The Gly385(388)Arg Polymorphism of the FGFR4 Receptor Regulates Hepatic Lipogenesis Under Healthy Diet.

CONTEXT: The effect of a lifestyle intervention to reduce liver fat content in nonalcoholic fatty liver disease in humans is influenced by genetics. We hypothesized that the amino acid exchange in human Gly388Arg (mouse homolog: Gly385Arg) in fibroblast growth factor receptor 4 (FGFR4), which regulates bile acid, lipid, and glucose metabolism, could determine hepatic lipid accumulation and insulin sensitivity. Mechanisms of this substitution were studied in mice under normal chow and high-fat diets. DESIGN: In humans, the Gly388Arg polymorphism was studied for its relationship with changes in liver fat content and insulin sensitivity during 9 months of a lifestyle intervention. We also studied a knock-in mouse strain with an Arg385 allele introduced into the murine FGFR4 gene under normal chow and high-fat diets. RESULTS: In humans, the FGFR4 Arg388 allele was not associated with liver fat content or insulin sensitivity in subjects who were overweight and obese before lifestyle intervention. However, it was associated with less decrease in liver fat content and less increase in insulin sensitivity during the intervention. In mice receiving normal chow, the FGFR4 Arg385 allele was associated with elevated hepatic triglyceride content, altered hepatic lipid composition, and increased hepatic expression of genes inducing de novo lipogenesis and glycolysis. Body fat mass and distribution, glucose tolerance, and insulin sensitivity were unaltered. The FGFR4 Arg385 allele had no effect on glucose or lipid metabolism under the high-fat diet. CONCLUSION: Our data indicate that the FGFR4 Arg388(385) allele affects hepatic lipid and glucose metabolism specifically during healthy caloric intake.

Genetic ablation of cGMP-dependent protein kinase type I causes liver inflammation and fasting hyperglycemia.

OBJECTIVE: The nitric oxide/cGMP/cGMP-dependent protein kinase type I (cGKI) signaling pathway regulates cell functions that play a pivotal role in the pathogenesis of type 2 diabetes. However, the impact of a dysfunction of this pathway for glucose metabolism in vivo is unknown. RESEARCH DESIGN AND METHODS: The expression of cGKI in tissues relevant to insulin action was analyzed by immunohistochemistry. The metabolic consequences of a genetic deletion of cGKI were studied in mice that express cGKI selectively in smooth muscle but not in other cell types (cGKI-SM mice). RESULTS: In wild-type mice, cGKI protein was detected in hepatic stellate cells, but not in hepatocytes, skeletal muscle, fat cells, or pancreatic ß-cells. Compared with control animals, cGKI-SM mice had higher energy expenditure in the light phase associated with lower body weight and fat mass and increased insulin sensitivity. Mutant mice also showed higher fasting glucose levels, whereas insulin levels and intraperitoneal glucose tolerance test results were similar to those in control animals. Interleukin (IL)-6 signaling was strongly activated in the liver of cGKI-SM mice as demonstrated by increased levels of IL-6, phospho-signal transducer and activator of transcription 3 (Tyr 705), suppressor of cytokine signaling-3, and serum amyloid A2. Insulin-stimulated tyrosine phosphorylation of the insulin receptor in the liver was impaired in cGKI-SM mice. The fraction of Mac-2-positive macrophages in the liver was significantly higher in cGKI-SM mice than in control mice. In contrast with cGKI-SM mice, conditional knockout mice lacking cGKI only in the nervous system were normal with respect to body weight, energy expenditure, fasting glucose, IL-6, and insulin action in the liver. CONCLUSIONS: Genetic deletion of cGKI in non-neuronal cells results in a complex metabolic phenotype, including liver inflammation and fasting hyperglycemia. Loss of cGKI in hepatic stellate cells may affect liver metabolism via a paracrine mechanism that involves enhanced macrophage infiltration and IL-6 signaling.

Bipolar radiofrequency ablation using internally cooled electrodes in ex vivo bovine liver: prediction of coagulation volume from applied energy.

OBJECTIVE: We sought to evaluate the relationship between parameters of bipolar radiofrequency (RF) ablation using internally cooled electrodes. MATERIALS AND METHODS: Bipolar RF ablations (n = 24) were performed in ex vivo bovine liver using an internally cooled applicator with 2 electrodes located on the same shaft. The power-output was systematically varied (20-75 W). On the basis of our experimental data, mathematical functions were fitted and the goodness-of-fit was assessed by the parameter R. RESULTS: The duration to induce an increase of tissue resistance and the amount of applied energy increased with a decreased power-output. The maximum short-axis was 4.5 cm (20 W) and required an application of 64 kilojoules (kJ). The volume of coagulation can be determined as a function of the duration of energy application (R = 0.954) and the amount of applied energy (R = 0.945). CONCLUSION: The amount of applied energy and the duration of energy application can predict the volume of induced coagulation and may be useful to control internally cooled bipolar RF ablation.

