Elevated Aminotransferase Values Research Articles

Treatment response and clinical event-free survival in autoimmune hepatitis: A Canadian multicentre cohort study

We sought to identify predictors of outcome for people living with autoimmune hepatitis (AIH). We evaluated the clinical course of people with AIH across 11 Canadian centres. Biochemical changes were analysed using linear mixed-effect and logistic regression. Clinical outcome was dynamically modelled using time-varying Cox proportional hazard modelling and landmark analysis. In 691 patients (median age 49 years, 75.4% female), with a median follow-up of 6 years (25th-75th percentile, 2.5-11), 118 clinical events occurred. Alanine aminotransferase (ALT) normalisation occurred in 63.8% of the cohort by 12-months. Older age at diagnosis (odd ratio [OR] 1.19, 95% CI 1.06-1.35) and female sex (OR 1.94, 95% CI 1.18-3.19) were associated with ALT normalisation at 6 months, whilst baseline cirrhosis status was associated with reduced chance of normalisation at 12 months (OR 0.52, 95% CI 0.33-0.82). Baseline total bilirubin, aminotransferases, and immunoglobulin G (IgG) values, as well as initial prednisone dose, did not predict average ALT reduction. At baseline, older age (hazard ratio [HR] 1.25, 95% CI 1.12-1.40), cirrhosis at diagnosis (HR 3.67, 95% CI 2.48-5.43), and elevated baseline total bilirubin (HR 1.36, 95% CI 1.17-1.58) increased risk of clinical events. Prolonged elevations in ALT (HR 1.07, 95% CI 1.00-1.13) and aspartate aminotransferase (HR 1.13, 95% CI 1.06-1.21), but not IgG (HR 1.01, 95% CI 0.95-1.07), were associated with higher risk of clinical events. Higher ALT at 6 months was associated with worse clinical event-free survival. In people living with AIH, sustained elevated aminotransferase values, but not IgG, are associated with poorer long-term outcomes. Biochemical response and long-term survival are not associated with starting prednisone dose. Using clinical data from multiple Canadian liver clinics treating autoimmune hepatitis (AIH), we evaluate treatment response and clinical outcomes. For the first time, we apply mixed-effect and time-varying survival statistical methods to rigorously examine treatment response and the impact of fluctuating liver biochemistry on clinical event-free survival. Key to the study impact, our data is 'real-world', represents a diverse population across Canada, uses continuous measurements over follow-up, and our findings help inform risk stratification of patients. We provide evidence for treating clinicians, as well as those developing and evaluating new therapies, to seek evidence of good treatment response by keeping aminotransferase activity values within the reference range. Our results challenge the role of IgG as a marker of treatment response and if normalisation of IgG should remain an important part of the definition of biochemical remission. Our analysis further highlights that baseline markers of disease severity may not prognosticate early treatment response. Additionally, the initial prednisone dose may be less relevant for achieving aminotransferase normalisation. This is important for patients and treating clinicians given the relevance and importance of side-effects of treatment for patients.

A Prospective Multicenter Study of Hepatocellular Carcinoma in Italian Hemophiliacs With Chronic Hepatitis C

AbstractTo assess the risk factors, natural history, and eligibility for curative treatment of early-detected hepatocellular carcinoma (HCC), 385 hemophiliacs who were treated with blood or plasma derivates for at least 10 years and had persistently elevated aminotransferase values underwent an annual screening with an abdominal ultrasound examination and measurement of the serum alpha-fetoprotein (AFP) level. Of these, 355 had serum antibody to hepatitis C virus (anti-HCV), 29 had anti-HCV and hepatitis B surface antigen (HBsAg), and one had HBsAg alone; 141 had serum antibody to human immunodeficiency virus (anti-HIV). During 48 months of follow-up study, six patients developed HCC. All HCC patients had a HCV-related cirrhosis and had been exposed to HCV risk at a median age of 40 years. All patients had a multicentric tumor, which was not eligible for curative treatment. Univariate analysis showed age, cirrhosis, and baseline AFP levels to be significantly associated with an increased risk of HCC. By multivariate analysis, the risk of HCC was infinite in patients with cirrhosis, 31.0 for those with baseline AFP higher than 11 ng/mL, and 17.9 for those more than 45 years of age. In conclusion, the risk of cancer was greater for patients infected later in life, particularly those with cirrhosis and high AFP. Annual screening of hemophiliacs with ultrasound and AFP fails to identify potentially curable tumors because the diagnosis is made at a late stage of the disease.

