Search PubMed⌕ Search

Biomedical subjects

Kris V Kowdley

Publications and source records attributed to Kris V Kowdley.

At least 19 recordsLinked to original sources
PubMed2025

Association of HFE genotypes with hemochromatosis-related phenotypes in the All of Us research program.

PURPOSE: Type 1 hereditary hemochromatosis (HH) can result in iron overload and liver disease if not detected and treated early. Most cases are found among people homozygous for HFE p.Cys282Tyr variants. Compound heterozygosity with the HFE p.His63Asp variant is associated with disease to a lesser degree. We sought to examine the association of HFE variation with HH-related phenotypes and assess the prevalence of testing and diagnosis of HH using All of Us data. METHODS: We used data from 133,978 participants with genetic information linked to medical records. For different HFE genotypes, we examined the prevalence of HH diagnosis codes and related biochemical and clinical phenotypes. RESULTS: Among participants who were p.Cys282Tyr homozygotes, the prevalence of HH diagnosis codes was 22.6% among males and 15.6% among females. Serum transferrin-iron saturation measures were available only for 31.4% of males and 21.1% of females who were p.Cys282Tyr homozygotes. Liver disease, including cirrhosis or hepatocellular carcinoma, was present more among males who were p.Cys282Tyr homozygotes compared with males with no p.Cys282Tyr or p.His63Asp variants (15.5% vs 8.5%, P = .0001). Of the 71 participants who were p.Cys282Tyr homozygotes with indication of liver disease, 32 (45.1%) did not have a serum transferrin-iron saturation measure, and 37 (52.1%) did not have diagnosis codes for HH. CONCLUSION: Limited serum transferrin-iron saturation measures or HH diagnosis codes among p.Cys282Tyr homozygotes, even those with liver disease, suggests potential undertesting and underdiagnosis of type 1 HH in clinical practice and a need for improved awareness, education, and testing around HH.

C282Y homozygosity↗
PubMed2007

Correlation of proton transverse relaxation rates (R2) with iron concentrations in postmortem brain tissue from alzheimer's disease patients.

Iron accumulates in the Alzheimer's disease (AD) brain and is directly associated with beta-amyloid pathology. The proton transverse relaxation rate (R(2)) has a strong linear relationship with iron concentrations in healthy brain tissue; however, an independent test of this relationship has not been extended to AD brain tissue. In this study in vitro single spin-echo (SE) measurements were made on tissue samples from four human AD brains using a 4.7T MRI research scanner. R(2) values were calculated for 14 cortical and subcortical gray matter (GM) and white matter (WM) regions. Atomic absorption spectroscopy was used to measure iron concentrations in the corresponding excised brain regions. Significant positive linear correlations were observed between R(2) values and iron concentrations in GM regions assessed across individual tissue samples and data averaged by brain region. With the use of a predictive model for R(2), a threshold iron concentration of 55 microg Fe/g wet tissue was determined above which R(2) appears to be dominated by the affects of iron in AD brain tissue. High-field MRI may therefore be a useful research tool for assessing brain iron changes associated with AD.

Aged↗
PubMed2006

Incidence of minor complications and time lost from normal activities after screening or surveillance colonoscopy.

BACKGROUND: Few studies address the development of minor complications after screening or surveillance colonoscopy. OBJECTIVES: Our purpose was to examine in previously asymptomatic people the incidence of new symptoms after colonoscopy, risk factors for symptoms, and patients' perceptions of this examination. DESIGN: Prospective cohort study. Patients completed a standardized interview at 7 and 30 days after colonoscopy. PATIENTS: A total of 502 patients aged 40 years and older undergoing colonoscopy for colorectal cancer screening, surveillance, or follow-up of another abnormal screening test result. Patients were excluded if they had a history of inflammatory bowel disease, visible GI bleeding, or anemia. MAIN OUTCOME MEASURES: Incidence of minor complications and patient perceptions about colonoscopy. RESULTS: Minor complications occurred in 162 subjects (34%) before day 7 and in 29 subjects (6%) between day 7 and day 30, most commonly bloating (25%) and abdominal pain (11%). Six subjects had unexpected emergency department visits or hospitalizations within 30 days, including 2 with postpolypectomy bleeding. On multivariate analysis, minor complications were more common in women (odds ratio 1.78, 95% CI 1.21-2.62) and when the procedure lasted 20 minutes or longer. Bowel preparation was rated the most difficult part of the examination for 77%. Most subjects (94%) lost 2 or fewer days from normal activities for the colonoscopy itself, preparation, or recovery. CONCLUSIONS: Minor complications were common after screening and surveillance colonoscopy. The bowel preparation was the most difficult part of the examination for most patients. Most subjects lost 2 or fewer days from normal activities because of colonoscopy.

Adult↗
PubMed2006

Association of hepatic iron overload with invasive fungal infection in liver transplant recipients.

