Higher Total Bilirubin Levels Research Articles

Nonalcoholic fatty liver disease in patients with type 2 diabetes

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is reported commonly in patients with type 2 diabetes mellitus (DM), which has been suggested as a risk factor for the progressive form of NAFLD, or nonalcoholic steatohepatitis. The aim of this study was to assess the outcome of patients with NAFLD and DM. Methods: A cohort of patients with NAFLD was identified, and patients with other causes of liver disease (alcohol, medication, etc.) were excluded. Clinical, pathological, and mortality data were available for this cohort. Patients were categorized and compared according to the presence or absence of DM. Results: Of 132 patients with NAFLD, 44 patients (33%) had an established diagnosis of DM. Patients with DM were older and had greater serum glucose and triglyceride levels and a greater aspartate aminotransferase-alanine aminotransferase ratio. Liver biopsy specimens from patients with DM showed more vacuolated nuclei and acidophilic bodies. Cirrhosis (histological or clinical) occurred in 25% of patients with DM (11 of 44 patients) and NAFLD compared with only 10.2% (9 of 88 patients) of patients without DM with NAFLD ( P = 0.04). After adjusting for potential confounders (age, body mass index, and the presence of cirrhosis), both overall mortality (risk ratio [RR], 3.30; 95% confidence interval [CI], 1.76–6.18; P = 0.002) and mortality related to liver disease (RR, 22.83; 95% CI, 2.97–175.03; P = 0.003) were greater in diabetic patients with NAFLD. Markers of hepatic dysfunction (low albumin level, high total bilirubin level, and prolonged prothrombin time) were the only independent predictors of increased mortality. Conclusions: Patients with NAFLD and DM are at risk for the development of an aggressive outcome, such as cirrhosis and mortality. This study supports the potential role of insulin resistance in the development of poor clinical outcomes in patients with NAFLD.

Hepatic venoocclusive disease in blood and bone marrow transplantation in children and young adults: incidence, risk factors, and outcome in a cohort of 241 patients.

To describe recent characteristics of incidence, risk factors, treatment, and outcome of venoocclusive disease (VOD) in children and young adults undergoing blood and bone marrow transplantation (BMT). All children and young adults (n = 241) undergoing first myeloablative transplant at the UCSF Pediatric BMT unit between 1992 and 2000 were included. Retrospective chart review was done. Descriptive statistics and univariate and multivariate analyses of risk factors are presented. Venoocclusive disease developed in 65 patients (27%); it was severe in 13/65 patients (20%). Matched unrelated donor transplantation, advanced-stage malignancies, and transplantation in the recent period (1998-2000) were identified as significant risk factors for VOD in univariate and multivariate analyses. Heparin prophylaxis did not decrease the incidence of VOD. Venoocclusive disease was diagnosed at a median day 8 after BMT. Five of 13 patients with severe VOD (38%) survived for more than 1 year after BMT, even after renal and respiratory failure and high total bilirubin levels up to 35 mg/dL. Nine of the 13 patients received fibrinolytic treatment with tissue plasminogen activator, anti-thrombin 3, or defibrotide. The survival rate at day 100 after BMT for children with VOD was 77%; it was 94% for those without VOD. The persistently high incidence of VOD, its significant impact on posttransplant survival, and the demonstration of recovery from even severe VOD underscore the importance of early diagnosis and initiation of specific therapy. The use of Bearman's model of prediction of severity of VOD and the application of fibrinolytic drugs when adequate are highly recommended.

Serum levels of γ-globulin and total bilirubin influence the prevalence of multiple extrahepatic complication in patients with hepatitis C virus infection

