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The condition of hereditary hemochromatosis (HH) is caused by gene-dependent protein abnormalities involved in iron absorption, storage, or modulation of iron; these abnormalities result in iron overload. The clinical laboratory plays a significant role in case finding, diagnostic validation, and monitoring HH therapy. Elevated serum iron, transferrin saturation, and ferritin suggest HH, but results can also indicate other forms of hepatocyte injury such as alcoholic or viral hepatitis, or other inflammatory disorders involving the liver. In the context of elevated serum iron, transferrin saturation, and ferritin, and after ruling out secondary causes of iron overload, HFE gene evaluation is the preferred test to confirm the diagnosis of HH. However, 5% to 15% of patients with phenotypic HH do not have HFE gene mutations. In these cases, MRI evaluation or liver biopsy with iron quantification is indicated. The clinical role of hepcidin, the iron modulating protein, is undetermined at this time. Because hepcidin also plays a key role in antimicrobial and inflammatory activities, interpretation of hepcidin serum or urine concentration will require thorough understanding of its complex role in iron regulation., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: To report the results of treating patients with orbital pseudolymphomas with the anti-CD20 monoclonal antibody rituximab., Patients and Methods: Patients were included in the study if they had an orbital mass and biopsy-proven orbital pseudolymphomas between January 1, 1998, and December 31, 2005. The study focused on patients treated with rituximab., Results: Ninety-eight patients were evaluated, and the biopsy results revealed malignant non-Hodgkin lymphoma in 72 (73%); the other 26 (27%) had a pseudolymphoma. Eleven (42%) of the 26 patients with a pseudolymphoma were treated with rituximab, 375 mg/m2, intravenously each week for 4 doses, and 10 (91%) of the 11 responded. Seven patients were either treated with maintenance rituximab or successfully retreated with rituximab after relapse. None of the 10 responders has become refractory to rituximab., Conclusion: Benign lymphoproliferative tumors are responsive to monoclonal antibody therapy targeted to B lymphocytes. Rituximab should be considered a treatment option for orbital pseudolymphomas.

Background & Aims: Copper absorption in humans probably occurs in the stomach and duodenum. Copper is essential for the structure and function of the nervous system and acquired copper deficiency in humans has been recognized to cause a myelopathy that resembles vitamin B12 deficiency. Acquired copper deficiency is not a well-recognized complication of gastric surgery. In Menke's disease a defect in enterocyte transport of absorbed copper results in increased copper content in the duodenal mucosa and hypocupremia., Methods: We report 2 patients who developed neurologic deficits with copper deficiency many years after gastric surgery. In 2 other patients with hypocupremic myelopathy but no history of gastric surgery, colonic copper was measured to determine if an absorptive defect similar to that seen in Menke's disease may be responsible for hypocupremia., Results: In all 4 patients copper deficiency was identified as the cause of the myelopathy. In 2 patients the copper deficiency occurred after gastric surgery. Eight additional patients with copper deficiency after gastric surgery were identified from the literature. Six of these 8 patients also had neurologic manifestations. Colonic mucosa copper content was increased in the 2 patients with hypocupremia without prior gastric surgery., Conclusions: Acquired copper deficiency may be a delayed complication of gastric surgery and may result in a myelopathy similar to that seen with vitamin B12 deficiency. In some patients with acquired copper deficiency no cause for the hypocupremia may be evident and a primary absorptive defect should be considered.

We describe mortality and resource utilization for inpatient care of hepatitis C (HCV) in comparison to alcohol-induced liver disease (ALD) in the United States and identify factors that affect outcomes. The Healthcare Cost and Utilization Project database, a national inpatient sample was used to identify hospitalization records with diagnoses related to liver disease from HCV and ALD. Outcome of hospitalizations was analyzed in terms of in-hospital deaths and health care resource utilization. For 1995, we estimate that there were 26,700 hospitalizations and 2,600 deaths in acute, nonfederal hospitals in the United States for liver diseases caused by HCV. Total charges for these hospitalizations were $514 million. In comparison, ALD was associated with 101,200 hospitalizations, 13,400 deaths, and $1.8 billion in charges. Simultaneous HCV and alcohol abuse was associated with younger ages at the time of hospitalization and death compared with HCV or ALD alone. In a logistic regression analysis, alcohol abuse (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.2-1.5) and human immunodeficiency virus (HIV) infection (OR, 4.5; 95% CI, 4.0-4.9) were associated with an increased risk of death among those with HCV. Liver transplantation and patient death were associated with the largest increase in hospitalization charges. Major complications of cirrhosis, such as variceal bleeding, encephalopathy, and hepatorenal syndrome, and sociodemographic factors, such as race and health insurance, were also significantly associated with the risk of death and hospitalization charges, which were similar in HCV and ALD. This study provides new estimates regarding the public health impact of HCV, for use in health policy decisions and cost-effectiveness analyses of preventive and therapeutic interventions.