Progressive bicytopenia due to persistent parvovirus B19 infection after immunochemotherapy with fludarabine/cyclophosphamide and rituximab for relapsed B cell lymphoma.

Human parvovirus B 19 is known as a virus causing erythema infectiosum, arthropathy, transient aplastic crisis and intrauterine fetal death. Healthy hosts are able to clear the virus within weeks after infection. There are a few reports available in the literature regarding immunocompromised renal transplant recipients with persistent infection without seroconversion. Herein, we describe a 56-year old woman with a relapse of grade II follicular lymphoma who received a combined immunochemotherapy of rituximab, fludarabine and cyclophosphamide and subsequently developed a persistent parvovirus B19 infection. In the absence of serum immunoglobulin antibodies, PCR analysis of peripheral blood and bone marrow aspirate were positive for parvovirus B19. Treatment with IVIG treatment resulted in normalization of peripheral blood counts within 7 weeks.

Alpha2-Heremans-Schmid glycoprotein/fetuin-A is associated with insulin resistance and fat accumulation in the liver in humans.

OBJECTIVE: The alpha(2)-Heremans-Schmid glycoprotein (AHSG; fetuin-A in animals) impairs insulin signaling in vitro and in rodents. Whether AHSG is associated with insulin resistance in humans is under investigation. In an animal model of diet-induced obesity that is commonly associated with hepatic steatosis, an increase in Ahsg mRNA expression was observed in the liver. Therefore, we hypothesized that the AHSG plasma protein, which is exclusively secreted by the liver in humans, may not only be associated with insulin resistance but also with fat accumulation in the liver. RESEARCH DESIGN AND METHODS: Data from 106 healthy Caucasians without type 2 diabetes were included in cross-sectional analyses. A subgroup of 47 individuals had data from a longitudinal study. Insulin sensitivity was measured by a euglycemic-hyperinsulinemic clamp, and liver fat was determined by (1)H magnetic resonance spectroscopy. RESULTS: AHSG plasma levels, adjusted for age, sex, and percentage of body fat, were higher in subjects with impaired glucose tolerance compared with subjects with normal glucose tolerance (P = 0.006). AHSG plasma levels were negatively associated with insulin sensitivity (r = -0.22, P = 0.03) in cross-sectional analyses. Moreover, they were positively associated with liver fat (r = 0.27, P = 0.01). In longitudinal analyses, under weight loss, a decrease in liver fat was accompanied by a decrease in AHSG plasma concentrations. Furthermore, high AHSG levels at baseline predicted less increase in insulin sensitivity (P = 0.02). CONCLUSIONS: We found that high AHSG plasma levels are associated with insulin resistance in humans. Moreover, AHSG plasma levels are elevated in subjects with fat accumulation in the liver. This is consistent with a potential role of AHSG as a link between fatty liver and insulin resistance.

Lymphatic endothelial progenitor cells contribute to de novo lymphangiogenesis in human renal transplants.

De novo lymphangiogenesis influences the course of different human diseases as diverse as chronic renal transplant rejection and tumor metastasis. The cellular mechanisms of lymphangiogenesis in human diseases are currently unknown, and could involve division of local preexisting endothelial cells or incorporation of circulating progenitors. We analyzed renal tissues of individuals with gender-mismatched transplants who had transplant rejection and high rates of overall lymphatic endothelial proliferation as well as massive chronic inflammation. Donor-derived cells were detected by in situ hybridization of the Y chromosome. We compared these tissues with biopsies of essentially normal skin and intestine, and two rare carcinomas with low rates of lymphatic endothelial proliferation that were derived from individuals with gender-mismatched bone marrow transplants. Here, we provide evidence for the participation of recipient-derived lymphatic progenitor cells in renal transplants. In contrast, lymphatic vessels of normal tissues and those around post-transplant carcinomas did not incorporate donor-derived progenitors. This indicates a stepwise mechanism of inflammation-associated de novo lymphangiogenesis, implying that potential lymphatic progenitor cells derive from the circulation, transmigrate through the connective tissue stroma, presumably in the form of macrophages, and finally incorporate into the growing lymphatic vessel.

Multipolar radiofrequency ablation with internally cooled electrodes: experimental study in ex vivo bovine liver with mathematic modeling.