Patients with chronic hepatitis C virus (HCV) infection develop various extrahepatic complications. In this study, we analyzed as following. (1) The prevalence and interrelation of multiple extrahepatic manifestations. (2) Exact factors that are related to multiple extrahepatic manifestations. Consecutive autopsies of 261 cases with HCV infection that had undergone autopsy in 1988–1998 were enrolled. One hundred and forty consecutive patients who had gastro enteric carcinoma and underwent autopsy after death in our institution during the same period were used as controls. These 140 patients did not have hepatitis virus and chronic hepatitis or liver cirrhosis histologically. The prevalence of glomerulonephritis (GN), sialadenitis, thyroiditis, and idiopathic pulmonary fibrosis (IPF) was determined histologically. ‘Multiple extrahepatic complications’ was defined as the presence of two or more of the above four extrahepatic complications. Multiple logistic regression analyses of the risk for the multiple extrahepatic manifestations were performed. GN was present in 58.6% (153 cases), sialadenitis in 16.1% (42 cases), thyroiditis in 7.7% (20 cases), and IPF in 5% (13 cases) in cases of HCV infection. In addition, 37 out of 261 (14.2%) and seven (2.7%) cases had two and three extrahepatic complications, respectively. Multivariate analysis showed that multiple extrahepatic complications correlated with high serum γ-globulin levels (≥2.5 g/dl) and high serum total bilirubin levels (≥1.2 mg/dl) about 1 year before death. Moreover, about 70–80% of patients with sialadenitis, IPF, or thyroiditis had other extrahepatic manifestations. HCV-positive patients with high serum γ-globulin or high total bilirubin are at high risk of multiple extrahepatic complications.

Predictive Factors of Malaria in Travelers to Areas Where Malaria Is Endemic

The differentiation of malaria from other causes of fever is difficult. The development of tools for rapid and specific clinical diagnosis is of paramount importance for the identification of individuals infected with malaria. A 4-year prospective study to identify the clinical and biological variables associated with malaria included all patients suspected of having malaria who presented in the emergency department (ED) of a French hospital. Of 783 patients admitted to the ED with suspected malaria, 145 had positive findings of a thick smear for Plasmodium species, mainly Plasmodium falciparum (90.3%). In univariate analysis, the following 12 variables were significantly associated with diagnosis of malaria: older than 30 years, male sex, immigration to France from an area where malaria is endemic, a visit to sub-Saharan Africa, insufficient antimalaria prophylaxis, fever, chills, absence of diarrhea, a leukocyte count within the reference range, thrombocytopenia, and increased lactate dehydrogenase and bilirubin levels. In multivariate analysis, the factors predictive of malaria included a visit to sub-Saharan Africa (odds ratio [OR], 7.7; 95% confidence interval [CI], 2.8-21.3), a temperature of at least 38.5 degrees C (OR, 6.2; 95% CI, 2.8-13.3), chills (OR, 3.0; 95% CI, 1.4-6.6), thrombocytopenia (OR, 16.5; 95% CI, 7.1-38.3), and abnormally high total bilirubin levels (OR, 21.5; 95% CI, 6.4-72.5). However, alone or combined, these features had insufficient sensitivity (95.0%) and low specificity (55.0%) for the diagnosis of malaria. Malaria should be suspected in all patients presenting with complaints after travel to an area where malaria is endemic, and these patients should undergo blood microscopy.

Relative Risk of Liver Failure in Dairy Cows with Left Abomasal Displacement

Dairy cows with left abomasal displacement (LDA) are in substantial negative energy balance and mobilize considerable amounts of non-esterified fatty acids. Thus, fatty liver is a common hepatic disorder in LDA cows. Results of a previous study showed that approximately 4-5% of LDA cows referred to our clinic for surgical correction of abomasal displacement died or were sacrified due to liver coma. We found not only cows with severe fatty liver but also cows with moderate or even mild fatty liver affected by liver failure. Characteristically, cows with liver failure showed typical clinical signs of a hepatic encephalopathy (general depression, ataxia, recumbency or coma) and a low plasma amino acid ratio (Val+Leu+Ile/Phe+Tyr), low plasma cholesterol concentrations and high plasma levels of ammonia, total bilirubin and hepatic enzymes.
 Thus, aim of the study was to calculate the risk of liver failure of dairy cows with LDA related to the hepatic triglyceride content.

Effect of troglitazone on the liver of a Gunn rat model of genetic enzyme polymorphism.

