Bone disease in patients with primary sclerosing cholangitis.

BACKGROUND & AIMS: Osteopenic bone disease occurs frequently among patients with chronic liver disease but has not been well studied in those with primary sclerosing cholangitis (PSC). We investigated the prevalence, rate of progression, and independent predictors of bone disease in a large number of patients with all stages of PSC. METHODS: Bone mineral density of the lumbar spine, hip, and total body was measured yearly for 10 years in 237 patients with PSC. RESULTS: Osteoporosis (T-score less than -2.5) was found in 15% of patients and occurred 23.8-fold (95% confidence interval [CI], 4.6-122.8) more frequently in those with PSC than expected from a matched population. By multivariate analysis, age 54 years or older (odds ratio [OR], 7.8; 95% CI, 3.3-18.3), body mass index ≤ 24 kg/m(2) (OR, 4.9; 95% CI, 1.9-12.6), and inflammatory bowel disease for ≥ 19 years (OR, 3.6; 95% CI, 1.5-8.4) correlated with the presence of osteoporosis. Osteoporosis was present in 75% of patients with all 3 risk factors but in only 3.1% of those without all of them. Patients with PSC lost 1% of bone mass per year; this rate of bone loss was significantly associated with duration of inflammatory bowel disease. CONCLUSIONS: Osteoporosis occurs frequently among patients with PSC. Old age, low body mass index, and long duration of inflammatory bowel disease can be used to identify patients with PSC who might derive the most benefit from measurements of bone density and treatments for bone diseases.

Thalidomide for the treatment of metastatic hepatic epithelioid hemangioendothelioma: a case report with a long term follow-up.

Hepatic epithelioid hemangioendothelioma (HEH) is an unusual, low-grade malignant vascular tumor of the liver. Here we describe a case of a 40-year-old woman who presented with abdominal pain in the upper right quadrant and giant hepatomegaly, in which imaging studies and a fine-needle liver biopsy confirmed the presence of a large EHE with an isolated lung metastasis. After balancing all possible therapeutic modalities the patient was treated conservatively with thalidomide (300 mg/day). The drug was well tolerated with minimal toxicity and the patient continues on therapy 109 months after treatment was started with no disease progression. Current therapeutic options for HEH are discussed in light of the clinical case with particular emphasis on anti-angiogenic therapies.

Viral hepatitis and injection drug use in Appalachian Kentucky: a survey of rural health department clients.

OBJECTIVES: We identified correlates of exposure to hepatitis B and C viruses among health department clients in Appalachian Kentucky, a rural region noted for high poverty and low education. Additionally, we investigated risk factors for transmission, and the frequency of use of preventive measures. METHODS: Patients screened for hepatitis B or C at four county health departments in Appalachian Kentucky were administered a routine prescreening questionnaire and an additional survey designed to obtain detailed personal and behavioral risk factor data. These data were linked to produce a more comprehensive dataset for analysis, including test results, which were attached to the prescreening questionnaire. RESULTS: In total, 92 health department clients participated in the study survey. Of these, test results were available for 80 of the clients. Very few subjects who enrolled in this study tested positive for hepatitis B. Twelve out of 80 participants (15%) tested positive for previous exposure to hepatitis C. No participants reported having human immunodeficiency virus. CONCLUSIONS: Transmission of hepatitis C in these rural Appalachian communities is predominantly due to injection drug use. Patients with hepatitis C exposure are similar in their demographic and risk profiles as those seen in urban areas and, despite small numbers, can have a serious impact on small, rural public health systems.

Alpha-fetoprotein and tumour size are associated with microvascular invasion in explanted livers of patients undergoing transplantation with hepatocellular carcinoma.

BACKGROUND: To determine factors associated with outcomes and microvascular invasion (MVI) in patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC). METHODS: Between July 1996 and August 2008 at the Universities of Kentucky or Tennessee, LT recipients were retrospectively analysed. RESULTS: One hundred and one patients had HCC in the explanted liver; one patient was excluded because of fibrolamellar histology. Seventy-nine (79%) were male and 81 (81%) were older than 50. HCC was incidental in 32 patients (32%). Median follow-up was 31 months. Ten patients (10%) developed recurrence, which was associated with poor survival (P= 0.006). Overall 1-, 3-, and 5-year survival rates were 87%, 69% and 62%, respectively. Excluding patients with lymph node metastasis (LNM) or MVI yielded 91%, 81% and 75% survival at the same time points. MVI was independently associated with recurrence (OR 28.40, 95% CI 1.77-456.48, P= 0.018) and decreased survival (OR 4.70, 95% CI 1.24-17.80, P= 0.023), and LNM with decreased survival (OR 6.05, 95% CI 1.23-29.71, P= 0.027). Tumour size (OR 4.1, 95% CI 1.2-13.5, P= 0.013) and alpha-fetoprotein (AFP) > 100 (OR 5.0, 95% CI 1.4-18.1, P= 0.006) were associated with MVI. CONCLUSIONS: MVI greatly increases the risk of recurrence and death after LT for HCC, and is strongly associated with tumour size and AFP > 100.

