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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↗
PubMed2003

Serum ferritin level predicts advanced hepatic fibrosis among U.S. patients with phenotypic hemochromatosis.

BACKGROUND: DNA-based HFE gene testing can confirm hereditary hemochromatosis in most people of Northern European descent. However, liver biopsy is important to detect cirrhosis. OBJECTIVE: To develop noninvasive criteria to predict the presence or absence of advanced hepatic fibrosis or cirrhosis in Americans with hemochromatosis. DESIGN: Cross-sectional study. SETTING: Six tertiary care referral clinics. PATIENTS: 182 patients with phenotypically defined hemochromatosis. MEASUREMENTS: Liver histopathology and serum ferritin, aspartate aminotransferase, and alanine aminotransferase levels. Multivariate logistic regression analysis was used to examine factors associated with cirrhosis (defined as bridging fibrosis or unequivocal cirrhosis on biopsy). RESULTS: Cirrhosis was present in 40 of 182 (22%) patients in the overall group and in 35 of 147 (24%) of C282Y homozygotes. Only 1 of 93 patients with a serum ferritin level less than 1000 microg/L had cirrhosis compared with 39 of 89 patients with serum ferritin levels greater than 1000 microg/L (P < 0.001). No C282Y homozygotes or C282Y/H63D compound heterozygotes with serum ferritin levels less than 1000 microg/L had cirrhosis. Elevated serum aminotransferase levels (P = 0.001) and serum ferritin levels greater than 1000 microg/L (P = 0.001), but not age older than 40 years (P = 0.2), were independently associated with cirrhosis. In a multivariate model, the probability of cirrhosis was 7.4% among patients with serum ferritin levels less than 1000 microg/L compared with 72% among patients with serum ferritin levels greater than 1000 microg/L after adjustment for age and elevated serum liver enzyme levels. CONCLUSIONS: Patients with hemochromatosis and serum ferritin levels less than 1000 microg/L are unlikely to have cirrhosis. Liver biopsy to screen for cirrhosis may be unnecessary in such patients, regardless of age or serum liver enzyme levels.

Adult↗
PubMed2003

Hepatitis C, iron status, and disease severity: relationship with HFE mutations.

BACKGROUND & AIMS: Mild to moderate hepatic iron loading is common in patients with chronic hepatitis C. We sought to determine whether mutations in the hemochromatosis gene, HFE, are associated with iron overload and acceleration of disease progression in hepatitis C patients. METHODS: A total of 316 patients with chronic hepatitis C were studied: 198 consecutive patients undergoing liver biopsy for compensated liver disease and 118 who underwent liver transplantation for end-stage liver disease. Serum iron studies, quantitative hepatic iron concentration, histologic activity index, and HFE genotype were determined. RESULTS: Among patients with compensated liver disease, the presence of HFE mutations was independently associated with elevations in serum iron level, serum transferrin-iron saturation, serum ferritin level, and hepatic iron index (P < 0.05). After adjustment for duration of infection with hepatitis C virus, HFE mutations were also independently associated with the presence of bridging fibrosis or cirrhosis (odds ratio, 18; 95% confidence interval, 1.7-193). HFE mutations were not independently associated with iron loading in patients with end-stage liver disease. There was no significant difference in the prevalence of HFE mutations between patients with compensated and end-stage liver disease (42% vs. 33%, respectively; P = 0.67). CONCLUSIONS: The presence of HFE mutations is independently associated with iron loading and advanced fibrosis in patients with compensated liver disease from chronic hepatitis C, especially after controlling for duration of disease. These results suggest that HFE mutations accelerate hepatic fibrosis in hepatitis C but may not be responsible for progression to end-stage liver disease.

Disease Progression↗
PubMed2003

The North American Study for the Treatment of Refractory Ascites.

BACKGROUND AND AIMS: The clinical utility of transjugular intrahepatic portosystemic shunts (TIPS) vis-à-vis total paracentesis in the management of refractory ascites is unclear. METHODS: A multicenter, prospective, randomized clinical trial was performed in which 109 subjects with refractory ascites were randomized to either medical therapy (sodium restriction, diuretics, and total paracentesis) (n = 57) or medical therapy plus TIPS (n = 52). The principal end points were recurrence of tense symptomatic ascites and mortality. RESULTS: A technically adequate shunt was created in 49 of 52 subjects. TIPS plus medical therapy was significantly superior to medical therapy alone in preventing recurrence of ascites (P < 0.001). The total number of deaths in the 2 groups was identical (TIPS vs. medical therapy alone: 21 vs. 21). There were no significant differences in the 2 arms with respect to overall and transplant-free survival. There was a higher incidence of moderate to severe encephalopathy in the TIPS group (20 of 52 vs. 12 of 57; P = 0.058). There were no significant differences in the number of subjects who developed liver failure (7 vs. 3), variceal hemorrhage (5 vs. 8), or acute renal failure (3 vs. 2). There were also no significant differences between the 2 groups in the frequency of emergency-department visits, medically indicated hospitalizations, or quality of life. CONCLUSIONS: Although TIPS plus medical therapy is superior to medical therapy alone for the control of ascites, it does not improve survival, affect hospitalization rates, or improve quality of life.

