Bradford Waters

Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease.

OBJECTIVE:Nonalcoholic steatohepatitis (NASH) is a common but poorly understood liver disease. Our aim was to study a large group of patients referred for Hepatology consultation to further characterize this disorder, in particular its demographics and range of severity. We also sought to better understand its etiology and its relationship to the insulin resistance syndrome, known as the metabolic syndrome or syndrome X.METHODS:Retrospective review of 90 patients seen over a 4-yr period.RESULTS:Ninety patients aged 14–70 with NASH seen at the Liver Clinics at either the University of Tennessee or the Medical University of South Carolina. Eleven had complications of portal hypertension and seven of these had undergone or were awaiting transplantation. NASH was seen in nine families either in siblings or in subsequent generations. Diabetes or insulin resistance were present in almost all in this cohort of patients with NASH. Diabetes, hyperlipidemia, hypertension, and atherosclerotic disease, the components of syndrome X, were common in this population.CONCLUSION:NASH affects males and females equally, and presents over a wide age range. Despite its usually benign course, 28% of patients had cirrhosis and almost half of those had complications of portal hypertension, necessitating liver transplantation. Obesity was common in affected patients and cirrhosis was more common in the morbidly obese. Familial clustering was common, with 18% of patients having a similarly affected first degree relative. The clinical features that define syndrome X (diabetes, hypertension, hyperlipidemia, and atherosclerotic disease) are common in affected patients. Studies of glucose tolerance demonstrated unsuspected diabetes in six, and insulin resistance (the hallmark of syndrome X) in 85% of those tested. We hypothesize that NASH is a disorder of genetic etiology and is the hepatic manifestation of syndrome X, the insulin resistance syndrome.

Serious hepatitis A : an analysis of patients hospitalized during an urban epidemic in the United States