Analysis of smoking in patients referred for liver transplantation and its adverse impact of short-term outcomes.

Smoking has been reported to adversely affect the outcome of patients undergoing liver transplantation (LT). We present a clinical and demographic analysis of smoking in patients from a rural Appalachian region referred to our center for LT. We reviewed 237 consecutive patients referred for LT between January 2002 and December 2003. We also reviewed charts of 65 patients that underwent LT at our center during this period and analyzed the length of stay (LOS), one-year survival post LT, and hospital charge information. The mean MELD score was similar between smokers and nonsmokers at the time of referral (12.3 vs. 12.1, respectively, p = 0.8). Smokers had a tendency towards a higher CPT score (8.2 vs. 7.9, p = 0.06). The incidence of difficult-to-manage ascites and encephalopathy was significantly higher in smokers (p < 0.O1 for both ascites and encephalopathy). Of the 65 patients that underwent LT, 69.2% were smokers. While one-year post LT survival was similar (approximately 90%) for both smokers and nonsmokers, the mean length of stay and hospital charge for smokers was significantly higher (13.4 vs. 7.9 days; P = .02 and $129,185 vs. $99,694; P = .02). In conclusion, smokers have a higher incidence of ascites and encephalopathy and thus may be disadvantaged by the MELD allocation scheme for liver transplantation. While post-transplant one-year survival is similar between smokers and nonsmokers, smokers have higher LOS and resource utilization.

Liver transplantation for the treatment of liver metastases from neuroendocrine tumors: an analysis of the UNOS database.

OBJECTIVE: To determine outcomes in patients undergoing liver transplantation (LT) for metastatic neuroendocrine tumors (NETs). DESIGN: Retrospective analysis. SETTING: University of Kentucky Medical Center. PATIENTS: Patients undergoing LT performed for NET metastases from October 1, 1988, through January 31, 2008, were analyzed using the United Network for Organ Sharing database. Main Outcome Measure  Patient survival. RESULTS: During the study period, 87 280 LTs were performed. One hundred fifty LTs were performed for metastatic NETs. Among those 150 patients undergoing LT, 51 patients (34.0%) had carcinoid, 6 had insulinoma (4.0%), 3 had glucagonoma (2.0%), 11 had gastrinoma (7.3%), and 9 had vasoactive intestinal peptide-secreting tumors (6.0%); an additional 70 (46.7%) had an unspecified NET. The mean (SE) age of the patients was 45.1 (12.5) years. The mean (SE) cold ischemic time was 8.9 (4.1) hours. One hundred forty-four patients were adults and 6 were children. Thirteen patients received another organ at the time of LT. During the same period, 4693 patients underwent transplantation for hepatocellular carcinoma. Overall, 1-, 3-, and 5-year survival rates for patients with NETs undergoing isolated LT were 81%, 65%, and 49%, respectively. No difference in survival was observed in patients with carcinoid vs noncarcinoid tumors (P = .84). No significant difference was observed in patient survival between those with metastatic NETs and those with hepatocellular carcinoma. Patients waiting for LT longer than 2 months had improved survival (P = .005). CONCLUSIONS: Patients with liver metastases from NETs who were undergoing LT had long-term survival similar to that of patients with hepatocellular carcinoma. Longer wait times were associated with better outcomes in our series. Waiting for disease to stabilize before considering patients with liver metastases from NETs for transplantation may be appropriate. Excellent results can be obtained in highly selected patients.

PI-103 and sorafenib inhibit hepatocellular carcinoma cell proliferation by blocking Ras/Raf/MAPK and PI3K/AKT/mTOR pathways.

BACKGROUND: Aberrant Ras/Raf/MAPK and PI3K/AKT/mTOR signaling pathways are found in hepatocellular carcinoma (HCC). This study reports how sorafenib (a multi-kinase inhibitor) and PI-103 (a dual PI3K/mTOR inhibitor) alone and in combination inhibit the proliferation of the HCC cell line, Huh7. MATERIALS AND METHODS: Huh7 proliferation was assayed by 3H-thymidine incorporation and by MTT assay. Western blot was used to detect phosphorylation of the key enzymes in the Ras/Raf and PI3K pathways. RESULTS: Sorafenib and PI-103, as single agents inhibited Huh7 proliferation and epidermal growth factor (EGF)-stimulated Huh7 proliferation in a dose-dependent fashion; the combination of sorafenib and PI-103 produced synergistic effects. EGF increased phosphorylation of MEK and ERK, key Ras/Raf downstream signaling proteins; this activation was inhibited by sorafenib. However, sorafenib as a single agent increased AKT(Ser473) and mTOR phosphorylation. EGF-stimulated activation of PI3K/AKT/mTOR pathway components was inhibited by PI-103. PI-103 is a potent inhibitor of AKT(Ser473) phosphorylation; in contrast, rapamycin stimulated AKT(Ser473) phosphorylation. It was found that PI-103, as a single agent, stimulated MEK and ERK phosphorylation. However, the combination of sorafenib and PI-103 caused inhibition of all the tested kinases in the Ras/Raf and PI3K pathways. CONCLUSION: The combination of sorafenib and PI-103 can significantly inhibit EGF-stimulated Huh7 proliferation by blocking both Ras/Raf/MAPK and PI3K/AKT/mTOR pathways.