SAT-671 Glycogenic Hepatopathy. A Rare and Dramatic Manifestation of Poorly Controlled Type 1 Diabetes

Background: Glycogenic hepatopathy (GH) is a well described, yet underdiagnosed disorder in type 1 diabetes. Erratic blood glucose values and high insulin levels promote the excessive deposition of glucose storage in the liver as glycogen, resulting in hepatomegaly, right upper quadrant pain and abnormal liver function. GH was first described with the introduction of insulin as a therapy to treat type 1 diabetes in the early 20th century. As our ability to effectively treat type 1 diabetes mellitus has improved, GH is seen much less commonly. Today, GH generally effects adolescent or young adult patients with poorly controlled type 1 diabetes mellitus and DKA. It is reversible with successful treatment of hyperglycemia.Clinical Case: An 18 year old woman with a history of poorly controlled type 1 diabetes mellitus and frequent admissions for DKA was admitted for DKA and pyelonephritis. On admission, the patient complained of significant right upper quadrant pain and was found to have elevated transaminase values of: AST 1199 U/L (<37 U/L), ALT 371 U/L (56 U/L), an elevated alkaline-phosphatase of 319 IU/L (<135 IL/L) and normal indices of biosynthetic function (INR/PT). After inpatient treatment of DKA and pyelonephritis, the right upper quadrant pain persisted and required pharmacologic analgesia. Radiographic evaluation demonstrated severe hepatomegaly (24 cm in maximum length) without focal lesions. Laboratory evaluation for viral hepatitis, autoimmune hepatitis, Celiac Disease, Wilson’s Disease and hemochromatosis were unremarkable. Given the patient’s persistent symptoms and severity of hepatomegaly, hepatic biopsy was performed.Biopsy findings were consistent with glycogenic hepatopathy demonstrating steatosis and glycogen deposition with nucleic glycogenation and mega mitochondria.Our patient had higher than usual insulin requirements for type 1 diabetes (~1 unit/kg/day). Abdominal pain, hepatomegaly and elevated LFTs resolved over a 2 month duration with improvement in her blood glucose control. Conclusions: GH is an established yet rare complication of poorly controlled type 1 diabetes. Glycogen deposition in the liver leads to painful hepatomegaly due to stretching of the liver capsule. GH has a female predominance (77%) and is characterized by elevated AST >>ALT with preserved liver biosynthetic function.It is postulated that GH is a result of elevated blood glucose levels and elevated insulin levels. The patient we describe has long standing poorly controlled type 1 diabetes mellitus, frequent admissions for DKA and high insulin requirements. To our knowledge, insulin requirements have not been investigated or previously reported as a potential risk factor for this condition.

863: Pragmatic laboratory studies to differentiate acute fatty liver of pregnancy and HELLP syndrome on admission

Acute fatty liver of pregnancy (AFLP) and hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome are both associated with significant maternal and perinatal morbidity and mortality. Because of the overlap of several clinical and laboratory findings of these syndromes, differentiation can be difficult. Our group has previously suggested application of commonly available laboratory analytes to identify cases of AFLP. The purpose of this analysis was to use these laboratory analytes to distinguish between cases of AFLP and HELLP syndrome in women presenting with elevated transaminases. This was a retrospective observational analysis of women admitted to a tertiary medical center with either AFLP or HELLP syndrome. Women with AFLP were diagnosed using the Swansea criteria and in some cases liver histology, whereas HELLP syndrome were identified using the Tennessee classification system/Mississippi classification system (Class I and II). Clinical and laboratory findings at the time of admission were analyzed in an attempt to differentiate the two syndromes. There were 66 women with AFLP identified from 1975-2018 and these were compared with 67 randomly selected women with HELLP syndrome. Table 1 displays selected demographic and clinical features. There were no significant differences noted among demographic features of age, race, and parity (all p>0.05). Abdominal pain was common in both groups, whereas nausea and vomiting were significantly associated with AFLP (P<0.001). Women with AFLP had markedly abnormal laboratory analytes that included hypofibrinogenemia, hyperbilirubinemia, and hypocholesterolemia, as well as evidence of acute renal insufficiency (Table 2). All of these were significantly different from women with HELLP syndrome (all p<0.001). For these specific analytes, the HELLP values were within the normal range in the third trimester of pregnancy. A pentad of commonly available laboratory analytes can assist with the evaluation of cases of AFLP and HELLP syndrome on admission when elevated transaminase values are identified. We propose the acronym FaCCT —Fibrinogen, and Cholesterol, Creatinine, Total Bilirubin—as a simple moniker to assist when differentiating women with either AFLP or HELLP syndrome.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Rifaximin in non-alcoholic steatohepatitis: An open-label pilot study.

