The Natural History of Severe Acute Liver Injury.

OBJECTIVES: Acute liver failure (ALF) is classically defined by coagulopathy and hepatic encephalopathy (HE); however, acute liver injury (ALI), i.e., severe acute hepatocyte necrosis without HE, has not been carefully defined nor studied. Our aim is to describe the clinical course of specifically defined ALI, including the risk and clinical predictors of poor outcomes, namely progression to ALF, the need for liver transplantation (LT) and death. METHODS: 386 subjects prospectively enrolled in the Acute Liver Failure Study Group registry between 1 September 2008 through 25 October 2013, met criteria for ALI: International Normalized Ratio (INR)≥2.0 and alanine aminotransferase (ALT)≥10 × elevated (irrespective of bilirubin level) for acetaminophen (N-acetyl-p-aminophenol, APAP) ALI, or INR≥2.0, ALT≥10x elevated, and bilirubin≥3.0 mg/dl for non-APAP ALI, both groups without any discernible HE. Subjects who progressed to poor outcomes (ALF, death, LT) were compared, by univariate analysis, with those who recovered. A model to predict poor outcome was developed using the random forest (RF) procedure. RESULTS: Progression to a poor outcome occurred in 90/386 (23%), primarily in non-APAP (71/179, 40%) vs. only 14/194 (7.2%) in APAP patients comprising 52% of all cases (13 cases did not have an etiology assigned; 5 of whom had a poor outcome). Of 82 variables entered into the RF procedure: etiology, bilirubin, INR, APAP level and duration of jaundice were the most predictive of progression to ALF, LT, or death. CONCLUSIONS: A majority of ALI cases are due to APAP, 93% of whom will improve rapidly and fully recover, while non-APAP patients have a far greater risk of poor outcome and should be targeted for early referral to a liver transplant center.

Pancreatic neuroendocrine tumors in patients with tuberous sclerosis complex.

We explored pancreatic neuroendocrine tumors (PanNETs) associated with tuberous sclerosis complex (TSC) to determine their incidence in the TSC population; define their clinical, radiological, and pathological characteristics; and investigate their association with underlying genotypes. Retrospectively reviewed abdominal imaging of 219 patients with TSC, evaluating the incidence, size, and architecture of pancreatic lesions. Pathology records at Massachusetts General Hospital (MGH) were reviewed for all PanNET diagnoses in patients with TSC. Literature was reviewed for TSC-related PanNET cases. Nine patients with TSC were found to have a pancreatic lesion(s) on abdominal imaging and six patients have been diagnosed with a PanNET by pathology at MGH. Twelve cases of TSC-associated PanNETs have been reported in the literature. Of these 18 PanNET cases, one third were cystic, and the average age at resection was 26 years. Germline TSC2 mutations were found in all patients for whom genetic data were available (n = 3). We did not identify pancreatic angiomyolipomas in this series. Our results suggest that PanNETs are the most common pancreatic lesion in patients with TSC. Focal pancreatic mass lesions, solid or cystic, in patients with TSC should be considered possible PanNETs, and resection of the lesion may be clinically indicated.

Hepatitis C in clinical practice.

Hepatitis C virus infection is now one of the most important causes of chronic liver disease. Primary care physicians play an important role in the diagnosis and initial work-up of patients infected with this virus. Understanding which patients may be at risk is the first step. By understanding the correct use of hepatitis C virus diagnostic testing and the risk and benefits of antiviral therapy, providers will be better equipped to screen and counsel their patients.

Prospective characterization of full-length hepatitis C virus NS5A quasispecies during induction and combination antiviral therapy.