Diffuse malignant infiltration of the liver manifesting as a case of acute liver failure.

BACKGROUND: A 54-year-old male with a history of coronary artery disease, diabetes mellitus and 120 pack years of tobacco abuse presented to the emergency room with right upper quadrant abdominal pain, decreased appetite and dark urine. INVESTIGATIONS: Laboratory investigations, chest radiograph, portal duplex, CT of the abdomen and pelvis, liver serologies and autopsy. DIAGNOSIS: Fulminant hepatic failure secondary to metastatic small-cell lung carcinoma. MANAGEMENT: Supportive care.

Predictors of relapse to alcohol and illicit drugs after liver transplantation for alcoholic liver disease.

BACKGROUND: Alcoholic liver disease (ALD) is a common indication for transplantation worldwide. This study identifies factors predicting posttransplant recidivism. METHODS: Clinical and laboratory data were reviewed. Uni- and multivariate analyses for survival and relapse to alcohol and illicit drugs were performed. RESULT: Between July 1995 and November 2007, 387 patients underwent liver transplantation at our institution. Of these, 147 patients (38%) were found to have ALD. Five patients (3.4%) were excluded because of perioperative mortality. Overall survival was 96.2%, 89.6%, and 84.4% at 1, 3, and 5 years, respectively, with a median follow-up of 41.2 months. Twenty-seven patients (19%) returned to alcohol after transplantation. By univariate analysis, depression was the only significant factor affecting survival (P=0.01), whereas posttransplant relapse to alcohol trended toward significance (P=0.059). Multivariate analysis showed both factors to be independently associated with poor survival (P=0.008 and 0.017, respectively). Factors associated with relapse included less than 12 months of abstinence before transplant (P=0.019) and participation in rehabilitation (P=0.026). Multivariate analysis showed pretransplant abstinence less than 12 months as the only independent factor (P=0.037) associated with alcohol relapse after transplantation. Twenty-five patients (17.2%) had documented drug use after transplantation. Drug abuse before transplantation was the only independent predictor of drug abuse after transplantation (P=0.017). CONCLUSIONS: Excellent results can be obtained in patients undergoing liver transplantation for ALD, though depression and recidivism adversely impact survival. In our series, abstinence less than 12 months was associated with relapse to alcohol. Similarly, those with prior drug abuse are more likely to continue drug use after transplantation.

Lípidos séricos como factor de riesgo coronario: influencia de la dieta en 358 hombres sanos / Serum lipids and coronary risk: diet influence in 358 healthy men

La dieta puede ser un condicionante de riesgo de cardiopatía coronaria si modifica en forma desfavorable los niveles séricos de colesterol total (CT), colesterol de HDL (CH) y la relación entre ellos (CT/CH). En 358 hombres sanos, se estimó la ingesta mediante encuesta alimentaria por registro de 3 días. Se realizaron correlaciones univariadas y multivariadas para establecer la influencia de la dieta, edad e índice de masa corporal (IMC) sobre el CT, CH y CT/CH. Los sujetos consumieron un promedio de 2.388 Kcals/día distribuídas en un 30% como lípidos, un 49,6% como carbohidratos (H de C), un 14,1% como proteínas y 6,3% como alcohol. La ingesta de colesterol promedio ñ DS fue de 287 ñ 143 mg/día y la relación ácidos grasos poliinstaurados/saturados (IP/S), de 0,88. Los H de C fueron los únicos nutrientes que influyeron significativamente sobre los lípidos séricos, demostrándose una asociación inversa entre el consumo de carbohidratos y los niveles de CT y de CH, pero sin inducir cambios en la relación CT/CH. El índice de masa corporal en cambio se asoció positivamente con la razón CT/CH, modificando un 7% de la varianza de este indicador. Se concluye que en esta población la composición de la dieta no constituye un factor de mayor riesgo coronario. La obesidad, evaluada por IMC, incrementa la relación CT/CH elevando así el riesgo de enfermedad coronaria

Alcohol y factores de riesgo de cardiopatía coronaria: estudio en 571 hombres / Alcohol and risk factors for coronary heart disease: a study in 571 males

In 571 health professional males we correlated alcohol consumption with serum total cholesterol (C), HDL-C, triglycerides, blood sugarm cigarette consumption, body mass index and arterial blood pressure. An autstanding finding was a positive independent, correlation of alcohol consumption and serum HDL-C levels (r0.22, p<0.0001). Univariate analysis showed correlation of alcohol consumption woth body mass index, blood pressure and total serum C, however this was dependent on age and/or body mass. No correlation was found between alcohol consumption and blood sugar or TG levels. Alcohol consumption did not identify a group of subjects with high risk factors. Consumption of more than 10 cigarettes per day decreased the strenght of the association between elevated HDL levels and alcohol consumption. We conclude that a moderate intake of alcohol is associated to increased serum HDL levels with no significant change of other coronary risk factors