There is a possibility that serious liver dysfunction rarely observed in diabetic patients given troglitazone is attributable to idiosyncratic abnormalities in liver drug-metabolism. In addition, the results of blood biochemical examinations in serious cases of liver dysfunction showed a tendency for a high level of total bilirubin (T-Bil) over a long period compared with other indicators of liver dysfunction. Thus, we focused on genetic variation of UDP-glucuronosyltransferases (UGTs) that are involved in the conjugation of troglitazone and bilirubin. In this study, Gunn rats, which are hereditarily deficient in the UGT1 family of UGT isozymes, and Wistar rats, the parent strain of Gunn rats, were treated with troglitazone for 3 months at dose levels of 0, 100 or 400 mg/kg to investigate two possibilities: first, whether the genetic deficiency in UGT1s induces an alteration of the metabolic profile of troglitazone followed by liver dysfunction, and second, whether the dosing of troglitazone to Gunn rats which show hyperbilirubinemia result in liver dysfunction. As a result, the metabolic profile of troglitazone in Gunn rats was much the same as that of Wistar rats, suggesting that genetic deficiencies in UGT1s did not influence the metabolic profile of troglitazone. Moreover, no elevation of blood biochemical parameters, such as asparate aminotransferase (AST) and alanine aminotransferase (ALT), or histopathological liver injuries, such as hepatocellular degeneration and necrosis, were observed in either strain of rats, and hyperbilirubinemia in Gunn rats was not aggravated by the dosing of troglitazone. These results strongly suggest that troglitazone was not metabolized by UGT1s but by other UGT isozyme (s) in rats, and that glucuronidation of troglitazone did not compete with glucuronidation of bilirubin in vivo. Thus, it is suggested that high levels of total bilirubin in patients with liver dysfunction induced by troglitazone are attributable to hypofunction due to hepatocellular injury, not to metabolic competition of bilirubin with troglitazone. Moreover, it is also suggested that the deficiency in the UGT1 family of UGT isozymes itself may not be the cause of liver dysfunction associated with troglitazone treatment.

Preoperative portal vein embolization: an audit of 84 patients.

Preoperative portal vein embolization (PVE) was performed in 84 patients before extensive liver resection for various diseases. By the criteria of liver volumetric determination, some patients were candidates for PVE, whereas others were not, even though the same surgical procedure, such as extended right lobectomy (ERL), was scheduled. PVE using gelatin sponge powder induced hypertrophy in the nonembolized lobe (0%-171%; median, 30%) and proportional atrophy in the embolized lobe in 2 weeks without eliciting any major inflammatory or necrotic reaction, as evidenced histologically and by the minimal elevations in the serum aspartate transaminase (AST) and alanine transaminase (ALT) values. Alterations in the total bilirubin level and prothrombin time were also insignificant and transient, indicating that hepatocyte functions were not impaired by PVE. Not all patients who undergo PVE proceed with the scheduled hepatic resection procedure, so it is a great advantage that gelatin sponge causes minimal damage compared with other embolizing materials such as cyanoacrylate and absolute ethanol, which have been reported to induce an inflammatory reaction or histological alteration. Our multiple regression analysis showed that three factors, diabetes mellitus, a high total bilirubin level at the time of PVE, and being male, each reduced the extent of hypertrophy in the nonembolized lobe (r2 =.30). By contrast, cholestasis appeared to accelerate the process of atrophy in the embolized lobe (r2 =.16). In conclusion, PVE by gelatin sponge powder is a safe and effective preoperative maneuver that induces hypertrophy of the section of the liver that will remain after partial hepatectomy.

EVALUATION OF FACTORS CONTRIBUTING THE FORM OF THE COMMON BILE DUCT AT CONGENITAL BILIARY DILATATION IN CHILDREN

Twenty-three cases of congenital biliary dilatation in children experienced at the hospital in a recent two decade were didided into two groups by type of the common bile duct, namely, cystic type dilatation (C-type; 12 cases) and fusiform type dilatation (F-type; 11 cases). There were five male and 18 female patients. Averaged age at operation was 2.8, ranging from 2 months to 10 years old. Items investigated included the age of onset of the disease, symptoms at the onset, blood biochemical data (white blood cell count, CRP, and total bilirubin), histopathologic types.The onset age was younger in C-type patients who manifested the disease less than one year of age. Higher total bilirubin level in serum noted in C-type cases than F-type cases. Elevated amylase level in the common bile duct was noted in F-type cases compared to the others.In C-type cases there were more pancreatico-choledochus types, and in C-type cases there were more choledoco-pancreas types in a type of pancreatico-biliary maljunction. Pathological sections of the common bile duct revealed severe chronic inflammation such as wall thickness and fibrosis in C-type cases.It is suggested that the age of onset, the presence of obstructive mechanism at the common bile duct, and type of pancreatico-biliary maljunction might be contributing factors to the type of dilatation.