The hepatitis C virus (HCV) nonstructural 5A (NS5A) protein has been controversially implicated in the inherent resistance of HCV to interferon (IFN) antiviral therapy in clinical studies. In this study, the relationship between NS5A mutations and selection pressures before and during antiviral therapy and virologic response to therapy were investigated. Full-length NS5A clones were sequenced from 20 HCV genotype 1-infected patients in a prospective, randomized clinical trial of IFN induction (daily) therapy and IFN plus ribavirin combination therapy. Pretreatment NS5A nucleotide and amino acid phylogenies did not correlate with clinical IFN responses and domains involved in NS5A functions in vitro were all well conserved before and during treatment. A consensus IFN sensitivity-determining region (ISDR(237-276)) sequence associated with IFN resistance was not found, although the presence of Ala(245) within the ISDR was associated with nonresponse to treatment in genotype 1a-infected patients (P<0.01). There were more mutations in the 26 amino acids downstream of the ISDR required for PKR binding in pretreatment isolates from responders versus nonresponders in both HCV-1a- and HCV-1b-infected patients (P<0.05). In HCV-1a patients, more amino acid changes were observed in isolates from IFN-sensitive patients (P<0.001), and the mutations appeared to be concentrated in two variable regions in the C terminus of NS5A, that corresponded to the previously described V3 region and a new variable region, 310 to 330. Selection of pretreatment minor V3 quasispecies was observed within the first 2 to 6 weeks of therapy in responders but not nonresponders, whereas the ISDR and PKR binding domains did not change in either patient response group. These data suggest that host-mediated selective pressures act primarily on the C terminus of NS5A and that NS5A can perturb or evade the IFN-induced antiviral response using sequences outside of the putative ISDR. Mechanistic studies are needed to address the role of the C terminus of NS5A in HCV replication and antiviral resistance.

The protein kinase-interacting domain in the hepatitis C virus envelope glycoprotein-2 gene is highly conserved in genotype 1-infected patients treated with interferon.

The hepatitis C virus (HCV) envelope glycoprotein-2 inhibits the interferon (IFN)-induced, double-stranded RNA-activated protein kinase (PKR) via the PKR eukaryotic initiation factor-2alpha phosphorylation homology domain (PePHD). The present study examined the genetic variability of the PePHD in patients receiving IFN therapy. The PePHD from 12 HCV genotype 1 (HCV-1)-infected patients receiving daily IFN therapy was amplified by reverse-transcriptase polymerase chain reaction and analyzed by direct and clonal sequencing. The PePHD was highly conserved in 38 HCV GenBank isolates. There was no difference in pretreatment PePHD sequences isolated from IFN responders versus nonresponders. The major PePHD quasi-species variant did not change after 6 weeks of daily IFN therapy, and in 1 patient the major quasi-species variant did not change during 9 months of observation. Sequencing of 25 pretreatment PePHD clones from 3 patients confirmed that there was extremely low sequence variability surrounding the PePHD. The PePHD is highly conserved in HCV-1-infected IFN responders and nonresponders and does not appear to evolve in response to IFN therapy.

Pretreatment symptoms and dosing regimen predict side-effects of interferon therapy for hepatitis C.

We analysed data from a multicentre interferon (IFN) treatment trial to evaluate symptoms in patients with chronic hepatitis C and to identify factors that might predict development of debilitating IFN side-effects. Two hundred and twenty-two patients (120 US, 102 French) received 3 or 5 million units (MU) of IFN-alpha three times weekly (t.i.w.) for 3 months. Those who had detectable hepatitis C virus (HCV) RNA, as detected by the branched DNA signal amplification (bDNA) assay, at 3 months were intensified to daily therapy, while patients who were bDNA negative continued t.i.w. dosing for the subsequent 3 months of treatment. Symptoms were assessed at baseline, and adverse effects were evaluated at 6 months of therapy. Prior to treatment, the most common symptom that interfered with daily functioning was fatigue, occurring in 25% of patients. The frequency of debilitating fatigue, myalgia, arthralgia, headache, the presence of dry eyes and dry mouth, and use of antidepressant medication increased significantly from baseline to 6 months of IFN therapy (all P < 0.01). In multivariate analysis, the development of a debilitating side-effect at 6 months of treatment was associated with the presence of that symptom prior to therapy in all cases. Symptoms and adverse effects varied by gender and country. Compared with patients maintained on t.i.w. dosing, those who were dose intensified to daily IFN reported more debilitating fatigue, malaise, myalgia, arthralgia, fever, nausea, and headache, and the presence of dry mouth (all P < 0.05). In conclusion, patient characteristics, including pretreatment symptoms, gender and nationality, as well as daily IFN dosing are associated with the development of debilitating adverse effects on IFN therapy.

Maternal hemodynamics and pregnancy outcome in women with prior orthotopic liver transplantation.