Gut microbial dysbiosis is implicated in the pathogenesis of non-alcoholic steatohepatitis (NASH). We investigated downstream effects of gut microbiota modulation on markers of hepatic inflammation, steatosis, and hepatic and peripheral insulin sensitivity in patients with NASH using rifaximin therapy. Patients with biopsy-proven NASH and elevated aminotransferase values were included in this open-label pilot study, all receiving 6weeks rifaximin 400mg twice daily, followed by a 6-week observation period. The primary endpoint was change in alanine aminotransferase (ALT) after 6weeks of rifaximin. Secondary endpoints were change in hepatic lipid content and insulin sensitivity measured with a hyperinsulinemic-euglycemic clamp. Fifteen patients (13 men and 2 women) with a median (range) age of 46 (32-63)years were included. Seven had diabetes on oral hypoglycemic medications and 8 had no diabetes. After 6weeks of therapy, no differences were seen in ALT (55 [33-191] vs. 63 [41-218]IU/L, P = 0.41), peripheral glucose uptake (28.9 [19.4-48.3] to 25.5 [17.7-47.9]μmol/kg/min, P = 0.30), hepatic insulin sensitivity (35.2 [15.3-51.7]% vs. 30.0 [10.8-50.5]%, P = 0.47), or hepatic lipid content (21.6 [2.2-46.2]% vs. 24.8 [1.7-59.3]%, P = 0.59) before and after rifaximin treatment. After 12weeks from baseline, serum ALT increased to 83 (30-217)IU/L, P = 0.02. There was a significant increase in the homeostasis model assessment-estimated insulin resistance index (P = 0.05). The urinary metabolic profile indicated a significant reduction in urinary hippurate with treatment, which reverted to baseline after cessation of rifaximin, although there was no consistent difference in relative abundance of fecal microbiota with treatment. These data do not indicate a beneficial effect of rifaximin in patients with NASH.

Myositis Portends Primary Biliary Cirrhosis: A Case Series

Purpose: Although the presence of anti-mitochondrial antibody (AMA) is 98% specific for primary biliary cirrhosis (PBC), AMA is associated with other autoimmune diseases, including inflammatory myopathies. A recent study in Brain found 23 case reports of concurrent PBC and polymyositis (PM), and only one of autoimmune hepatitis (AIH)-PBC overlap with PM. We present two patients from our institution with AIH-PBC overlap and PM, and discuss their management. Case 1: A 60-year-old woman with sicca syndrome was referred to us for persistently elevated aminotransferase values, immunoglobulin M (IgM) (666mg/dL), and immunoglobulin G (IgG) (1,950 mg/dL). A liver biopsy confirmed Scheuer stage I PBC with AIH, and she was started on prednisone and ursodiol. Concurrent to her PBC diagnosis and before prednisone therapy, she developed progressive proximal muscle weakness. Muscle biopsy, electromyography, and elevated muscle enzyme levels suggested PM. On prednisone, her liver enzyme levels normalized while muscle strength responded to several months of intermittent intravenous immunoglobulin. Three years later, she developed diastolic heart failure, which improved on diltiazem. Her disease was complicated by severe osteoporosis, treated with zoledronic acid, calcium, and vitamin D. Currently, she is doing well on ursodiol 500 mg daily, and prednisone 5 mg every other day. Case 2: A 58-year-old man presented to a neurologist after 1 year of truncal weakness. His muscle biopsy, elevated muscle enzymes, and symptoms suggested PM. He responded to prednisone, but was subsequently referred to hepatology for persistently elevated liver test results (AST 89, ALT 99, ALK PHOS 305). AMA (1:160), IgG (2350 mg/dL) and IgM (402 mg/dL) were elevated. Liver biopsy confirmed stage I PBC with confluent necrosis, suggesting AIH overlap. Prednisone 60 mg daily and ursodiol 500 mg twice-a-day were initiated. After 3 months of treatment, the patient's symptoms improved and liver enzyme activity normalized. Discussion: Although AIH-PBC with PM is an infrequently recognized syndrome, we encountered two such cases. The natural course of AIH-PBC and PM is unknown, but some studies show that PM with concurrent PBC may have a more indolent PM with frequent cardiac involvement, as seen in our first patient. Both patients responded to and are being maintained on prednisone and ursodiol. For PM with AIH, if prednisone treatment alone fails, the addition of immunosuppressive agents given singly or in combination with corticosteroids may be considered. Since corticosteroid use may worsen osteoporosis associated with advanced PBC, assessment of bone density with the potential use of bisphosphonates may be valuable.