Identification of Cholesta‐3,5‐dien‐7‐one by Gas Chromatography‐Mass Spectrometry in the Erythrocyte Membrane of Alcoholic Patients

Lipids and oxidized lipids were analyzed by gas chromatography-mass spectrometry in the erythrocyte membranes of alcoholic and control subjects. Cholesta-3,5-dien-7-one and cholesta-trienes were detected in alcoholic samples examined, but not in significant amounts in controls. Levels of polyunsaturated fatty acids (arachidonic acid, 20:4; docosahexaenoic acid, 22:6; and docosatetraenoic acid, 22:4) in alcoholic samples declined significantly, whereas cholesta-3,5-dien-7-one levels increased. A high level of total bilirubin was observed in most patients. A possible mechanism of the accumulation of cholesta-3,5-dien-7-one in the erythrocyte membrane of alcoholics is discussed.

Retrospective analysis of deep-seated candidiasis among cases autopsied between 1982 to 1991

Candida is present in the flora of the oral cavity, skin, intestinal tract and vagina, and is also known to be an opportunistic pathogen. Infection with this fungus has been increasing annually along with wide spread use of broad-spectrum antimicrobial agents. The subjects included 95 patients (48 males and 47 females) who had been diagnosed as having had deep-seated candidiasis, among patients autopsied between 1982 to 1991. In regard to annual changes in deep-seated candidiasis, the incidence reached a peak in the 1985 to 1988 period, and thereafter decreased. The number of cases with leukemia as the underlying disease was the largest, 36 (37.9%), followed by malignant lymphoma in 10, and aplastic anemia 5. The number of cases with infection of the stomach was largest, 42 (44.2%), followed by the esophagus in 33 (34.7%), the lung and kidney. The cases with deep-seated candidiasis showed low values of or level of lymphocyte, hemoglobin, CRP, total protein and cholesterol and high values or levels of LDH, urea N, creatinine and total bilirubin. Cases with marked decrease in neutrophils showed no regional infiltration of inflammatory cells in any of the organs infected with Candida. Cases with disseminated candidiasis showed vascular invasion by Candida. The laboratory findings also showed that most of the cases had been undernourished and had high values of CRP which supports the presence of inflammation. Common sites of infection are the esophagus, stomach, and intestinal tract. In the presence of granulocytopenia and immunodeficiency, tissue invasion become severe and associated with vascular invasion.

Hyperbilirubinemia associated with sepsis in the elderly

In order to elucidate the frequency of hyperbilirubinemia associated with sepsis in the elderly, as well as in clinical and histological characteristics, a total of 117 autopsy cases with sepsis were analyzed retrospectively. Based on the clinico-pathological findings, 48 cases with primary hepato-biliary, cardiac, hematological and shock complications, were excluded because these disorders were thought to affect liver function tests. Four cases out of the remaining 69 cases, 5.8% of the total, showed hyperbilirubinemia above 2 mg/dl (average 4.1 mg/dl), which was thought to be associated with sepsis itself. In these 4 cases, disproportionately high levels of blood total bilirubin were characteristic compared to changes of GOT, GPT, LDH, ALP and gamma-GTP levels. Blood culture of these 4 cases revealed Gram-negative organisms in 3 cases and Gram-positive in 1 case. Histological findings of the liver included cholestasis, Kupffer cell hyperplasia and cell infiltration in the sinusoid and portal areas, however these findings were mild and nonspecific. It is important to recognize the presence of hyperbilirubinemia associated with sepsis in order to properly treat febrile elderly patients with hyperbilirubinemia.

Neonatal status and hearing loss in high-risk infants

Neurophysiologic and behavioral assessments of auditory function were performed on 224 very low birth weight (less than or equal to 1500 gm) infants requiring intensive care in the nursery. The subjects were studied prospectively from 36 weeks to 4 years of age, as available for follow-up. To classify them according to their neonatal status, we applied a principal components analysis to a number of variables representative of the extent of illness and of patient care in early postnatal life. The subjects were then divided into neonatal status quartiles and evaluated for hearing outcome. All those with sensorineural hearing loss fell exclusively into the lowest neonatal status quartile. Sensorineural hearing loss was statistically associated (1) with greater amounts of furosemide administration for longer durations and in combination with aminoglycoside antibiotics and (2) with more episodes of low pH, hypoxemia, or both, higher total bilirubin levels, and substantially lower neonatal status scores. Birth weight, gestational age, highest creatinine level, Apgar score, and aminoglycosides alone were not systematically related to hearing capacity. Subjects in the lowest neonatal status quartile also had a considerably higher incidence of middle ear disorders, characterized by elevated thresholds and prolonged auditory brain stem-response latencies reflective of conductive hearing loss. We conclude that protracted illness and its associated treatment, independently of specific diagnostic categories, constitute important risk factors for permanent hearing loss and for transient hearing loss in early life.

