Hepatic cystadenoma: an unusual presentation.

A 53-yr-old woman with a history of hepatic cystadenoma 25 yr before presented with a simple hepatic cyst, which evolved over 9 yr into a complex cystadenoma with septations and internal bleeding. She was treated with a left hepatectomy. Review of the literature shows that hepatic cystadenomas, although rare, frequently can recur years later and have potential for malignant transformation. Histologic similarities of one variant with ovarian stroma raises interesting possibilities regarding the origin of these lesions. The best treatment results are obtained with radical excision.

Response to higher doses of interferon alfa-2b in patients with chronic hepatitis C: a randomized multicenter trial. Hepatitis Interventional Therapy Group.

To evaluate response rates to 3, 5, or 10 million units (MU) of interferon alfa-2b, given thrice weekly, and to determine whether higher doses of interferon increase the likelihood or durability of the response, a multicenter, randomized trial was performed at nine academic medical centers in the United States. Two hundred forty eight patients with chronic hepatitis C were randomized to receive 3, 5, or 10 MU of interferon alfa-2b thrice weekly for 12 weeks. Based on the alanine aminotransferase (ALT) response at treatment-week 12, the patients were rerandomized to additional therapy at the same or at increased doses for an additional 12 to 36 weeks; in the case of no response to the highest dose, the patients were discontinued from the study. Serum ALT concentrations and liver histology were measured. The overall complete response rates to 3, 5, or 10 MU were not different at treatment-week 12 (31% vs. 42% vs. 40%, not significant). The majority of week-12 responders continued to respond during additional treatment. When the treatment was discontinued, 15.4% to 19.0% of patients maintained their response. Of the nonresponders to 3 MU at week 12, who were continued on 3 MU for an additional 12 weeks, none responded. However, response to additional therapy occurred in 12% of week-12 nonresponders, whose dose was escalated from 3 or 5 MU to 10 MU. The only baseline features associated with the treatment response were the absence of fibrosis or cirrhosis on the pretreatment liver biopsy and viral genotype. We conclude that the initial response to interferon in patients with chronic hepatitis C is not increased by treatment with higher doses of the drug. Patients who do not respond to 3 MU by treatment-week 12 will not respond with continued therapy at that dose; however, a proportion of patients who do not respond to 12 weeks of treatment with 3 or 5 MU may respond to higher doses. Although the long-term sustained response rates are marginally increased with interferon doses above 3 MU three times per week, the side effects are difficult to tolerate. The analysis of baseline factors in relation to response identified no single baseline factor associated with a low-enough response rate to warrant withholding interferon therapy from patients with chronic hepatitis C.

Hepatic expression of hepatitis C virus RNA in chronic hepatitis C: a study by in situ reverse-transcription polymerase chain reaction.

Hepatitis C virus (HCV) replicates at a low rate and this makes its detection and intrahepatic localization difficult. To evaluate the clinical implications and effect of interferon alfa (IFN-alpha) therapy on hepatic expression of HCV RNA, HCV RNA was detected by in situ reverse-transcription polymerase chain reaction (IS-RT-PCR) in formalin-fixed paraffin-embedded liver sections from 26 patients with chronic hepatitis C. Results were compared with RT-PCR of HCV RNA extracted from liver sections/tissue. Twenty-four paired post-IFN-alpha treatment biopsy specimens were also assessed. Using RT-PCR of the extracted RNA as a positive standard and non-HCV liver sections as the negative standard, the sensitivity and specificity of IS-RT-PCR were 69% and 100%, respectively. HCV RNA was detected in the cytoplasm of hepatocytes (median, 5% hepatocytes positive; range, 0 to 35%) and very occasionally in infiltrating mononuclear cells. There was no correlation between hepatic expression of HCV RNA and the clinical, biochemical parameters, total and activity scores of histology activity index. Presence of HCV RNA in liver as detected by IS-RT-PCR was associated with higher serum HCV RNA levels (4.9 x 10(6) vs. 0.4 x 10(6) genome Eq/mL, P < .01). There was no difference in the pretreatment proportion of HCV RNA-positive hepatocytes among patients with different biochemical responses to IFN-alpha therapy. In the posttreatment samples, HCV RNA was undetectable by IS-RT-PCR in 16 of 24 patients (P < .01), including all 4 patients who had complete and sustained response (SR). We conclude that HCV RNA was detected by IS-RT-PCR in 0 to 35% of hepatocytes in patients with chronic HCV infection, detection of HCV RNA in liver by IS-RT-PCR was associated with higher viremia levels and IFN-alpha therapy reduced hepatocytic expression of HCV RNA.