Objective: Because many patients with chronic viral hepatitis do not progress to end-stage liver disease, it is possible that host factors such as human leukocyte antigen (HLA) differences are important. Our aims were to determine HLA marker-specific rates of progression to liver transplantation among patients with chronic hepatitis C; and to determine if polymerase chain reaction (PCR)-based HLA DRB1 typing can be performed on stored serum samples., Methods: Forty-two hepatitis C virus RNA-positive liver transplant patients and 87 untransplanted patients were included in a Cox proportional hazards model to test whether the occurrence of certain HLA DRB1 markers were associated with progression to liver transplantation. HLA DRB1 typing was performed on stored serum samples using a PCR method., Results: There were no differences among the HLA DRB1 markers with regard to the HLA marker-specific rate of progression to transplantation among patients with chronic hepatitis C., Conclusions: HLA DRB1 markers do not appear to be associated with progression of disease in chronic viral hepatitis C. It is possible to perform PCR-based HLA DRB1 typing on stored frozen serum samples.

Liver transplant recipients frequently have chronic liver diseases and should be considered for vaccination against hepatitis A virus (HAV). However, persistence of protective antibodies after orthotopic liver transplantation (OLT) has not been shown in this population, which may have implications for future vaccine recommendations. We evaluated the prevalence and epidemiological significance of immunoglobulin G (IgG) antibody to HAV (anti-HAV) in a nonvaccinated population before OLT (immunity from previous exposure) and determined the persistence of IgG anti-HAV at 1 and 2 years after OLT. One hundred consecutive patients were identified who underwent OLT and had at least 2 years of follow-up post-OLT. They were not vaccinated against HAV infection at any time. Clinical data were summarized from medical records, and stored sera were tested for IgG anti-HAV before OLT and at 1 and 2 years after OLT by a commercially available enzyme immunoassay. Of 100 patients, 24 had IgG anti-HAV before OLT. No epidemiological differences were noted between those with or without detectable IgG anti-HAV before OLT. Among patients with detectable IgG anti-HAV before OLT, 4 of 22 patients (18%) and 7 of 24 patients (29%) became negative for IgG anti-HAV at 1 and 2 years post-OLT, respectively. None of the patients with undetectable IgG anti-HAV before OLT became positive at any time. Most of our patients with end-stage liver disease had no serological evidence for immunity against HAV. A significant proportion of patients with detectable protective antibodies before OLT lost their antibodies at 2 years after OLT.

Objective: The TT virus (TTV) is a novel DNA virus that has recently been identified. The clinical significance of TTV infection in patients with chronic hepatitis C has not been determined. The aim of this study was to determine the prevalence and possible role of TTV in a well characterized population with chronic hepatitis C infection., Methods: Ninety patients with chronic HCV and known time of HCV acquisition were selected from approximately 250 patients followed at our institution. Characteristics including age, sex, histology, and length of disease were recorded. Direct sequencing of the NS5 region was used for HCV genotyping. TTV DNA detection was based on PCR., Results: TTV infection was present in 24 of 90 (27%) HCV patients. Patients were divided into four groups based on stage of disease; chronic hepatitis (CH, 29 patients), compensated cirrhosis (CC, 17 patients), decompensated cirrhosis (DC, 28 patients), and hepatocellular carcinoma (HCC, 16 patients). TTV was present in 2/29 (7%), 2/17 (12%), 11/28 (39%), and 9/16 (56%) in those with CAH, CC, DC, and HCC respectively. TTV was significantly more prevalent among those with advanced disease (DC and HCC) compared to those with stable disease (CH and CC; p = 0.001). Mean age, sex, and the time from exposure to HCV to development of complications were similar in TTV-positive and -negative patients. TTV infection was more common in patients infected with HCV genotype 1b. Univariate analysis showed that length of HCV infection, HCV genotype 1b, and TTV infection were important in predicting the stage of liver disease in HCV patients. However, after adjusting for length of HCV infection, TTV but not HCV genotype was important in predicting the stage of liver disease., Conclusions: We conclude that 1) TTV infection is common in patients with chronic HCV; 2) TTV infection is more prevalent among patients with advanced HCV-associated liver disease (DC and HCC) than in those with stable disease (CH and CC); and 3) TTV infection is more common in patients with HCV genotype 1b but is independent from genotype in predicting the stage of HCV-associated liver disease.