An effective vaccine for the hepatitis A virus (HAV) is now available, but the recommended indications for its use remain limited [1]. The Memphis, Tennessee, metropolitan area is experiencing an epidemic of hepatitis A. Memphis and Shelby County have a population of approximately 830 000 persons, 50% of whom are African American. For each year from 1989 to 1993, an average of 57 cases of hepatitis A were reported, but 210 cases were reported in 1994 and 1538 cases were reported in 1995 [2]. Neighboring counties in Mississippi and Arkansas noted similar increases [3]. This epidemic has not been associated with a common food source or a breakdown in public sanitation. Few recent urban epidemics of hepatitis A in industrialized countries have not been traced to a common source [4]. We present an analysis of the clinical features of patients hospitalized during this epidemic. Methods The computerized medical records of the 15 acute care hospitals (2 of which are pediatric hospitals) in Shelby County were queried for the discharge diagnosis of acute hepatitis A (International Classification of Diseases, Ninth Revision [ICD-9] codes 070.1 [acute hepatitis A without coma] and 070.0 [acute hepatitis A with coma]) for the study period of 1 January 1994 through 31 December 1995. The paper charts for the retrieved patient names were reviewed by five of the authors, who used a standardized form to record demographic data, epidemiologic risk factors, reasons for hospitalization, underlying medical conditions, and serious complications. A diagnosis of acute hepatitis A required positivity for HAV IgM antibody in conjunction with compatible symptoms and laboratory findings. We sought information on the following risk factors for transmission of HAV: exposure to day care, household contact, association with a restaurant, being a homosexual man, occupational exposure, hemophilia, active use of injection drugs, travel to areas in which hepatitis A is endemic, consumption of raw shellfish, and unknown. We also sought information on underlying medical conditions, including chronic liver disease, significant alcohol consumption (>50 g/d for >5 years), HIV infection, cardiovascular disease, underlying cancer, chronic immunosuppression, and diabetes. Complications sought included acalculous cholecystitis, hemolysis, autoimmune hepatitis (antinuclear antibody titer > 1:160 or positive smooth-muscle antibody titer > 1:80 and compatible liver biopsy findings), pancreatitis, prolonged cholestasis (serum bilirubin level > 136 mol/L [8 mg/dL] for >12 weeks), and relapsing hepatitis. If two or more unrelated complications were present, they were all recorded. If a complication was caused by an underlying condition (for example, acute renal failure in a patient with fulminant hepatitis), only the underlying complication was recorded. Any unanticipated complication that was encountered during chart review was recorded. This study was approved by the institutional review board of the University of Tennessee. The Fisher exact test was used to analyze the data. Statistical significance was defined as a P value less than 0.05. Results We identified 313 patients and reviewed their charts. Fifty charts were excluded because patients lacked documented HAV IgM antibody. Four charts could not be retrieved. Three patients who were seen in two hospitals were not counted twice. The remaining 256 charts belonged to patients who met the criteria for hepatitis A. Demographic data for the study patients are shown in Table 1. Two hundred thirty-one patients were residents of Shelby County, and 25 were from surrounding communities. Table 1. Characteristics of Hospitalized Patients with Hepatitis A* The source of hepatitis A was identified in only 21% of patients (Table 1). The two restaurant-associated cases were from a large outbreak in Arkansas. On admission, 89% of patients had prolonged nausea or vomiting, or both; 26% had coagulopathy (prothrombin time 3 seconds prolonged); 21% had marked jaundice (bilirubin level > 170 mol/L [10 mg/dL]); and 18% had abdominal pain. Preexisting underlying disease alone or in combination was present in 17% of patients; this was alcoholism in 24 patients (9%), diabetes in 16 (6%), chronic hepatitis B or C in 10 (4%), and HIV infection in 4 (2%). No association was seen between the presence of underlying disease and the occurrence of a serious complication (P > 0.2). The clinical complications encountered are shown in Table 2. Thirty-five patients (14%) had 39 serious complications; 20 of these complications were extra-hepatic and 19 were hepatobiliary. Most were present on admission or were evident within 2 days after admission. Twenty-five percent of patients 40 years of age or older and 11% of patients younger than 40 years of age had at least one complication (P = 0.014). Of the 35 patients with serious complications, only 2 (5.7%) would have been advised to receive vaccine under current guidelines (1 had chronic hepatitis C and 1 was an active user of injection drugs) [1]. Table 2. Complications of Hepatitis A by Age Ten patients had findings consistent with acalculous cholecystitis, but none required cholecystectomy. Three patients had prolonged cholestasis with jaundice lasting up to 20 weeks. A 3-year-old child presented with hypoglycemia, hyperammonemia, and mental status changes that resolved with supportive treatment. Ten patients had evidence of hemolysis and 3 patients had acute renal failure; 2 of the 3 required hemodialysis but recovered. Four patients were known to be pregnant. Two of the 4 presented in the first trimester, and the other 2 presented in the third trimester and had preterm labor with premature delivery. Both mothers and babies recovered. Two patients presented with new-onset diabetes with ketoacidosis. A 14-year-old girl developed pericardial and pleural effusions that required pericardiocentesis for cardiac tamponade. Five patients died (Table 2). Two of the five died of complications of fulminant hepatic failure; one was awaiting liver transplantation at the time of death. This 28-year-old man developed hepatic coma within 72 hours and herniated from refractory increased intracranial pressure. The other patient who died of complications of fulminant hepatic failure was a 23-year-old man who developed the adult respiratory distress syndrome and died of cardiac arrest. Two patients had prolonged illness with antinuclear antibody titers greater than 1:640 and liver biopsy results consistent with autoimmune hepatitis. Neither of these patients was known to have previous liver disease. One improved clinically while receiving prednisone and azathioprine but died of infectious complications. The other died of gastrointestinal hemorrhage, liver failure, and increased intracranial pressure before immunosuppressive therapy was started. One patient with chronic hepatitis C and a history of ethanol abuse died of progressive liver failure. Three of the 53 patients (5.7%) 40 years of age and older and 2 of the 203 patients (1%) younger than 40 years of age died (P = 0.062). Discussion Hepatitis A is usually self-limited, and full recovery is seen by 3 months in 85% of cases [5]. Previous reports have shown a case-fatality rate of only 0.01% to 0.03% [6] but an increased risk for death with age [7]. Risk for death is also increased in patients with chronic liver diseases [8]. The financial burden of hepatitis A on the U.S. health care system is substantial [9]; the estimated cost of a recent outbreak of 43 cases was

Prospective multicenter study of eligibility for antiviral therapy among 4,084 U.S. veterans with chronic hepatitis C virus infection