The aim of this study is to evaluate the hemodynamics and pregnancy outcome of women with prior orthotopic liver transplantation. Hemodynamic measurements by Doppler technique were performed on pregnant subjects with prior orthotopic liver transplantation. Maternal characteristics, renal function, pregnancy complications, delivery indications, delivery mode, and neonatal outcomes were evaluated. Six pregnancies occurred in 5 women after orthotopic liver transplantation at the University of Washington Medical Center (Seattle, WA) between 1991 and 1999. Four of the 6 pregnancies were complicated by chronic hypertension, fetal growth restriction, and preterm delivery. Two pregnancies had worsening hypertension characterized by vasoconstriction in the second trimester despite antihypertensive therapy. These 2 subjects were administered cyclosporine for maintenance immunosuppression and had greater mean arterial pressures preconception and in the first trimester than the other subjects. One of these pregnancies resulted in fetal demise at 25 weeks' gestation. The other subject was delivered at 28 weeks' gestation for nonreassuring fetal status and superimposed preeclampsia. All pregnancies were complicated by renal insufficiency; however, the 2 subjects with poor obstetric outcome had preconception serum creatinine levels greater than 1.5 mg/dL and creatinine clearances less than 40 mL/min. Pregnancies complicated by second-trimester vasoconstriction and moderate renal insufficiency are at risk for preeclamspia, fetal growth restriction, and fetal demise. Good obstetric outcome can occur in women with mild renal insufficiency and well-controlled chronic hypertension. Improved hypertensive control preconception may decrease the risk for preeclampsia and poor obstetric outcome.

Depression, fatigue, and functional disability in patients with chronic hepatitis C.

OBJECTIVE: To examine the extent to which fatigue and functional disability correlate with severity of depressive symptoms in patients with chronic hepatitis C. METHODS: Fifty patients with chronic hepatitis C were evaluated using structured psychiatric interviews and standardized rating instruments. RESULTS: Fourteen (28%) of patients had current depressive disorders. Depressed and nondepressed patients did not differ with regard to demographics or hepatic disease severity. Severity of depressive symptoms was highly correlated with fatigue severity while measures of hepatic disease severity, interferon treatment, and severity of comorbid medical illness were not. Severity of depressive symptoms was associated with functional disability and somatization. CONCLUSIONS: Disability and fatigue are more closely related to depression severity than to hepatic disease severity. Antidepressant treatment trials in patients with hepatitis C are indicated to determine whether improvement in depressive symptoms leads to improvement in fatigue and functioning.

Infection complicating percutaneous liver biopsy in liver transplant recipients.

There is controversy about the frequency of and risk factors for infectious complications of percutaneous liver biopsy in liver transplant recipients. The aim of this study was to identify the incidence and nature of complications associated with liver biopsy after orthotopic liver transplantation (OLT), with particular emphasis on infection. The medical records of all patients undergoing OLT between January 1990 and August 1994 were reviewed retrospectively to identify complications requiring hospitalization within one week of percutaneous liver biopsy. The nature and severity of complications were recorded and possible risk factors for infectious complications were examined. One hundred ninety-eight patients underwent 1,136 percutaneous liver biopsies. There were eleven complications (0.96%), including as follows: 7 infections, 3 bleeding episodes, and 1 vasovagal reaction. Infections after percutaneous liver biopsy included fever and bacteremia (n = 6), and fever without bacteremia (n = 1). All infections developed only in patients with underlying biliary tract abnormalities; the frequency of infection was higher (9.8%) in patients with choledochojejunostomy when compared with those with choledochocholedochostomy (1.4%). Bacteremia was more likely caused by skin flora in patients with choledochocholedochostomy (CDC) and by enteric bacteria in patients with choledochojejunostomy (CDJ). All infections were treated successfully with parenteral antibiotics. We conclude that biliary tract abnormalities are the primary risk factors for infection after percutaneous liver biopsy, although the risk is higher in patients with CDJ than with CDC. These data support the use of antibiotic prophylaxis before percutaneous liver biopsy in OLT recipients with biliary tract abnormalities.

Evaluation of an extended blood culture protocol to isolate fastidious organisms from patients with AIDS.