Objectives: Hepatitis G virus (HGV) is a recently discovered member of the flavivirus family that has been associated with acute and chronic hepatitis. HGV infection has been reported to coexist in 10-20% of patients with chronic hepatitis C. The significance of simultaneous infection with HGV and hepatitis C virus (HCV) remains to be clarified, as do the effects on HGV of therapeutic interventions such as interferon treatment or liver transplantation., The Aims of Our Study Were: 1) to examine the frequency of HGV infection in the settings of liver transplantation and interferon therapy for hepatitis C; and 2) to compare HGV RNA levels before and after liver transplantation or interferon treatment., Methods: Pre-treatment sera were available in 65 patients with chronic hepatitis C treated with interferon; pretransplant sera were available in 49 patients transplanted for end stage liver disease associated with chronic hepatitis C. Information collected included age, sex, risk factors for hepatitis, concurrent liver disease, patient and allograft survival, biochemical response to interferon, histological activity index, and degree of fibrosis/cirrhosis. HCV genotyping was performed by sequencing the NS-5 region. HGV quantitation was performed using a research-based branched DNA (bDNA) assay with a set of probes directed at the 5' untranslated region., Results: HGV was detected in 10 of 49 patients (20%) before transplant and in 13 of 65 patients (20%) treated with interferon. There was a female predominance among HGV-positive compared with HGV-negative transplant patients (80% vs 20%; p < 0.01), but such a difference was not observed in the interferon-treated group. Hepatic iron concentration was lower in hepatic explants from patients who were HGV-positive than in those who were HGV-negative (318 +/- 145 microg/g dry weight vs 1497 +/- 2202 microg/g dry weight; p = 0.02). HCV exposure after 1980 was more common in the HGV-positive patients than in those who were HGV-negative for the entire study population (10 of 20 [50%] vs 16 of 66 [24%]; p = 0.03), as well as for the nontransplant subgroup (8 of 12 [67%] vs 12 of 39 [31%]; p = 0.03). HGV RNA levels declined at 1 yr after transplant in seven of eight patients. Among nine patients tested during or after interferon treatment, HGV RNA levels declined from pretreatment levels in all and disappeared in three., Conclusions: Among patients with chronic hepatitis C treated with either interferon or liver transplantation, the frequency of coinfection with HGV is about 20%. HGV may be a more recent virus in the US than HCV. Coinfection with HGV does not appear to affect the likelihood of response to interferon in patients with hepatitis C. Finally, HGV RNA levels appear to decline after both liver transplantation and interferon therapy, suggesting possible suppression by increased HCV replication in the former case, and a possible drug treatment effect in the latter.

Hepatitis C virus infection is common, often silent, and almost always chronic and can lead to cirrhosis and hepatocellular cancer. Deaths related to chronic hepatitis C are expected to increase dramatically in the future. Many cases of infection are asymptomatic and are undiagnosed because of a lack of recognition by patients and physicians. All patients currently or previously at risk of infection should undergo screening, including those who received blood transfusions before 1992. Interferon is the only effective therapy, but disappearance of virus is sustained in only 10 to 15% of patients. The combination of interferon and oral ribavirin therapy may increase the sustained response rate to about 40%. New agents such as hepatitis C virus-specific protease inhibitors may be available in the next 5 to 10 years, and treatment is evolving toward multiple-drug regimens analogous to those used for human immunodeficiency virus (HIV) infection. In contrast to public funding for drug development in HIV, such funding for hepatitis C has been limited.

The only effective and approved therapy for chronic hepatitis C is interferon-alpha. Because sustained response rates with interferon alone are disappointingly low, multidrug treatment regimens are currently being investigated. Ursodeoxycholic acid has been used in other chronic liver diseases and can limit hepatocyte injury. To evaluate the potential benefit of ursodeoxycholic acid in combination with interferon-alpha for the treatment of chronic hepatitis C, we conducted a prospective, double-blinded, randomized, placebo-controlled trial comparing the combination therapy of interferon-alpha 2b and ursodeoxycholic acid with interferon alone. Thirty-one patients with chronic hepatitis C were randomized to receive 3 million units of interferon-alpha 2b subcutaneously three times per week and either 13 to 15 mg/kg/day ursodeoxycholic acid or placebo orally for 6 months. The 6-month treatment period was followed by 6 months of observation. Biochemical normalization at the end of treatment occurred in 5 of 14 (36%) patients receiving monotherapy versus 8 of 15 (53%) patients (p = 0.34) receiving combination therapy. No patient treated with interferon alone had a sustained biochemical response 6 months after therapy; however, 3 of 12 patients (25%) treated with combination interferon and ursodeoxycholic acid maintained biochemical normalization at 6 months after therapy (p = 0.08). No difference in liver histology or clearance of hepatitis C viral RNA was noted 6 months after treatment. We conclude that combination therapy with ursodeoxycholic acid and interferon-alpha 2b was no more effective than interferon monotherapy in inducing a biochemical response in previously untreated patients with chronic hepatitis C. Ursodeoxycholic acid, however, may be useful in prolonging the biochemical response to interferon therapy.