PTU-113 Rifaximin in Non-Alcoholic Steatohepatitis: an Open-Label Pilot Study

IntroductionMounting evidence implicates gut microbial dysbiosis in the pathogenesis of non-alcoholic steatohepatitis (NASH) by mechanisms including caloric salvage, lipopolysaccharide production, upregulation of proinflammatory cytokines, increased insulin resistance and consequent increases...

Chemoprevention of Patients with Hepatitis B Receiving Chemotherapy or Bone Marrow Transplant

Hepatitis B virus (HBV) reactivation is a common but preventable complication of immunosuppression. With the advent of new therapies that provide efficient and prolonged immunosuppression, the incidence of HBV reactivation is likely to increase. The clinical presentation can range from mildly elevated aminotransferase values to fatal fulminant hepatitis. Despite prompt antiviral therapy, the mortality rates remain high, and it can adversely affect the outcome of immunosuppressive therapy for the underlying hematological disease. Over the past decade, several studies evaluated the risk of HBV reactivation, role of serological tests, and effectiveness of antiviral therapies in preventing severe hepatic dysfunction among patients undergoing immunosuppressive therapy. Studies show that HBV antiviral therapy given prior to chemotherapy may prevent HBV replication, and reduce the risk of HBV reactivation during the immunosuppression period. This article reviews the current literature and society guidelines on HBV reactivation, risk factors, and prophylaxis for HBV reactivation in patients undergoing chemo-/immunosuppressive therapy.

Randomized Controlled Trial of Quinacrine for the Treatment of HBsAg-Positive Chronic Hepatitis

Several drugs which react with DNA decrease hepatitis B viral (HBV) DNA polymerase activity in vitro. Because such an alteration of viral replication, if produced in patients with hepatitis B surface antigen (HBsAg)-positive chronic hepatitis, may lead to elimination of viral infection, we conducted a controlled trial of the use of the intercalating agent, quinacrine hydrochloride, in treatment of HBsAg-positive chronic hepatitis. No patient converted from HBsAg positive to negative during the trial and no consistent effect on HBV DNA polymerase activity was noted. Following treatment, elevated transaminase values and alterations of HBV markers were observed in several patients. Fluctuations of transaminase values and HBV markers may reflect alterations in host immunity and viral replication. Quinacrine alone is ineffective in therapy of chronic HBV infection. Additional study with intercalating agents, perhaps in conjunction with other drugs, is suggested.

Index of Suspicion

Index of Suspicion

Selenium, glutathione and glutathione peroxidases in blood of patients with chronic liver diseases.

Disturbances in the antioxidant system could play a role in pathogenesis of chronic liver disease. The aim of our study was to evaluate the levels/activities of antioxidants in blood of patients with chronic liver disease. We estimated selenium and glutathione concentrations and glutathione peroxidase activities in blood of 59 patients with chronic hepatitis B or C virus infection (group 1) and 64 patients with alcoholic, autoimmune or cryptogenic chronic liver disease (group 2). The results were compared with 50 healthy controls. Whole blood and plasma selenium and red cell glutathione concentrations were significantly lower in the patients compared with the controls. Red cell glutathione peroxidase activity was slightly reduced in both subgroups of group 1 and in group 2 with normal alanine aminotransferase values. Plasma glutathione peroxidase activity was slightly but significantly higher in patients with elevated aminotransferase values. The findings suggest that disturbances in antioxidant parameters in blood of patients with chronic liver disease may be the cause of the peroxidative damage of cells.