Recent reports of fastidious pathogens suggest the need for special blood cultures for immunocompromised patients. Blood cultures from 45 human immunodeficiency virus (HIV)-infected patients with unexplained fever (> or = 38.0 degrees C) and CD4 counts of < 125 cells per mm3 were collected into a vacuum tube with sodium polyanetholsulfonate, an Isolator tube, and BACTEC aerobic and anaerobic bottles. Blood from the sodium polyanethosulfonate tube was inoculated into BACTEC 13A bottles, which were read weekly for 16 weeks. Isolator sediment was divided among eight agar media, including four sheep blood agar media: chocolate agar, brain heart infusion blood agar, heart infusion blood agar, and brucella blood agar. Other agar plates included Sabouraud's, buffered charcoal-yeast extract, Middlebrook 7H11 (M7H11) with hemoglobin, and M7H11 with mycobactin J. Incubation conditions included air and CO2-enriched aerobic, microaerophilic, and anaerobic atmospheres. Aerobic BACTEC broths received an acridine orange stain on day 8 and were subcultured at 2, 4, and 8 weeks. Anaerobic BACTEC bottles were subcultured at 4 weeks. All solid media, including subcultures, were incubated for 8 weeks, providing a total of 16 weeks of incubation for each specimen. Clinically significant isolates included eight Mycobacterium avium complex isolates and one each of Bartonella henselae, Bartonella quintana, Shigella flexneri, Klebsiella oxytoca, and Cryptococcus neoformans. All isolates were detected with commercially available media and, with the exception of Bartonella spp., were recovered within incubation times routinely used in most clinical laboratories.

Lactobacillemia in three patients with AIDS.

Lactobacillemia, an uncommon cause of bacteremia, has been reported to occur in one renal transplantation patient who was also infected with human immunodeficiency virus (HIV). We present the cases of three patients with AIDS in whom lactobacillemia developed. All three patients had late-stage AIDS with CD4 cell counts of < 55/mm3, all had indwelling central venous catheters, and all were recently or concomitantly blood culture-positive for coagulase-negative staphylococci. In addition, two of the three patients had recently received vancomycin therapy. These three cases provide the first association of lactobacillus bacteremia and AIDS.

Bartonella (Rochalimaea) species as a cause of apparent "culture-negative" endocarditis.

Bartonella quintana (formerly Rochalimaea quintana) is a recently recognized cause of apparent "culture-negative" endocarditis. We describe a 39-year-old, homeless man who developed aortic valve endocarditis caused by B. quintana. He had a history of alcoholism and was seronegative for the human immunodeficiency virus. We established that B. quintana was the cause of the endocarditis on the basis of the isolation of B. quintana from blood cultures, the compatibility of histochemical stains of cardiac valve tissue, the reactivity of the polymerase chain reaction specific for B. quintana on cardiac valve tissue, and the failure to isolate an alternative causative organism despite extensive efforts. This is the second report of endocarditis caused by B. quintana and the fourth report of endocarditis caused by a Bartonella species. On the basis of the findings of this report and those of other recent reports, further study is warranted to determine the overall role of Bartonella species in apparent culture-negative endocarditis.

Bartonella (Rochalimaea) quintana bacteremia in inner-city patients with chronic alcoholism.

BACKGROUND: Bartonella (Rochalimaea) quintana is a fastidious gram-negative bacterium known to cause trench fever, cutaneous bacillary angiomatosis, and endocarditis. Between January and June 1993 in Seattle, we isolated B. quintana from 34 blood cultures obtained from 10 patients not known to be infected with the human immunodeficiency virus (HIV). METHODS: After identifying the isolates as B. quintana by direct immunofluorescence and DNA-hybridization studies, we determined strain hybridization with studies of restriction-fragment-length polymorphisms (RFLPs) of the intergenic spacer (noncoding) region of ribosomal DNA amplified by the polymerase chain reaction (PCR). To characterize the epidemiologic and clinical features of bartonella infections in these patients, we performed a retrospective case-control study using as controls 20 patients with blood cultures obtained at approximately the same time as those obtained from the index patients. RESULTS: B. quintana isolates from the 10 patients were indistinguishable by PCR-RFLP typing. All 10 patients had chronic alcoholism, and 8 were homeless (P = 0.001 for both comparisons with controls). The six patients who underwent HIV testing were seronegative. At the time of their initial presentation, seven patients had temperatures of at least 38.5 degrees C. Six patients had three or more blood cultures that were positive for B. quintana, and in four of these patients B. quintana was isolated from blood cultures obtained 10 or more days apart. Subacute endocarditis developed in two patients and required surgical removal of the infected aortic valve in one of them. Nine patients recovered; one died of sepsis from Streptococcus pneumoniae infection. CONCLUSIONS: B. quintana is a cause of fever, bacteremia, and endocarditis in HIV-seronegative, homeless, inner-city patients with chronic alcoholism.