Background: The significance of hepatitis G (HGV) infection in liver transplant recipients is not known. We set out to determine the pre-orthotopic liver transplantation (OLT) prevalence, the pre- and postoperative viral titers of HGV, and the allograft histology in patients infected with HGV who underwent OLT for cryptogenic cirrhosis., Methods: HGV RNA was measured using a research-based branched DNA assay. The assay used a target-specific probe set that was based on the 5'-untranslated region of the HGV genome. Allograft histology was assessed with protocol liver biopsies in all patients who survived longer than 6 months., Results: The preoperative prevalence of HGV infection in recipients transplanted for cryptogenic cirrhosis was 26%. Thirty-seven percent (12 of 33) of recipients who had serum available in the first postoperative month had HGV infection. Mean HGV RNA levels were 9.8 (+/-4.2) (viral molecular equivalents/ml x 10[6]) before OLT and 37.5 (+/-10.7) at 1 year after OLT. In 4 of the 11 cryptogenic recipients in whom HGV RNA was detectable in the first postoperative month, HGV RNA fell to undetectable levels at the most recent follow-up (mean 70 months). Of the five cryptogenic recipients who continue to have measurable HGV RNA, three have unexplained hepatitis histologically., Conclusions: These findings suggest the following: 1) The prevalence of HGV infection in patients undergoing OLT for cryptogenic cirrhosis is about 25%. 2) In recipients persistently infected with HGV, mean HGV RNA titers increase after OLT. 3) HGV RNA becomes undetectable in about one third of recipients who had detectable HGV RNA in the first month after OLT. 4) Hepatitis of uncertain etiology occurs in 60% (3 of 5) of persistently HGV-infected cryptogenic recipients.

Background: Interferon-alpha is effective in only a small number of patients with chronic hepatitis C, although prolonged treatment may increase the response rate. There is concern that the expense of interferon-alpha therapy may not be justified by the low response rates and uncertain long-term benefit., Objective: To compare clinical and economic outcomes after 6 months and 12 months of interferon-alpha therapy for chronic hepatitis C., Design: A Markov model depicting the natural progression of chronic hepatitis C. On the basis of this model, a simulated trial compared no therapy with 6 and 12 months of interferon-alpha therapy at standard doses (3 million U three times weekly)., Patients: Four age-specific cohorts (30, 40, 50, and 60 years of age) with chronic hepatitis C., Measurements: Number of deaths from liver disease, total costs, and cumulative quality-adjusted life-years (QALYs)., Results: Six and 12 months of interferon-alpha treatment gained 0.25 QALYs at an incremental cost of $1000 and 0.37 QALYs at an incremental cost of $1900, respectively. Thus, although 6 months of interferon-alpha therapy was less efficacious than 12 months of therapy, it was more cost-effective ($4000 per QALY gained compared with $5000 per QALY gained). Nonetheless, in patients younger than 60 years of age, both 6 and 12 months of therapy compared favorably with other established medical interventions, such as screening mammography and cholesterol reduction programs. Important variables affecting the cost-effectiveness of interferon-alpha treatment included the cost and efficacy of interferon-alpha, the cost of treatment for decompensated cirrhosis, and quality of life in patients with chronic hepatitis C., Conclusion: From the standpoint of cost-effectiveness, interferon-alpha therapy for 6 or 12 months may be justified in patients with chronic hepatitis C. The possible exception is patients older than 60 years of age.