Invasive fungal infection is a serious complication of orthotopic liver transplantation, but its risk factors remain incompletely defined. Iron overload has already been associated with increased risk of fungal infections, but it has not yet been assessed as a risk factor in liver transplantation. We retrospectively studied a cohort of 153 consecutive patients who underwent their first liver transplantation at a single center and who survived at least 7 days after transplantation. The association between various pretransplant patient characteristics, including hepatic explant iron and risk of invasive fungal infections, was analyzed by univariate and multivariate models. Iron in the hepatic explant was assessed by Perl's Prussian blue stain by a pathologist blinded to clinical outcome. During the first year after transplantation, 28 of 153 patients developed a total of 31 invasive fungal infections, of which 21 (68%) were caused by Candida, 7 (23%) by Aspergillus, 2 (6%) by Cryptococcus, and 1 (3%) by Saccharomyces. Stainable iron in the hepatic explant was found in 48 patients (31%). Stainable iron in the hepatic explant was found to be strongly and independently associated with posttransplantation fungal infections in multivariate analysis (hazard ratio 3.09; 95% confidence interval 1.45-6.56; P = 0.003). Hepatic iron overload is strongly and independently associated with posttransplantation invasive fungal infections. Studies to confirm this finding in other centers and define the mechanism are warranted.

Adolescent↗
PubMed2006

Iron Overload (with Attention to Genetic Testing and Diagnosis/Management of HFE Wild Type Patients).

The discovery of the HFE, HJV, HAMP, TfR2, and SLC40A1 genes and preliminary understanding of their roles in iron homeostasis have contributed tremendously to our understanding of the pathogenesis of genetic hemochromatosis. Although several new models of iron metabolism have been proposed, some key "sensor" steps of iron absorption in the enterocytes and of iron storage in hepatocytes and other cells remain unclear. A diagnosis of non-HFE genetic hemochromatosis should be considered in patients with unexplained iron overload who do not have the common mutations in the HFE genes. Phenotypic evaluation such as liver biopsy and measurement of hepatic iron concentration remain important in non-HFE hemochromatosis because mutations in other genes are rare and there are no other available noninvasive tests to confirm the diagnosis. Phlebotomy remains the mainstay of therapy also for non-HFE hemochromatosis. However, phlebotomy may not be well tolerated in certain forms of non-HFE hemochromatosis such as "ferroportin disease."

Journal Article↗
PubMed2006

Natural history of nonalcoholic steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is being increasingly recognized as one of the most common chronic liver diseases. The natural history of this liver disease remains unclear due to its indolent nature, the paucity of prospective studies, and the lack of consensus regarding the various forms of this disorder. Based on retrospective studies, it appears that the histologic features of NAFLD may be important determinants of the clinical course of this disease; patients with nonalcoholic steatohepatitis (NASH) appear to have a higher likelihood of progression to cirrhosis. There is an increased risk of hepatocellular carcinoma and end-stage liver disease among patients with NASH-related cirrhosis and those with cryptogenic cirrhosis, which likely represents a late stage of NAFLD. Recurrence of NASH has been described among patients who have undergone liver transplantation for NASH-related end-stage liver disease.

Biopsy↗
PubMed2005

Hepatitis B and liver transplantation.

Liver transplantation is the treatment of choice for patients with liver failure secondary to chronic hepatitis B. However, liver transplantation is complicated by the risk of recurrent hepatitis B virus infection, which significantly impairs graft and patient survival. The main risk factor for the development of recurrent hepatitis B virus infection is the virus load at the time of transplantation. The development of antiviral medications, such as lamivudine and adefovir, and the implementation of effective prophylactic regimens using hepatitis B immune globulin have significantly improved the outcomes of hepatitis B after liver transplantation. However, current approaches continue to be hampered by the extremely high cost of treatment and the emergence of drug-resistant viral mutations. Ongoing studies are necessary to establish the most cost-effective approaches to prevent recurrent hepatitis B virus infection after liver transplantation.

Antiviral Agents↗
PubMed2005

Identification of differentially expressed genes in response to dietary iron deprivation in rat duodenum.