Selenium, glutathione and glutathione peroxidases in blood of patients with chronic liver diseases.

Disturbances in the antioxidant system could play a role in pathogenesis of chronic liver disease. The aim of our study was to evaluate the levels/activities of antioxidants in blood of patients with chronic liver disease. We estimated selenium and glutathione concentrations and glutathione peroxidase activities in blood of 59 patients with chronic hepatitis B or C virus infection (group 1) and 64 patients with alcoholic, autoimmune or cryptogenic chronic liver disease (group 2). The results were compared with 50 healthy controls. Whole blood and plasma selenium and red cell glutathione concentrations were significantly lower in the patients compared with the controls. Red cell glutathione peroxidase activity was slightly reduced in both subgroups of group 1 and in group 2 with normal alanine aminotransferase values. Plasma glutathione peroxidase activity was slightly but significantly higher in patients with elevated aminotransferase values. The findings suggest that disturbances in antioxidant parameters in blood of patients with chronic liver disease may be the cause of the peroxidative damage of cells.

Combination of interferon and ribavirin in chronic hepatitis C: Re-treatment of nonresponders to interferon

Chronic infection with hepatitis C virus (HCV) may result in cirrhosis, liver failure, and hepatocellular carcinoma. A minority of patients have a sustained response to antiviral therapy, and nonresponders remain at risk of developing progressive liver disease. We conducted a randomized, controlled trial of therapy with the combination of interferon (IFN) and ribavirin in patients with chronic hepatitis C who had not responded to an initial course of therapy with IFN alone. A total of 124 patients were randomized to receive the combination of IFN and ribavirin for either 24 or 48 weeks and followed for an additional 24 weeks after stopping therapy. Thirty-eight treated patients (30.6%) achieved a sustained virologic response (undetectable HCV RNA at the 24-week follow-up point). This was associated with significant improvement in necroinflammatory activity noted on liver biopsy. Interestingly, there was not a statistically significant difference in response rates based on the duration of treatment; HCV genotype was the strongest predictor of a sustained response. Sustained responses were noted even in patients with poor predictive factors, including those with advanced hepatic fibrosis or cirrhosis, high levels of HCV RNA in serum, and those infected with HCV genotype 1. The study included 24 patients with normal serum alanine transaminase (ALT) values before therapy who had similar responses to those with initially elevated transaminase values. This study suggests that the combination of IFN and ribavirin is a useful modality of therapy in patients with chronic hepatitis C who did not respond to IFN alone.

Herpes Simplex Type 2 Causing Fulminant Hepatic Failure

Although exceedingly rare, fulminant hepatic failure (FHF) in immunocompetent patients can develop with primary or recurrent infection due to herpes simplex virus (HSV). The diagnosis is frequently obscured by the absence of mucocutaneous involvement. Elevated transaminase values with leukopenia and a relatively low bilirubin level may provide clues to the diagnosis. We describe an immunocompetent woman who died of FHF before a definitive diagnosis of HSV type 2 hepatitis was established. Herpes simplex virus hepatitis is one of the few causes of FHF for which potentially effective therapy is available. Thus, early diagnosis is paramount and usually requires liver biopsy. Recent studies suggest that transjugular liver biopsy is safe and effective in establishing the cause of FHF. Since the diagnosis and management of FHF are frequently influenced by the results of transjugular liver biopsy, it may become a standard diagnostic tool for managing FHF in centers where such expertise exists.

Disease-related conditions in relatives of patients with hemochromatosis.