Background: Recurrence of hepatitis C virus (HCV) infection after liver transplantation is universal, but the relationship between hepatitis C genotype and posttransplant outcome has been controversial. The aim of this study was to assess the relationship between hepatitis C genotype on posttransplant frequency of recurrent hepatitis, histologic severity of recurrence, and progression to cirrhosis., Methods: We studied 42 HCV RNA positive patients who received transplants between 1985 and 1994. Sera were tested for HCV RNA and protocol liver biopsies were in obtained the posttransplant period. Biopsies were scored according to the histologic activity index (HAI) and staged in a blinded fashion., Results: The distribution of hepatitis C genotypes distribution was as follows: 1a, 19 (45%); 1b, 17 (40%); 2b, 3 (7%); and 1 each of 2a, 3a, and 4a. There was histologic evidence of hepatitis in 38 of 42 (90.4%) of patients. Hepatitis C was mild, moderate, or severe (HAI>3) in 38% of grafts and minimal (HAI 0-3) in 62%. Overall HAI scores and histologic stage were higher in the genotype 1b group. Six of 17 (35%) genotype 1b patients had cirrhosis compared with 2 of 25 (8%) in the non-1b genotype group., Conclusions: (1) Histologic evidence of recurrent hepatitis C is seen in 90% of liver allografts; (2) Histologic hepatitis C recurs with similar frequency in genotype 1b and non-1b recipients; (3) Genotype 1b is associated with more severe histologic disease recurrence than non-1b genotypes; (4) Genotype 1b appears to be associated with a higher degree of posttransplant fibrosis and cirrhosis than non-1b genotypes.

Unlabelled: Infection with hepatitis C virus (HCV) genotype 1b has been reported to be associated with more severe liver disease and an unfavorable outcome. Liver transplantation allows for a complete examination of the explanted liver for the detection of hepatocellular carcinoma (HCC)., Objective: To study the prevalence of HCC in patients with liver cirrhosis secondary to chronic infection with HCV genotype 1b compared with those infected with other genotypes., Methods: Sera were collected from 48 consecutive patients undergoing liver transplantation for end stage liver disease secondary to HCV infection. RNA was extracted from serum using chaotropic lysis and isopropanol precipitation. Reverse transcriptase-polymerase chain reaction of the NS5 region was performed, followed by automated sequencing on desalted amplification products. Genotype assignment followed Simmonds's classification. All explanted livers were examined for the presence of HCC., Results: HCV genotypes in our patients were as follows: subtype 1a, 20 patients (42%); 1b, 18 patients (37.5%); 2a, one patient (2%); 2b, six patients (12.5%); 3a, one patient (2%); and 4a, two patients (4%). Although five of 18 patients infected with HCV genotype 1b (28%) had HCC, only one of 30 patients (3%) infected with all other genotypes (1a, 2a, 2b, 3a, and 4a) had HCC (p = 0.02)., Conclusion: Infection with HCV genotype 1b may carry a higher risk for the development of HCC than infection with other HCV genotypes.

Background/aims: There is limited information on treatment options for massive, highly symptomatic polycystic liver disease. The aim of the study was to analyze the immediate and long-term outcome of combined liver resection and fenestration., Methods: Information was abstracted from medical records. Follow-up was obtained by mailed questionnaire. Liver volume was quantified by computed tomography., Results: Thirty-one patients underwent liver resection and fenestration between July 1985 and June 1993. Mean liver volume was 9357 mL before and 3567 mL after surgery. There was one death from postoperative intracerebral bleed. Eighteen patients experienced complications, usually transient pleural effusions or transient ascites. Twenty-eight of 29 surviving patients with adequate follow-up have experienced immediate and sustained relief of symptoms and improvement in quality of life. After median follow-up of 2.4 years (range, 0.2 to 7.9 years), most patients have not had clinically significant enlargement of the liver. Sequential computed tomography scans before and after surgery suggest that hepatic enlargement in the age range of the patients in the study mainly resulted from the expansion of existing cysts rather than from the development of new cysts., Conclusions: Selected patients with severe symptomatic polycystic liver disease and favorable anatomy benefit from liver resection and fenestration with acceptable morbidity and mortality. The extent of hepatic resection and fenestration is important for the long-term effectiveness of this procedure.

To discuss the clinical presentation, diagnosis, and treatment of hepatic venous outflow obstruction as a complication of polycystic liver disease, four cases diagnosed and treated at our institution have been reviewed and the information from six previously published case reports has been summarized. Eight of the 10 patients were women. All presented with severe ascites. Nine had polycystic kidneys. Three had moderate-to-advanced renal insufficiency, four were on hemodialysis, and one had a renal allograft. Possible predisposing factors were identified in seven patients; the most common was recent abdominal surgery, which, in three cases, was a bilateral nephrectomy. All patients had extrinsic compression of the hepatic veins and the inferior vena cava by hepatic cysts, and four had proven superimposed thrombosis of the inferior vena cava and/or hepatic veins. In the patients seen in this institution, magnetic resonance imaging was helpful in determining the level of obstruction in the inferior vena cava and the patency of the hepatic and portal veins. The outcome was worse in the patients with thrombosis; one recovered after a portocaval shunt, and the remaining three patients died. On the other hand, five of the six patients without thrombosis recovered after alcohol sclerosis of a large dominant cyst (one patient) or after hepatic resection and cyst fenestration (four patients). Hepatic venous outflow obstruction probably has been underrecognized as a cause of portal hypertension, ascites, and liver dysfunction in polycystic liver disease. The diagnosis can be reliably established with current imaging techniques, especially magnetic resonance imaging.(ABSTRACT TRUNCATED AT 250 WORDS)