Bacteremia caused by a novel Bordetella species, "B. hinzii".

Bordetella spp. cause respiratory tract diseases in warm-blooded animals. Only Bordetella bronchiseptica has been reported to cause bacteremia in humans, and this rare infection usually occurs with pneumonia in immunocompromised patients. We describe "Bordetella hinzii" bacteremia in an AIDS patient without a respiratory illness. Combining biochemical phenotyping with fatty acid analysis permitted preliminary identification of this previously undescribed pathogen; identity was confirmed by DNA-DNA hybridization. This report extends the spectrum of human infections caused by the bordetellae.

Detection of Bartonella (Rochalimaea) quintana by routine acridine orange staining of broth blood cultures.

Bartonella quintana was isolated from 34 BACTEC nonradiometric aerobic resin blood cultures for 10 adults. Nine patients were initially diagnosed by routine acridine orange staining of routine cultures that had been incubated for 8 days. All subcultures grew on chocolate agar within 3 to 12 days (median, 6 days). The PLUS 26 high-volume aerobic resin medium, combined with acridine orange stain and subculture, is an effective system for detection and isolation of B. quintana from blood.

Effects of media, atmosphere, and incubation time on colonial morphology of Arcanobacterium haemolyticum.

Arcanobacterium haemolyticum causes pharyngitis as well as skin and other wound infections. Although it is a beta-hemolytic organism, the hemolysis is less well defined than that of beta-hemolytic streptococci and may be overlooked in cultures with heavy growth of commensal throat flora. To determine whether routine throat culture conditions are sufficient to produce recognizable colonies of A. haemolyticum, the morphology of six distinct strains was studied after various combinations of incubation time, medium, and atmosphere. The agar media, containing 5% sheep blood, were Trypticase soy agar, Columbia agar, and heart infusion agar. Cultures were incubated in ambient air, 6 to 8% CO2, or an anaerobic atmosphere. Cultures were compared after 24, 48, and 72 h of incubation for colony size, clarity and size of hemolytic zone, and macroscopic evidence of agar pitting. A minimum of 48 h was needed for expression of beta-hemolysis and pitting. Trypticase soy agar was the superior medium and CO2 was the superior atmosphere for beta-hemolysis. Agar pitting was not significantly affected by variations in medium or atmosphere. Strains differed in their expression of hemolysis and production of pits at 48 h. After 72 h of incubation, beta-hemolysis and pitting were visible in over 96% of culture observations.

Weight-related behaviors and concerns of fourth-grade children.

Behaviors and concerns related to weight were measured among 457 fourth-grade children attending 10 rural schools in central Iowa. A questionnaire was used to gather data on the children's concerns about being overweight, concerns that certain types or amounts of food would contribute to their being overweight, alterations in food intake to avoid being overweight, and perceptions that peers and family members were concerned about being overweight. In addition, each child's height and weight were measured. Weight-related behaviors and concerns increased with increasing weight-for-age and body mass index (BMI) and were more prevalent among girls than boys. The frequency of drinking diet soft drinks was positively correlated with weight-for-age and BMI and tended to increase with an increase in weight-related behaviors and concerns. Girls were more likely than boys to report a desire to be thinner (60.3% vs 38.4%), whereas boys were more likely than girls to want to be taller (67.2% vs 49.1%). The desire for less body fat was significantly associated with an increase in the frequency of weight-related behaviors and concerns, the frequency of drinking diet soft drinks, weight-for-age, and BMI. These findings indicate a need for interventions that combat fear of obesity and restrictive eating among growing children.