Autoimmune hepatitis: the present status in Japan.

A nationwide survey using questionnaires was carried out concerning lupoid hepatitis and related diseases (518 cases) during the 8-year period from January, 1975 to December, 1982. The following results were obtained. A total of 253 cases of autoimmune hepatitis, consisting of 97 lupoid hepatitis and 156 lupoid type CAH, were reported. Autoimmune hepatitis was overwhelmingly predominant in females, while male cases of B type CAH with a gamma-globulin level of more than 2 g/dl significantly outnumbered female CAH cases of the same type. The liver function tests at the first examination demonstrated that transaminases, total bilirubin, ICG (R15) and gamma-globulin were increased, and ChE was decreased in lupoid hepatitis. Lupoid type CAH showed a close similarity with lupoid hepatitis rather than to the nLnB type or B type with regard to liver function. Of the 289 patients who could be followed up, 280 cases (97%) received steroid hormones, and 247 (85%) received no another drug. Immunosuppressive treatment was also performed in 40% of the HBs antigen-positive cases of B type CAH. The efficacy was about 90% in the lupoid hepatitis group as well as in the lupoid type CAH group. It was no greater than approximately 70% in any other group. Analysis of survival revealed the following: 1) The cumulative survival rates of autoimmune hepatitis was lowest among the different types of CAH. 2) Patients who had a high serum level of total bilirubin tended to die sooner than those who had a low level. There was no correlation between the cumulative survival rate and serum gamma-globulin concentration or antinuclear antibody titer. 3) The duration of steroid hormone therapy and the total dosage of immunosuppressants were thought to be important factors affecting the prognosis of autoimmune hepatitis.

The fundamental factor determining the clinical prognosis of prolonged jaundice--relation to the arterial ketone body ratio.

Factors related to the prognosis of patients with hyperbilirubinemia were investigated in 16 highly jaundiced patients. Patients who died within 3 weeks showed a deterioration of the hepatic energy status, measured by the arterial ketone body ratio, but patients who did not die within 3 weeks after the measurement of the ketone body ratio had a ratio within the normal range, despite high total bilirubin levels (18 mg/0.1 L). C3, C4 and CH50 in the former were also significantly lower than those in the latter. However, endotoxin and high fever occurred to the same extent, in the both groups. Thus, hepatic energy balance is the most pertinent factor related to prognosis, and is concerned with both the hepatocyte and reticuloendothelial systems. On the other hand, infection or endotoxin, when the energy balance is disturbed, becomes an aggravating but not a fundamental factor.

Immune status in mice with experimental biliary obstruction

Obstructive jaundice was induced in mice by common bile duct ligation (CBDL). High levels of total blood bilirubin (12.7 ± 1.5 mg/100 ml) were observed after 10–20 days of obstruction and 15.8 ± 2.3 mg/100 ml after 1–2 months. The spleen indices in the CBDL mice were significantly elevated, whereas the thymus weights and content of lymphoid cell in thymus were drastically reduced. Immunization of biliary-obstructed mice with a thymus-dependent antigen, sheep red blood cells (SRBC), exhibited a markedly suppressed direct plaque-forming and rosette-forming cell response, although there was no significant difference in serum hemagglutinin titers after second immunization with SRBC. The primary plaque-forming response of CBDL mice against a thymus-independent antigen, Escherichia coli lipopolysaccharide, was threefold higher in magnitude than controls. The mean survival time of skin allografts in CBDL mice was prolonged. On the other hand, splenic lymphoid cells isolated from biliary-obstructed mice and injected in allogeneic newborn recipients gave equal magnitude of graft versus host reaction as control cells. Incubation of normal lymphocytes with bilirubinemic serum caused nonspecific blastogenesis of the cells. The results presented here indicate that biliary obstruction alters the normal immune pattern. It is suggested that severe bilirubinemia leads to disruption of the balance of cell subpopulation reactivity leading to blocked T-cell function. This impaired function is reflected in depressed graft rejection, reduced primary response to thymus-dependent antigen, and greater response to a thymus-independent antigen. Possible explanations of the mechanism(s) involved are suggested.