809 706 [10]. The median age of the patients who died in our series was 40 years. Of the five patients who died, only one had evidence of chronic liver disease. Complications were more common in patients 40 years of age and older, and mortality rates also seemed to be higher in this group. However, two patients younger than 30 years of age died. Some patients with hepatitis A had unexpected clinical manifestations. Extrahepatic complications occurred in 8% of our patients. Acalculous cholecystitis, hemolysis, acute renal failure, and reactive arthritis have been reported [11-13]. Unusual extrahepatic manifestations included new-onset diabetes, preterm labor, and pericardial and pleural effusions. We identified two cases of autoimmune hepatitis associated with acute hepatitis A, and at least four similar cases have been reported [14]. The hepatitis A virus may serve as a trigger for autoimmune hepatitis in genetically susceptible persons, a phenomenon that has been reported after rubeola and Epstein-Barr virus infection [15, 16]. Between 1983 and 1992, the Viral Hepatitis Surveillance Program did not identify risk factors for HAV transmission in 40% of cases [17, 18]. We were unable to identify risk factors for transmission in 79% of patients; this points out a limitation of retrospective studies. In addition, study patients were hospitalized at 15 institutions and were cared for by multiple physicians, and the admission history was not uniform. For example, patients who had exposure to asymptomatic children with hepatitis A would not have been documented. The studies performed during hospitalization were not standardized, and some complications may have been overlooked, making our estimates imprecise. Biases related to which patients sought medical care and which physicians chose to hospitalize them may limit the generalizability of our findings. We were unable to assess patients who were not hospitalized. Immunity to hepatitis A approaches 100% in young adults in developing countries. In contrast, immunity in the United States is low: 38% overall, 11% in persons younger than 5 years of age, and 74% in persons older than 50 years of age [19, 20]. A substantial segment of the U.S. adult population is therefore susceptible to HAV infection, setting the stage for large-scale urban outbreaks. This is exemplified by a recent epidemic in Shanghai that affected more than 300 000 persons and caused

Effect of interferon-α treatment of chronic hepatitis C on health-related quality of life

BACKGROUND:Many veterans may not be candidates for hepatitis C virus (HCV) treatment due to contraindications to therapy. The aims of this study were to determine the proportion of HCV-infected veterans who were eligible for interferon alfa and ribavirin therapy and to evaluate barriers to HCV treatment.METHODS:We prospectively enrolled 4,084 veterans who were referred for HCV treatment over a 1-yr period at 24 Veterans Affairs (VA) Medical Centers. Treatment candidacy was assessed using standardized criteria and the opinion of the treating clinician.RESULTS:Overall, 32.2% (95% CI, 30.8–33.7%) were candidates for HCV treatment according to standardized criteria, whereas 40.7% (95% CI, 39.2–42.3%) were candidates in the opinion of the treating clinician. Multivariable analysis identified ongoing substance abuse (OR = 17.68; 95% CI, 12.24–25.53), comorbid medical disease (OR = 9.62; 95% CI, 6.85–13.50), psychiatric disease (OR = 9.45; 95% CI, 6.70–13.32), and advanced liver disease (OR = 8.43; 95% CI, 4.42–16.06) as the strongest predictors of not being a treatment candidate. Among patients who were considered treatment candidates, 76.2% (95% CI, 74.0–78.3%) agreed to be treated and multivariable analysis showed that persons ≥50 yr of age (OR = 1.37; 95% CI, 1.07–1.76) and those with >50 lifetime sexual partners (OR = 1.44; 95% CI, 1.08–1.93) were more likely to decline treatment.CONCLUSIONS:The majority of veteran patients are not suitable candidates for HCV treatment because of substance abuse, psychiatric disease, and comorbid medical disease, and many who are candidates decline therapy. Multidisciplinary collaboration is needed to overcome barriers to HCV therapy in this population.

Black patients with chronic hepatitis C have a lower sustained viral response rate than non-Blacks with genotype 1, but the same with genotypes 2/3, and this is not explained by more frequent dose reductions of interferon and ribavirin*.