The prevalence of spontaneous bacterial peritonitis (SBP) or its variants, bacterascites (BA), and culture-negative neutrocytic ascites (CNNA), may vary depending on the underlying liver disease and protein content of ascites. In this study, we compared the frequency of peritonitis (SBP, BA, CNNA) upon admission in alcoholic (ALD), cholestatic (CLD), and hepatocellular liver disease (HLD); determined the relationship between Child's class and prevalence of peritonitis; and assessed ascitic total protein as a risk factor for peritonitis. Between January 1989 and April 1991, 113 consecutive patients were admitted with chronic liver disease and ascites (49, ALD; 22, CLD; and 42, HLD). All had admission paracentesis. SBP was defined as polymorphonuclear cell count (PMN) > or = 250 mm3 with a positive culture, BA as PMN < 250/mm3 and positive culture, and CNNA as PMN > or = 250/mm3 with negative culture. No patients with obvious intraabdominal source for infection (i.e., secondary peritonitis) were included in the analysis. The prevalence of peritonitis was 8/113 (7%); four patients had SBP, one BA, and three CNNA. The occurrence of peritonitis was independent of the type of liver disease (ALD, 8%; CLD, 9%; HDL, 5%). Neither ascitic fluid total protein nor the severity of liver disease (Child's class) predicted the occurrence of peritonitis. We conclude that the occurrence of peritonitis is unrelated to the type of liver disease, and severity of liver disease did not predict the presence of peritonitis. Also, ascitic fluid total protein < 1.0 g/dl may not be a sensitive predictor of risk of peritonitis.

We report high-volume postobstructive choleresis in two patients who underwent transhepatic external drainage for malignant biliary obstruction. Excessive loss of bicarbonate-rich biliary fluid (up to 6.5 L/day) caused orthostatic hypotension, prerenal insufficiency, hyponatremia, and a decrease in serum bicarbonate. Therapy with isotonic fluids containing sodium, chloride, lactate, bicarbonate, and potassium was based on measurement of biliary fluid volume and electrolyte concentrations. Biliary fluid loss was terminated by conversion to internal biliary drainage. The reason for this rare complication of external drainage of biliary obstruction is unknown, but such patients must be closely monitored for volume loss. When high-volume choleresis occurs, biliary fluid and electrolyte losses should be precisely measured and replaced, and external biliary drainage converted to internal drainage.

Increased intracranial pressure is present in more than 80% of patients with fulminant hepatic failure. However, patients with encephalopathy secondary to chronic liver disease are thought not to develop elevated intracranial pressure. We report two patients with chronic liver disease in hepatic coma with raised intracranial pressure documented by an epidural intracranial pressure monitor. One patient rapidly deteriorated to coma over a period of 4 h. The other patient progressively worsened following intravenous sedation administered during upper endoscopy. Both patients had generalized tonic-clonic seizures, and one demonstrated decerebrate posturing and papilledema. Although all metabolic and structural abnormalities should be excluded in patients with hepatic encephalopathy, if the etiology remains in question, the possibility of increased intracranial pressure should be considered in patients with chronic liver disease.

The unexpected diagnosis of herpetic esophagitis in a patient with nausea led us to review our experience with this disease. Review of our records from 1979 to 1989 produced 23 cases proven by endoscopic culture or microscopic examination (Cowdry-type A inclusions), the largest such series reported to date. Twenty-two of the 23 patients were immunocompromised. Odynophagia and chest pain were each present in half of the cases, but 26% of patients had neither. Gastrointestinal bleeding was attributable to herpetic esophagitis in 30%. Thirty percent of patients had disseminated herpes simplex infection and 70% had simultaneous infections with other organisms. Endoscopic findings included nonspecific inflammation, discrete ulcers, coalescent ulcers, and pseudomembranous esophagitis. Herpes virus was not suspected endoscopically as the cause of esophagitis in 30% of cases. Culture was slightly more sensitive than microscopic examination for diagnosis (89% vs. 76%), but both methods should be employed in any immunocompromised patient with esophagitis.