We sought to identify novel genes involved in intestinal iron absorption by inducing iron deficiency in rats during postnatal development from the suckling period through adulthood. We then performed comparative gene chip analyses (RAE230A and RAE230B chips; Affymetrix) with cRNA derived from duodenal mucosa. Real-time PCR was used to confirm changes in gene expression. Genes encoding the apical iron transport-related proteins [divalent metal transporter 1 (DMT1) and duodenal cytochrome b] were strongly induced at all ages studied, whereas increases in mRNA encoding the basolateral proteins iron-regulated gene 1 and hephaestin were observed only by real-time PCR. In addition, transferrin receptor 1 and heme oxygenase 1 were induced. We also identified induction of novel genes not previously associated with intestinal iron transport. The Menkes copper ATPase (ATP7a) and metallothionein were strongly induced at all ages studied, suggesting increased copper absorption by enterocytes during iron deficiency. We also found significantly increased liver copper levels in 7- to 12-wk-old iron-deficient rats. Also upregulated at most ages examined were the sodium-dependent vitamin C transporter, tripartite motif protein 27, aquaporin 4, lipocalin-interacting membrane receptor, and the breast cancer-resistance protein (ABCG2). Some genes also showed decreased expression with iron deprivation, including several membrane transporters, metabolic enzymes, and genes involved in the oxidative stress response. We speculate that dietary iron deprivation leads to increased intestinal copper absorption via DMT1 on the brush-border membrane and the Menkes copper ATPase on the basolateral membrane. These findings may thus explain copper loading in the iron-deficient state. We also demonstrate that many other novel genes may be differentially regulated in the setting of iron deprivation.

Animals↗
PubMed2005

Quality of life in refractory ascites: transjugular intrahepatic portal-systemic shunting versus medical therapy.

Uncontrolled studies suggest that transjugular intrahepatic portal-systemic shunting (TIPS) may improve quality of life in patients with refractory ascites. We hypothesized that any improvement of quality of life in patients with TIPS would be matched in controls due to the competing effects of improved ascites and worsened hepatic encephalopathy. Thus, an analysis of quality of life was performed using original data from the North American Study for the Treatment of Refractory Ascites, a multicenter trial of 109 patients randomized to TIPS or repeated large volume paracentesis (LVP) for refractory ascites. Short form 36 (SF-36) surveys were completed at baseline and at 6- and 12-month follow-up. Variables analyzed were: randomization group, number of LVP performed, cumulative volume from LVP, shortness of breath, abdominal distention, abdominal pain, diuretic usage, confusion, hospitalizations, and emergency room visits. Outcomes were changes in physical component scale (PCS) and mental component scale (MCS) of SF-36 results. We constructed multivariable, mixed effects models, including randomization group and baseline MCS and PCS. Changes in PCS and MCS from baseline were similar between the two randomization groups. In multivariate analysis, PCS improvement was associated with lack of confusion, improved ascites, and lack of hospitalizations, but not directly with randomization group. Improvement in MCS was associated with randomization to TIPS and lack of confusion. In conclusion, patients with refractory ascites randomized to TIPS or repeated LVP had similar changes in quality of life. Competing effects of hepatic encephalopathy, requirement for repeated LVP, and need for hospitalizations explain similar changes in quality of life between the two groups.

Analysis of Variance↗
PubMed2005

Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis.

This placebo-controlled, randomized, multicenter trial compared the effects of MTX plus UDCA to UDCA alone on the course of primary biliary cirrhosis (PBC). Two hundred and sixty five AMA positive patients without ascites, variceal bleeding, or encephalopathy; a serum bilirubin less than 3 mg/dL; serum albumin 3 g/dL or greater, who had taken UDCA 15 mg/kg daily for at least 6 months, were stratified by Ludwig's histological staging and then randomized to MTX 15 mg/m2 body surface area (maximum dose 20 mg) once a week while continuing on UDCA. The median time from randomization to closure of the study was 7.6 years (range: 4.6-8.8 years). Treatment failure was defined as death without liver transplantation; transplantation; variceal bleeding; development of ascites, encephalopathy, or varices; a doubling of serum bilirubin to 2.5 mg/dL or greater; a fall in serum albumin to 2.5 g/dL or less; histological progression by at least two stages or to cirrhosis. Patients were continued on treatment despite failure of treatment, unless transplantation ensued, drug toxicity necessitated withdrawal, or the patient developed a cancer. There were no significant differences in these parameters nor to the time of development of treatment failures observed for patients taking UDCA plus MTX, or UDCA plus placebo. The trial was conducted with a stopping rule, and was stopped early by the National Institutes of Health at the advice of our Data Safety Monitoring Board for reasons of futility. In conclusion, methotrexate when added to UDCA for a median period of 7.6 years had no effect on the course of PBC treated with UDCA alone.

Adult↗
PubMed2005

Non-HFE hemochromatosis: genetics, pathogenesis, and clinical management.

Recent advances in our understanding of iron metabolism and the epidemiology of iron overload disorders have shown that hereditary forms of hemochromatosis can result from mutations in several iron metabolism genes other than HFE, including Hamp, HJV, TFR2, and SCL40A. These "non-HFE" forms of hemochromatosis are much rarer than HFE-related hemochromatosis but exhibit a similar phenotype, and with the exception of ferroportin disease, a similar pattern of inheritance and parenchymal iron accumulation. Therefore, these diseases can be thought of as variant forms of a primary hepatic iron overload syndrome; thus, a unified approach can be used for evaluation and diagnosis. Management generally consists of periodic phlebotomies until iron is depleted.

Adolescent↗