Ascites↗
PubMed2003

Durability of serologic response after lamivudine treatment of chronic hepatitis B.

Forty subjects with chronic hepatitis B and hepatitis B e antigen (HBeAg) seroconversion following lamivudine therapy in previous trials were monitored after treatment to assess the durability of serologic responses. Patient follow-up began a median of 4.3 months after completion of therapy in previous trials. At months 2, 4, 6, 9, and 12 of year 1, and every 6 months thereafter, we tested for HBeAg and hepatitis B surface antigen (HBsAg), hepatitis B virus (HBV) DNA, and alanine aminotransferase (ALT). After a median (range) of 36.6 (4.8-45.6) months of follow-up monitoring, HBeAg seroconversion was demonstrated at the last visit by 77% (30 of 39) of patients. In a post hoc analysis of a slightly different population of all 65 patients with HBeAg seroconversion in previous trials, the 3-year durability of HBeAg seroconversion measured from the time immediately after discontinuing lamivudine therapy was 64%. Nine (9 of 40, 23%) patients were HBsAg negative at the last assessment. Seventy-four percent (17 of 23) of patients with baseline undetectable HBV DNA and normal ALT maintained these responses at the last visit. Eight patients (8 of 40, 20%) initiated retreatment for reappearance of HBV markers, and 7 showed biochemical and/or virologic improvement (including regained HBeAg seroconversion in 2). No safety issues of concern emerged. In conclusion, most HBeAg responses achieved during lamivudine therapy were durable, and most responders experienced prolonged clinical benefit after HBeAg seroconversion and subsequent discontinuation of lamivudine. Lamivudine retreatment for reappearance of hepatitis B markers can achieve resumption of viral suppression.

Adult↗
PubMed2003

Racial differences in the relationship between hepatitis C infection and iron stores.

Black race and increased hepatic iron stores predict poor response to interferon treatment for chronic hepatitis C virus (HCV) infection. We tested the hypothesis that these 2 observations are linked by investigating whether HCV-infected African-Americans have increased iron stores relative to uninfected persons. Using data from the third National Health and Nutrition Examination Survey (NHANES III), we determined the risk of having increased iron stores, defined as elevation of both serum ferritin and transferrin-iron saturation (TS), in HCV-RNA-positive blacks (n = 100) and nonblacks (n = 126) relative to HCV-RNA-negative blacks (n = 4,002) and nonblacks (n = 10,943). HCV-positive blacks were 5.4 times (95% CI, 1.2 to 24) more likely to have increased iron stores than HCV-positive nonblacks. The proportion of HCV-positive blacks who had increased iron stores was 16.4% among those with abnormal liver enzymes and 2.8% among those with normal liver enzymes, compared with only 0.6% among HCV-negative blacks. After adjustment for age, alcohol intake, gender, menopausal status, education, body mass index, and poverty index, HCV-positive blacks with abnormal liver enzymes had an elevated risk of having increased iron stores (odds ratio, 17.8; 95% CI, 5.1 to 63). In contrast, among persons of other races, there was a much smaller difference in the proportion of persons with increased iron stores between HCV-positive persons with (3.4%) or without (1.4%) abnormal liver enzymes and HCV-negative persons (0.9%). In conclusion, a greater proportion of blacks than persons of other races respond to HCV infection with an increase in iron stores. This finding may partly explain the reduced response of HCV-positive African-Americans to antiviral treatment.

Adult↗
PubMed2003

CYP2E1 activity before and after weight loss in morbidly obese subjects with nonalcoholic fatty liver disease.

Previous studies suggest that hepatic cytochrome P450 2E1 (CYP2E1) activity is increased in individuals with chronic alcoholism, nonalcoholic steatohepatitis (NASH), and morbid obesity, and may contribute to liver disease. We studied 16 morbidly obese subjects with varying degrees of hepatic steatosis and 16 normal-weight controls. Obese subjects were evaluated at baseline, 6 weeks, and 1 year after gastroplasty, a procedure that leads to weight loss. Hepatic CYP2E1 activity was assessed by determination of the clearance of chlorzoxazone (CLZ), an in vivo CYP2E1-selective probe. Liver biopsy tissue was obtained during surgery for histopathology. Both the total and unbound oral CLZ clearance (Cl(u)/F) was elevated approximately threefold in morbidly obese subjects compared with controls (P <.001). The Cl(u)/F was significantly higher among subjects with steatosis involving >50% of hepatocytes, compared with those with steatosis in < or =50% of hepatocytes (P =.02). At postoperative week 6 and year 1, the median body mass index (BMI) of subjects who underwent gastroplasty decreased by 11% and 33%, total oral CLZ clearance declined by 16% (P <.01) and 46% (P <.05), and Cl(u)/F decreased by 18% (P <.05) and 35% (P =.16), respectively. Moreover, those subjects with a year 1 BMI <30 kg/m(2) exhibited a median Cl(u)/F that was 63% lower (P =.02) than the respective clearance for all other subjects. In conclusion, hepatic CYP2E1 activity is up-regulated in morbidly obese subjects. A positive association between the degree of steatosis and CYP2E1 activity preoperatively and between the extent of obesity and CYP2E1 activity postoperatively, suggests that CYP2E1 induction is related to or caused by hepatic pathology that results from morbid obesity.