To characterize the syndrome of hepatic cyst infection in autosomal dominant polycystic kidney disease (ADPKD) and to review its diagnosis and management, we retrospectively studied five such cases in patients from our institution and nine detailed case reports from the literature. The clinical manifestations were an acute (58%) or subacute (42%) febrile illness, typically associated with tenderness in the right upper quadrant, leukocytosis, a very high erythrocyte sedimentation rate, but minor abnormalities of liver function tests. Bacteremia was present in 7 of 11 patients. Enterobacteriaceae grew in pure culture from the cyst fluid in 9 of 12 patients. Complex cysts were observed by ultrasonography (in four of eight patients), computed tomography (in six of nine), and magnetic resonance imaging (in two of two). 111In leukocyte scans were positive in all four patients in whom they were done, and 67Ga scans were positive in only one of three patients. An unfavorable outcome was observed in six of seven patients treated with only antibiotics, in contrast with one of seven patients who received antibiotics and early drainage. In two patients, ciprofloxacin cyst levels were 2.3 and 4.8 times higher than the level in serum; in a third patient, cyst levels remained in therapeutic range 30 hours after the last dose of ciprofloxacin, at which time serum levels were undetectable. Clinical and laboratory features and the use of modern scanning techniques facilitate a prompt diagnosis of infection in hepatic cysts in ADPKD. The treatment of choice is a combination of percutaneous drainage and antimicrobial therapy.

A biopsy study of 60 allografts from 53 patients after orthotopic liver transplantation (OLT) revealed prominent centrilobular necrosis (CN) in 18% of the grafts that were suitable for analysis. The lesions often had a "punched-out" appearance, sometimes with unusual features such as giant cell formation. Persistent CN developed 4 weeks to 6 months after OLT, and persisted in two cases for 2 years and longer. In some instances, CN disappeared or healed by scarring. We found no association between CN and rejection arteritis or arteriopathy. Ductopenic (chronic) rejection subsequently occurred in six of eight livers with CN. Overall, patients with persistent CN had a worse prognosis than control patients. A comparison of cases with matched controls failed to reveal significant differences with respect to perioperative factors such as ischemia time, immunologic test results such as lymphocyte crossmatches, drug administration--in particular, of azathioprine, frequency of cellular (acute) rejection or infection episodes, or frequency of complications affecting major hepatic vessels or bile ducts. Morphologic evidence suggests that in some instances, rejection-induced endotheliitis/phlebitis of hepatic vein branches may lead to sinusoidal outflow blockage, sinusoidal dilatation, and dropout of hepatic cell plates. Although potentially reversible conditions such as ischemia or adverse drug reactions are among the possible causes of CN, severe rejection leading to ductopenia appears to be the most important underlying condition. Thus, presence of CN in repeated biopsy specimens from allografts should be considered a warning sign of irreversible rejection.

We investigated the hypothesis that lysosomes are the main source of biliary copper in conditions of hepatic copper overload. We used a rat model of oral copper loading and studied the relationship between the biliary output of copper and lysosomal hydrolases. Male Sprague-Dawley rats were given tap water with or without 0.125% copper acetate for up to 36 wk. Copper loading produced a 23-fold increase in the hepatic copper concentration and a 30-65% increase in hepatic lysosomal enzyme activity. Acid phosphatase histochemistry showed that copper-loaded livers contained an increased number of hepatocyte lysosomes; increased copper concentration of these organelles was confirmed directly by both x ray microanalysis and tissue fractionation. The copper-loaded rats showed a 16-fold increase in biliary copper output and a 50-300% increase in biliary lysosomal enzyme output. In the basal state, excretory profiles over time were similar for biliary outputs of lysosomal enzymes and copper in the copper-loaded animals but not in controls. After pharmacologic stimulation of lysosomal exocytosis, biliary outputs of copper and lysosomal hydrolases in the copper-loaded animals remained coupled: injection of colchicine or vinblastine produced an acute rise in the biliary output of both lysosomal enzymes and copper to 150-250% of baseline rates. After these same drugs, control animals showed only the expected increase in lysosomal enzyme output without a corresponding increase in copper output. We conclude that the hepatocyte responds to an increased copper load by sequestering excess copper in an increased number of lysosomes that then empty their contents directly into bile. The results provide direct evidence that exocytosis of lysosomal contents into biliary canaliculi is the major mechanism for biliary copper excretion in hepatic copper overload.