Studies of interferon-α (IFN-α)therapy for chronic hepatitis C have focused on viralclearance; however, few have evaluated patientshealth-related quality of life during therapy. Thisstudy evaluates health-related quality of life and theprevalence of anxiety and depression in patients withchronic hepatitis C before, during, and followingIFN-α therapy. Patients undergoing IFN-αtherapy for chronic hepatitis C were asked to completehealth status measures as well as anxiety and depressioninventories before, during, and following IFN-αtherapy. These measures were compared to the results of healthy adults in the general US population.Thirty-eight of forty-eight eligible patients (79%) withchronic hepatitis C completed the questionnaires.Respondents demonstrated a significant increase in depression during the sixth month ofinterferon therapy in comparison to pretreatmentresults. Anxiety scores improved significantly after onemonth of IFN-α in comparison to pretreatmentresults. Scores on the health status measures did notvary with IFN-α therapy. Patient responses wereanalyzed with respect to biochemical response(normalized transaminases) to IFN-α. IFN-αresponders, who were aware of their transaminase results,exhibited lower scores on anxiety subscales during andafter therapy (P = 0.02-0.04). Scores on the healthstatus subscale, role emotional, improved in IFN-α responders compared to nonresponders during thesixth month of therapy (P = 0.02). Response toIFN-α therapy was not associated with any otherdifferences on subscale analysis. Patients with chronichepatitis C exhibited health perceptions similar to thegeneral US population, and these were unchanged duringIFN-α therapy. However, the incidence ofdepression significantly increased during the sixthmonth of IFN-α therapy. IFN-α respondersexhibited fewer emotional problems as well as a lowerincidence of anxiety during and followingtherapy.

Electrophysiologic, morphologic, and serologic features of chronic unexplained nausea and vomiting: Lessons learned from 121 consecutive patients

Summary.  In previous hepatitis C virus (HCV) treatment studies, Black patients not only had a lower sustained viral response (SVR) rate to interferon and ribavirin (RBV) than non‐Black patients but also a higher frequency of HCV genotype 1 (GT‐1) infection. The aim of this community‐based study was to determine whether Black patients have a lower SVR rate independent of genotype. We prospectively enrolled 785 patients (24.8% Black, 71.5% White, 3.7% others) who received interferon alpha‐2b 3 MU three times weekly + RBV 1000–1200 mg/day for 24 weeks (GT‐2/3) or 48 weeks (GT‐1). Black patients were more commonly infected with GT‐1 (86.8%vs 64.8%, P < 0.001) and less frequently had an SVR compared with non‐Black patients (8.4%vs 21.6%, P < 0.001). Within GT‐1, Black patients had a lower SVR rate than non‐Black patients (6.1%vs 14.1%, P = 0.004) but not within GT‐2/3 (50.0%vs 36.5%, P = 0.47). Black patients had lower baseline haemoglobin levels (14.8 vs 15.3 g/dL, P < 0.001) and neutrophil counts (2900 vs 4100/mm3, P < 0.001) and required more frequent dose reductions of RBV (29.8%vs 18.5%, P < 0.001) and interferon (4.7%vs 1.6%, P = 0.012). However, dose reductions were not associated with lower SVR rates while early treatment discontinuations were (2.9%vs 25.7%, P < 0.001). Independent predictors of SVR were GT‐1 [odds ratio (OR) 0.33; 95% confidence interval (CI) 0.20–0.55; P < 0.001], Black race (OR 0.45; 95% CI 0.22–0.93; P = 0.030), and advanced fibrosis, stages 3 + 4 (OR 0.53; 95% CI 0.31–0.92; P = 0.023). In conclusion, Black patients infected with HCV GT‐1 (but not GT‐2/3) have a lower SVR rate than non‐Black patients. This is not explained by their lower baseline haemoglobin levels and neutrophil counts that lead to higher rates of ribavirin and interferon dose reductions.

Intraperitoneal Rupture of Ectopic Varices: Two Case Reports and a Review of Literature