Blood Glucose↗
PubMed2002

Liver involvement in patients with solid tumors of nonhepatic origin.

Metastatic disease represents the most common hepatic neoplasm in the Western world. The most common primary malignancies to spread to the liver are those that originate in the gastrointestinal tract. Of non-gastrointestinal malignancies, breast, lung, and melanoma malignancies are most likely to develop hepatic metastases. Some solid tumors, such as renal cell carcinoma, may cause liver-related abnormalities in the absence of hepatic metastases, presumably by way of cytokine-mediated mechanisms. Physical examination, laboratory testing, histologic evaluation, and various radiographic studies are useful in the detection and diagnosis of liver metastases. Multiple treatment modalities are available, including hepatic resection, hepatic arterial chemotherapy, systemic chemotherapy, chemoembolization, cryotherapy, ethanol injection, and radiofrequency ablation.

Humans↗
PubMed2002

Effect of lamivudine treatment on survival of 309 North American patients awaiting liver transplantation for chronic hepatitis B.

The primary aim of this study is to determine whether treatment with lamivudine improved pre-liver transplantation (pre-LT) and LT-free survival of patients awaiting LT for hepatitis B virus (HBV)-related cirrhosis. Data from 162 lamivudine-treated and 147 untreated transplant candidates managed at 20 North American transplant centers between 1996 and 1998 were collected and compared. Lamivudine-treated patients were more likely to be men, hepatitis B e antigen positive, HBV DNA positive, and have lower serum albumin levels at listing (P <.05). Actuarial pre-LT and LT-free survival were similar in lamivudine-treated and untreated patients. Using Cox regression analysis, the only significant predictor of pre-LT patient survival was the modified Child-Turcotte-Pugh (mCTP) score, whereas significant predictors of LT-free survival included ethnic background, lamivudine treatment, indication for LT, baseline serum alanine aminotransferase level, and baseline mCTP score. Lamivudine had no apparent effect on liver disease severity in patients undergoing LT, but appeared to improve disease severity in patients still awaiting LT. Breakthrough infection was noted in 11% of lamivudine-treated patients. We conclude that lamivudine therapy is not associated with improved pre-LT or LT-free survival in LT candidates with chronic hepatitis B. However, a subset of patients with less advanced liver failure may derive clinical benefit from lamivudine therapy, thus delaying the need for LT. In the absence of prospective, randomized, controlled trials of lamivudine in patients with decompensated cirrhosis, careful selection of patients and optimal timing of treatment are needed to balance the risk versus benefit of lamivudine therapy in LT candidates.

Antiviral Agents↗
PubMed2002

Prognostic factors in acute pancreatitis.

The assessment of the severity of acute pancreatitis (AP) is a critical early step in its management, as severity of AP predicts prognosis. A range of options are available for assessment of severity in AP, including clinical evaluation, standardized prognostic criteria, computed tomography (CT), and biochemical markers. Clinical assessment has limited accuracy for predicting severity early in the course of AP. Therefore, additional assessment using biochemical and radiologic criteria in combination with standardized criteria is appropriate to determine severity and prognosis in AP; a strategy emphasizing daily assessment of severity should be used. The APACHE II is the scoring system of choice for evaluating severity in AP, although it remains an imperfect tool. Computed tomographic grading of AP and the development of the CT severity index allow for heightened accuracy in the prediction of severity. C-Reactive protein is the standard for serum marker assessment of severity and prognosis in AP; other markers, including interleukin-6, polymorphonuclear elastase, and trypsinogen activation peptide, hold promise. The focus of this review is to examine the role of diagnostic tests in evaluating severity and predicting prognosis among patients with AP and to provide a diagnostic algorithm for initial management.

Acute Disease↗
PubMed2002

Temporary support for acute liver failure.

GOAL: To review treatment approaches for temporary liver support of patients with acute liver failure (ALF). STUDY A MEDLINE: search of English language reports published between 1960 and 1999 and a manual search of bibliographies of relevant papers were performed. Studies of humans in whom non-orthotopic liver transplant (OLT)-based approaches were used were reviewed, including case reports, case series, review articles describing unpublished cases, and controlled trials. Relevant clinical information was extracted with emphasis on improvement in liver function, successful bridging to OLT, recovery without OLT, and death. There was a lack of more than one controlled trial for each therapy, and most case reports were anecdotal in nature; therefore, no statistical analysis was attempted. Predefined outcomes from individual patients were synthesized collectively into tables. RESULTS: Both cell-based and non-cell-based therapies for ALF appear promising. Preliminary experience has established the safety of these approaches, but current data are inadequate to evaluate efficacy. CONCLUSIONS: Routine use of artificial liver support systems cannot be recommended at this time. However, the established safety of cell- and non-cell-based liver support devices warrants additional prospective (Phase III) controlled trials among patients with ALF. We suggest an algorithm for management of patients with ALF that incorporates recent data.

Humans↗