Primary sclerosing cholangitis is a chronic, cholestatic syndrome characterized by fibrosing inflammation of the bile ducts that may lead to cirrhosis and death from liver failure. Previous reports have suggested abnormal hepatic copper metabolism in this disease. Therefore, in 70 patients, we prospectively determined the levels of hepatic copper, serum copper, and serum ceruloplasmin, and the rate of urinary copper excretion to assess the diagnostic and prognostic usefulness of these tests. Virtually all patients had at least one abnormal copper test. Hepatic copper levels were elevated in 87% of patients [292 +/- 38 micrograms/g dry wt (mean +/- SE)] and 24-h urinary copper levels in 64% of patients [135 +/- 15 micrograms/24 h (mean +/- SE)] to values comparable to those seen in Wilson's disease or primary biliary cirrhosis. In advanced histologic stages of primary sclerosing cholangitis, progressively higher mean levels of hepatic and urinary copper were found. In the liver, mean copper content (in micrograms per gram dry weight) in disease stages I and II was 147 +/- 36 (mean +/- SE); in stage III (fibrosis), 302 +/- 68; and in stage IV (cirrhosis), 379 +/- 69. In the urine, mean copper excretion (in micrograms per 24 h) in stages I and II was 72 +/- 14 (mean +/- SE); in stage III, 100 +/- 14; and in stage IV, 207 +/- 30. Higher hepatic and urinary copper levels at initial evaluation were associated with decreased survival during a median follow-up period of 2.6 yr: patients with hepatic copper greater than 250 micrograms/g dry wt and urinary copper excretion greater than 200 micrograms/24 h at initial evaluation had an 18-mo survival of less than 60%. We conclude that abnormal copper metabolism is a universal feature of primary sclerosing cholangitis, that hepatic copper accumulates and urinary copper excretion increases as the disease progresses, and that the hepatic copper concentration and the 24-h urinary copper determination are useful prognostic indicators in this disease.

An elevated CAm/CCr ratio has been used as evidence for the frequent occurrence of acute pancreatitis in the postoperative period. We measured CAm/CCr pre and postoperatively in 28 patients undergoing extraperitoneal surgical procedures. None of the patients had clinical evidence of pancreatitis, although 2 of the 28 patients had elevated CAm/CCr ratios preoperatively. Mean CAm/CCr rose from a preoperative level of 2.3 +/- 0.3% (1 SE) to 3.2 +/- 0.3% on the first postoperative day (P less than 0.001). Of the 26 patients with normal preoperative CAm/CCr, 12% (3 of 26) developed a clearly abnormal ratio and 12% (3 of 26) developed borderline elevated values. An elevated CAm/CCr appears to be a nonspecific postoperative finding and cannot be used as evidence of acute pancreatitis during this period.

The aim of this study was to determine the prognostic significance of functional changes in the liver during progression of cirrhosis. Liver function was quantitated weekly by the aminopyrine breath test (measuring microsomal function) and the galactose breath test (measuring cytosolic function) in rats made cirrhotic by bile duct ligation (n = 14) and in sham-surgery controls (n = 9). Nine rats died spontaneously of cirrhosis. Both the aminopyrine breath test and galactose breath test were sensitive (89%) predictors of death within 1 week, but the galactose breath test was more specific (83%). Morphometric measurements of livers from surviving cirrhotic animals and controls (n = 5 each) showed that mean hepatocyte mass was maintained in the cirrhotic livers [cirrhosis (17.0 +/- 2.0) vs. controls (13.9 +/- 0.9 gm)]. The galactose breath test was also maintained, whereas the aminopyrine breath test was significantly decreased in the surviving cirrhotics. The galactose breath test, but not the aminopyrine breath test, correlated with hepatocyte mass (r = 0.67). The aminopyrine breath test correlated with microsomal aminopyrine N-demethylase activity (r = 0.78). Serial use of quantitative liver tests allows prediction of time of death from cirrhosis in this model.

From 1985 through 1987, we diagnosed acute hepatic failure in 13 patients. Spontaneous recovery occurred in three of these patients. Eight patients underwent liver transplantation, five of whom survived and three of whom died. In addition, two patients died before undergoing transplantation. The survival rate of 62% was better than that among our previous series of similar patients. This improvement seems to be related to the use of orthotopic liver transplantation as a therapeutic alternative among these patients. One of the three patients who died after liver transplantation had normal liver function, but respiratory failure caused by Pneumocystis carinii developed 4 months after the transplantation. The surgical procedure was less difficult in patients with acute fulminant hepatitis than in those with chronic liver disease because fewer problems arose from adhesions, venous collaterals, and ascites. The emerging role of orthotopic liver transplantation in patients with acute hepatic failure is demonstrated by the improvement of survival rates observed by various groups, including ours, when this therapeutic modality is available.