PURPOSE: To evaluate the size and geometry of thermally induced coagulation by using multipolar radiofrequency (RF) ablation and to determine a mathematic model to predict coagulation volume. MATERIALS AND METHODS: Multipolar RF ablations (n = 80) were performed in ex vivo bovine livers by using three internally cooled bipolar applicators with two electrodes on the same shaft. Applicators were placed in a triangular array (spacing, 2-5 cm) and were activated in multipolar mode (power output, 75-225 W). The size and geometry of the coagulation zone, together with ablation time, were assessed. Mathematic functions were fitted, and the goodness of fit was assessed by using r(2). RESULTS: Coagulation volume, short-axis diameter, and ablation time were dependent on power output and applicator distance. The maximum zone of coagulation (volume, 324 cm(3); short-axis diameter, 8.4 cm; ablation time, 193 min) was induced with a power output of 75 W at an applicator distance of 5 cm. Coagulation volume and ablation time decreased as power output increased. Power outputs of 100-125 W at applicator distances of 2-4 cm led to a reasonable compromise between coagulation volume and ablation time. At 2 cm (100 W), coagulation volume, short-axis diameter, and ablation time were 66 cm(3), 4.5 cm, and 19 min, respectively; at 3 cm (100 W), 90 cm(3), 5.2 cm, and 22 min, respectively; at 4 cm (100 W), 132 cm(3), 6.1 cm, and 27 min, respectively; at 2 cm (125 W), 56 cm(3), 4.2 cm, and 9 min, respectively; at 3 cm (125 W), 73 cm(3), 4.9 cm, and 12 min, respectively; and at 4 cm (125 W), 103 cm(3), 5.5 cm, and 16 min, respectively. At applicator distances of 4 cm (>125 W) and 5 cm (>100 W), the zones of coagulation were not confluent. Coagulation volume (r(2) = 0.80) and RF ablation time (r(2) = 0.93) were determined by using the mathematic model. CONCLUSION: Multipolar RF ablation with three bipolar applicators may produce large volumes of confluent coagulation ex vivo. A compromise is necessary between prolonged RF ablations at lower power outputs, which produce larger volumes of coagulation, and faster RF ablations at higher power outputs, which produce smaller volumes of coagulation.

Chronic renal failure and proteinuria in adulthood: Fabry disease predominantly affecting the kidneys.

The prognosis of Fabry disease has changed since enzyme-replacement treatment was introduced. Therefore, early diagnosis is instrumental. We describe a family presenting with chronic renal failure and proteinuria in which classic skin and neurological features were absent and the diagnosis of Fabry disease was difficult and not established until a second family member developed renal abnormalities. A 35-year-old man was admitted because he was overweight and had hypertension, with a serum creatinine level of 1.3 mg/dL (115 micromol/L) and protein excretion of 870 mg/d. Because 1 brother, who died years ago at the age of 32 years of acute myeloid leukemia, also had chronic renal failure and proteinuria, the diagnosis of Fabry disease was entertained. In the index patient, acroparesthesia, hypohidrosis, pain, angiokeratomas of the skin, and cornea verticillata suggesting Fabry disease were absent. Conversely, renal biopsy showed typical globotriaosylceramide deposits, and leukocyte alpha-galactosidase (alpha-GLA) A activity was decreased. Analysis of the alpha-GLA gene showed the mutation E66K. The mutation also was found in another asymptomatic 30-year-old brother who also had chronic renal failure and proteinuria, but normal extrarenal findings. In the brother who died, Fabry disease, missed at autopsy because of cancer-related findings, could be confirmed after repeated review of histological slides. Mutation carriers also included the mother, a sister (both without abnormalities), and a nephew (with episodic pains in his feet). We conclude that familial chronic renal failure combined with proteinuria is suggestive of Fabry disease, and such specific mutations as E66K predominantly may affect the kidneys.

Intravascular lymphoma - a rare cause of hemolytic anemia and neurologic disorders.

Intravascular lymphoma is an uncommon and often overlooked form of non-Hodgkin's lymphoma characterized by extensive proliferation of lymphoid cells within the lumina of small and medium-sized vessels. Clinical symptoms of the disease are variable and often nonspecific, mostly neurologic in nature. With an aggressive course, intravascular lymphomatosis has a poor prognosis and is rarely diagnosed ante mortem. We describe here a 76-year-old woman with the clinical diagnoses of hemolytic anemia and progressive lethargy where intravascular lymphomatosis turned out as the underlying cause of the disease.

Xanthogranulomatous cholecystitis resembling carcinoma with extensive tumorous infiltration of the liver and colon.

BACKGROUND: Xanthogranulomatous cholecystitis is a macrophage-rich inflammatory condition of the gallbladder that occasionally presents with tumorlike appearance. CASE PRESENTATION: In the present case the inflammation involved all the layers of the gallbladder, the surrounding connective tissue, and part of the right lobe of the liver and right transverse colon. The clinical and radiological findings were suggestive of advanced carcinoma of the gallbladder. However, intraoperative frozen section investigation revealed xanthogranulomatous cholecystitis, for which simple cholecystectomy is the treatment of choice. CONCLUSIONS: The original cause of the condition is unclear in most cases. In the present case it is possible that rupture of the gallbladder in association with the patient's known history of trauma have initiated the process.