma testosterone (r = -0.19; P = 0.002). Serum SHBG correlated positively with serum HDL-cholesterol (r = 0.33; P < 0.0001), plasma progesterone (r = 0.17; P = 0.007), and dietary intake of beta-tocopherol (r = 0.17; P = 0.006), and negatively with that of fructose (r = -0.13; P = 0.04). Principal component analysis (PCA) extracted 12 nutrient factors with eigenvalues > 1.0 from 54 nutrients and vitamins in food records. Multivariate regression analyses showed that the PCA-extracted nutrient factor most heavily loaded with beta-tocopherol and linoleic acid (P = 0.03) was an independent positive predictor of serum SHBG. When individual nutrients were the predictor variables, beta-tocopherol (P = 0.002), but not other tocopherols or fatty acids (including linoleic acid), was an independent positive predictor of serum SHBG. Circulating insulin (P = 0.02) and waist circumference (P = 0.002), but not serum lipids, were negative independent predictors of SHBG in all regression models. Additional studies are needed in women of other age groups and men to determine whether consumption of foods rich in beta-tocopherol and/or linoleic acid may increase serum SHBG concentrations and may thereby decrease the risk for metabolic syndrome and reproductive organ cancer.

Lean body mass, not estrogen or progesterone, predicts peak bone mineral density in premenopausal women.

Estrogen and body fat content are important predictors of bone mineral density (BMD) in postmenopausal women, but their association with BMD in premenopausal women is less clear. Mounting evidence suggests that dietary fats can have detrimental effects on bone health. In a cross-sectional sample of healthy 30- to 40-y-old women (n = 242), we investigated the predictors of BMD at the hip and spine by multilevel multiple regression analyses. Predictor variables in the models included dietary intake of various fats, serum concentrations of sex steroids, blood chemistries and markers of metabolic syndrome, anthropometric variables, and ethnicity. Among these premenopausal women, lean body mass was the strongest independent predictor (P < 0.0001) and African-American ethnicity (P < 0.05) was another positive independent predictor of BMD at the hip and spine. Dietary fats were not independent predictors of BMD of hip and spine. Lean body mass and being African-American explained 33% of the variance in hip BMD. Lean body mass, African-American ethnicity, and serum concentrations of triglycerides (a negative predictor, P = 0.0001) explained 28% of the variance in spine BMD. In contrast, luteal phase serum concentrations of estradiol, progesterone, and testosterone were not predictors of BMD. It remains to be determined whether efforts to increase lean body mass in premenopausal women with normal levels of endogenous estrogen may be an effective preventive strategy to preserve bone health.

Dietary intake of lactose as a strong predictor for secretor status of nipple aspirate fluid in healthy premenopausal nonlactating women.

Nipple aspirate fluid (NAF) is considered a potential source for discovering breast cancer biomarkers. However, the success rate of obtaining NAF was reported to vary from 48% to 77%, and mechanisms for its secretion are not fully understood. The purpose of this study was to investigate dietary, demographic, reproductive, hormonal, and anthropometric factors that are associated with the ability to obtain NAF by aspiration (secretor status) from premenopausal women.