BACKGROUND Despite substantive morbidity, unexplained nausea and vomiting has not been evaluated in a systematic manner via surgically obtained biopsies and direct electrophysiology of the gut, and this information has not been correlated with serologic information. We investigated consecutive patients with unexplained and refractory chronic nausea and vomiting to define the presence of morphologic, physiologic, and/or serologic abnormalities. METHODS In all, 101 of 121 consecutive patients who experienced chronic nausea and vomiting of unknown etiology evaluated in 1 tertiary referral center over a 10-year period were profiled qualitatively by full-thickness small bowel biopsies with hematoxylin and eosin (H&E) and Smiths Silver stains, quantitatively by intraoperative gastric electrophysiology, and semiquantitatively, when it became available, by serum autoimmune Western blot analysis. RESULTS Overall, 79 of 101 patients had abnormal full-thickness biopsy (70 neuropathies and 9 myopathies) and frequent serum autoimmune abnormalities (mean score = 13.2, normal < 3.0). In addition, 96 of 101 patients had abnormal frequency and/or uncoupling on gastric electrophysiology. Patients with small-intestinal myopathy showed a diversity of diagnoses; some patients with neuropathy had abdominal pain that correlated with autoimmune scores on Western blot. CONCLUSION Patients with refractory and unexplained nausea and vomiting have a high incidence of both small bowel morphologic abnormalities (primarily neuropathies) and gastric electrophysiologic abnormalities, which are associated commonly with serologic autoimmune activation. Similar histomorphologic, physiologic, and serologic measures should be considered in the diagnostic evaluation of any patient with refractory or unexplained nausea and vomiting.

Polyarteritis nodosa and cryoglobulinemic glomerulonephritis related to chronic hepatitis C

Intraperitoneal rupture of ectopic varices is a rare complication of portal hypertension. Few case reports have been published in the literature. We report 2 cases of ectopic varices with intraperitoneal hemorrhage. This review details their presentation, hospital course and treatment. The first patient was managed conservatively, and second had a successful TIPS (transjugular intrahepatic portosystemic shunt). Few guidelines for treatment are available. The management is individualized according to the condition of the patient and the resources available. Objectives of management include early diagnosis, aggressive fluid resuscitation, correction of coagulopathy, reduction of portal hypertension and if possible direct control of the bleeding vessel.

Biliary Strictures After Liver Transplantation. Predictive Factors for Response to Endoscopic Management and Long-term Outcome

Case Report:A 53-year-old man with hepatitis C virus (HCV) infection underwent cholecystectomy for presumed cholecystitis. Gallstones were not present, and histological examination demonstrated medium-sized arteritis, consistent with polyarteritis nodosa (PAN). The patient later developed rapidly progressive glomerulonephritis. Kidney biopsy demonstrated cryoglobulinemic glomerulonephritis. Because of the severity of the patient’s vasculitic manifestations, treatment included pulse methylprednisolone followed by oral prednisone and monthly intravenous cyclophosphamide for 6 months. During treatment, microhematuria resolved, proteinuria decreased, and serum creatinine concentration stabilized. The patient subsequently underwent treatment for HCV with interferon resulting in a marked decrease in HCV RNA. The patient has had no relapse of his vasculitis, his renal function is stable, and viral load remains low after completing 36 weeks of interferon. Conclusion:Life-threatening vasculitis related to HCV was successfully treated with immunosuppressive therapy. After obtaining clinical remission, antiviral therapy was instituted, resulting in a dramatic decrease in HCV RNA.

Neuropsychiatric complications after liver transplantation: role of immunosuppression and hepatitis C.

Background:Biliary strictures after liver transplantation are frequent. The long-term prognosis and predictive factors of response to endoscopic treatment are not well known. Methods:The aim of this study was to demonstrate the role of endoscopic treatment, predictive factors of response, and outcome in patients with biliary stricture after liver transplantation. We performed a retrospective review of medical records of all consecutive post-liver transplantation patients who underwent endoscopic retrograde cholangiography in our center during the period from October 2001 to October 2006. Results:Twenty-five of 43 patients referred for endoscopic retrograde cholangiography had biliary stricture. Eighteen had stricture at the area of the anastomosis alone, 2 patients had a stricture at the area of the anastomosis and also another area, and 5 had nonanastomotic biliary strictures. Twenty-one patients had a single stricture and 4 had more than 1 stricture. Initially 19 of 24 patients (79%) responded to endoscopic management with normalization of liver enzymes. Four patients (16%) did not respond clinically despite a successful endoscopic approach. All patients who did not respond to endoscopic dilation had more than 1 area of stricture. There was a significantly better response to endoscopic treatment in patients with an anastomotic stricture versus patients with nonanastomotic strictures 17/19 versus 2/5 (P = 0.042). Conclusions:In our experience, endoscopic treatment of anastomotic biliary strictures is highly effective with a good long-term outcome. The presence of nonanastomotic and multiple strictures should be considered a factor associated with poor response to endoscopic management.