Hemochromatosis occurs in approximately 5 white people per 1000 and is usually due to homozygosity for mutations in the HLA-linked HFE gene. Although screening has been proposed, the proportion of homozygotes with conditions related to hemochromatosis is uncertain. We studied the prevalence of disease-related conditions among relatives of probands with hemochromatosis. We identified probands who presented to a clinic with signs or symptoms of hemochromatosis or who had elevated transferrin-saturation values. We identified homozygous relatives, mainly siblings, on the basis of HLA identity with the proband and by HFE genotyping. Disease-related conditions were cirrhosis, hepatic fibrosis, elevated amino-transferase values, and hemochromatotic arthropathy. We identified 214 homozygous relatives of 291 homozygous probands. Of the 113 men in this group (mean age, 41 years), 96 (85 percent) had iron overload, and 43 (38 percent) had at least one disease-related condition. Of the 52 men over 40 years of age, 27 (52 percent) had at least one disease-related condition. Of the 101 female homozygous relatives (mean age, 44 years), 69 (68 percent) had iron overload, and 10 (10 percent) had at least one disease-related condition. Of the 43 women over 50 years of age, 7 (16 percent) had at least one disease-related condition. If the proband had a disease-related condition, relatives who were men were more likely to have morbidity than if the proband had no disease-related condition. A substantial number of homozygous relatives of patients with hemochromatosis--more commonly men than women--have conditions related to hemochromatosis that have yet to be detected clinically.

Retreatment with higher dose interferon alpha in children with chronic hepatitis B infection.

More than 50% of children with chronic hepatitis B infection do not respond to interferon-alpha (IFN-alpha) treatment and are prone to have progressive liver disease. The best treatment modality is unknown in these children. The aim of this study was to evaluate the possible benefit of a second higher dose IFN-alpha therapy for children with chronic hepatitis B diseases who failed previous therapy. Twenty-four children with chronic hepatitis B infection who had not responded to previous IFN-alpha treatment were enrolled into the study. All were hepatitis B virus DNA- and hepatitis B e antigen-positive for >6 months after initial treatment. They received 10 megaunits (MU)/m2 of IFN-alpha 2a three times a week for 24 weeks. Liver function tests, hepatitis B virus markers and hepatitis B virus DNA were determined regularly during treatment and follow-up. A complete response was defined as clearance of both hepatitis B virus DNA and hepatitis B e antigen (HBeAg). At the end of therapy 8 (33.3%) patients cleared hepatitis B virus DNA and seroconverted to anti-HBeAg. Patients were followed for an average period of 12.2 +/- 4.7 months after retreatment. During follow-up an additional 4 patients cleared hepatitis B virus DNA and seroconverted to anti-HBe, whereas one seroconverted patient became HBeAg-positive again. Thus 11 patients (45.8%) had complete response at the end of the follow-up period. Alanine aminotransferase normalized in 11 responder patients and in 5 nonresponders. Positive predictive factors were low baseline titers of hepatitis B virus DNA and elevated transaminase values (> 100 IU/l). IFN-alpha retreatment with a higher dose may be an alternative modality for treatment of children with chronic hepatitis B infections who failed previous IFN-alpha, especially in those with favorable predictive factors.

Fatal Disseminated Herpes Simplex in Pregnancy With Maternal and Neonatal Death

Disseminated herpes is rare in the adult and usually occurs in the immunocompromised. Twenty-one cases have been reported in which healthy women contracted life-threatening disseminated herpes simplex virus (HSV) infections in the third trimester of pregnancy. Most of these patients had nonspecific symptoms, and many did not have mucocutaneous lesions. On physical examination, they were usually febrile and anicteric and had markedly elevated aminotransferase values, without a corresponding elevation in bilirubin level. In our review of the literature, we found that prompt acyclovir therapy resulted in 100% survival. Those patients not receiving treatment or treated late in the terminal stages of their disease had a 63% mortality rate. We report a case of maternal disseminated HSV with subsequent maternal death at an estimated 31 weeks' gestation in which the diagnosis was made at the time of necropsy. The infant was started on acyclovir therapy but died of disseminated HSV.

Niemann-Pick disease type C: Diagnosis and outcome in children, with particular reference to liver disease

The records of 52 children with Niemann-Pick disease type C were reviewed to establish whether the disease process and outcome varied with the initial clinical pattern; 34 children (65%) had cholestatic liver disease and hepatosplenomegaly in infancy; 18 were seen at a mean age of 4 years with splenomegaly or neurologic disease or both. Of the 34 children with early cholestatic liver disease, three died in the neonatal period; cholestasis and hepatomegaly subsided in the remaining 31 children, although splenomegaly persisted. Of these 31 children, 15 had persistent liver disease with elevated aminotransferase values. Serial liver biopsy specimens showed that 3 of the 15 children had normal architecture and 12 had hepatic fibrosis, with progression to cirrhosis in 5. No other significant morbidity or additional deaths were associated with the liver disease. The clinical importance of persistent liver disease was overshadowed by the subsequent development of severe neurologic disease. There was no difference in the age at onset of the disease (mean, 4.5 years) or in the pattern of neurologic disease, including supranuclear ophthalmoplegia, whether or not the child had early liver disease. Overt neurologic disease has not yet developed in seven surviving children with liver disease at onset. Sixty-seven percent of children died during the study; the main cause of death was bronchopneumonia. We conclude that the diagnosis of Niemann-Pick disease type C should be considered in patients with unexplained neonatal hepatitis, especially if splenomegaly is a persistent feature. Because liver biopsy specimens may not demonstrate storage cells, bone marrow aspiration to detect the characteristic storage cells is recommended in such patients.

Efficacy and safety of omeprazole for severe gastroesophageal reflux in children

Omeprazole, a potent inhibitor of acid secretion, is effective in adults with severe gastroesophageal reflux, but no such data are available on children. We studied 15 children in whom treatment with histamine (type 2) blockers and prokinetic agents had failed; 4 had also had one or more fundoplications. Their ages were 0.8 to 17 years (mean, 8.1 years) and weights were 7.5 to 30.7 kg (mean, 18.6 kg). Of the 15 children, 8 were neurologically handicapped. All patients had endoscopic and histologic evidence of esophagitis; most had esophagitis grade 3 to 4. Patients were initially given omeprazole at 10 to 20 mg; the dose was titrated upward until results of a subsequent 24-hour intraesophageal pH study was normal. Symptoms and signs abated and evidence of esophagitis diminished in all patients. Omeprazole was given for periods of 5.5 to 26 months (mean, 12.2 months). The effective total dose was 20 to 40 mg (0.7 to 3.3 mg/kg) in 11 patients, 10 mg (0.7 mg/kg) in 1 patient, and 60 mg (1.9 to 2.4 mg/kg) in 3 patients. The dosage range was 0.7 to 3.3 to mg/kg per day (mean, 1.9 mg/kg). Mildly elevated transaminase values in 7 patients and elevated fasting gastrin levels in 11 patients were present; in 6 of the 11, gastrin levels were 3 to 5.5 times the upper limit of normal. We found omeprazole to be highly effective in this group of patients with severe esophagitis refractory to other measures. We recommend a starting dose of 0.7 mg/kg as a single morning dose; the adequacy of reflux control is then determined by follow-up 24-hour intraesophageal pH studies. Omeprazole appears to be safe for short-term use, but further studies are needed to assess long-term safety because the significance of chronically elevated gastrin levels in children is unknown.

Veno-occlusive Disease of the Liver and Multiorgan Failure after Bone Marrow Transplantation: A Cohort Study of 355 Patients

To determine the incidence and clinical course of veno-occlusive disease of the liver (VOD) after bone marrow transplantation and to analyze risk factors for severe VOD. Cohort study of 355 consecutive patients. A bone marrow transplantation center. Each patient was prospectively evaluated for VOD, and many risk factors for severe VOD were analyzed using logistic regression models. The relation of VOD to renal and cardiopulmonary failure was analyzed using time-dependent proportional hazards models. Veno-occlusive disease developed in 190 of 355 patients (54%; 95% CI, 48% to 59%): Fifty-four patients had severe VOD and 136 had mild or moderate VOD. Independent variables derived from a multivariate model for predicting severe VOD included elevated transaminase values before transplantation (relative risk, 4.6; P < 0.0001); vancomycin therapy during cytoreductive therapy (relative risk, 2.9; P = 0.003); cytoreductive therapy with a high-dose regimen (relative risk, 2.8; P = 0.01); acyclovir therapy before transplantation (relative risk, 4.8; P = 0.02); mismatched or unrelated donor marrow (relative risk, 2.4; P = 0.02); and previous radiation therapy to the abdomen (relative risk, 2.2; P = 0.04). Vancomycin therapy was a marker for persistent fever. Multiorgan failure was more frequent among patients with VOD and usually followed the onset of liver disease. Veno-occlusive disease, which developed in 54% of bone marrow transplant recipients, is frequently associated with renal and cardiopulmonary failure. Pretransplant transaminase elevations, use of high-dose cytoreductive therapy, and persistent fever during cytoreductive therapy are independent predictors of severe VOD.