Assessing health-related quality of life in chronic hepatitis C using the Sickness Impact Profile.

In a randomized, controlled trial that demonstrated the efficacy of interferon alfa-2b 3 million units three times a week for 24 weeks in controlling chronic hepatitic C (non-A, non-B), the Sickness Impact Profile (SIP) was used to evaluate the impact of disease and treatment on health-related quality of life (HRQOL). The SIP was self-administered by 160 patients before treatment, at the end of treatment, and at the study endpoint. Before treatment, patients with chronic hepatitis C scored significantly (P < 0.05) higher (worse) than an historical control group of the general population in mean total SIP score and in all categories except eating. The highest degree of impairment was observed in the work, sleep and rest, and recreation and pastimes categories. After treatment, patients who received interferon alfa-2b had significant (P < or = 0.05) improvement in work, sleep and rest, and recreation and pastimes scores. Numerical improvement was observed in total score, physical and psychosocial dimension scores, and most individual category scores. Mean SIP scores were unchanged or slightly worsened in untreated control patients. In responders (patients with improvement in serum alanine aminotransferase levels), the largest improvement was seen in work scores. The SIP appears to be a reliable and valid instrument for describing the impact of chronic hepatitis C on HRQOL but lacks disease-specificity and the ability to reflect clinically relevant changes. Thus the SIP is not the best instrument to evaluate the HRQOL effects of treatment with interferon alfa-2b in patients with chronic hepatitis C.

Clinical predictors of response to recombinant interferon-alpha treatment in patients with chronic non-A, non-B hepatitis (hepatitis C). The Hepatitis Interventional Therapy Group.

Chronic non-A, non-B hepatitis (NANBH) is a common and often progressive liver disease. Based on current serological tests, hepatitis C virus (HCV) infection is responsible for most cases. Interferon-alpha (IFN) treatment at a dose of 3 x 10(6) units given three times per week for 24 weeks has been shown to be effective in normalizing serum alanine aminotransferase (ALT) levels and reducing hepatic inflammation in approximately 40% of these patients. The purpose of this study was to identify pretreatment characteristics in patients with chronic hepatitis C(CH-C) which would best predict a favourable response to IFN treatment (normalization of serum ALT). One hundred and sixty-three adult patients who had participated in a large multicentre treatment trial were included in the study group; 84 had been treated with 3 x 10(6) units of recombinant IFN-alpha-2b (rIFN) subcutaneously three times per week for 24 weeks and 79 patients had been treated with 1 x 10(6) units rIFN in the same dosage schedule. Forty-one pretreatment historical, clinical, laboratory and histological variables were evaluated. In addition, early biochemical improvement during treatment was evaluated as a predictor of ultimate response. Univariate analysis identified six variables (dose, dose m-2, weight, body surface area, ongoing ethanol use, white blood cell count and the presence of symptoms) as potential predictors of response (two-tailed, P < 0.15). By multivariate analysis, however, only the 3 x 10(6) dose of rIFN was independently predictive of response (P < 0.01). When the analysis of response was confined to those patients who received treatment with 3 x 10(6) units of rIFN, seven variables [body weight, surface area, dose m-2, current ethanol use, serum albumin and the presence of chronic persistent hepatitis (CPH) on entry liver biopsy] were more frequent in patients who responded to therapy. In a multivariate model, only CPH and body weight predicted an increased likelihood of response (P < 0.01). However, the model was not a sensitive predictor of response as only 18% of the study group had CPH on liver biopsy. A decrease in serum ALT levels within the first 12-16 weeks of rIFN treatment was found to be the strongest indicator of an ultimate response to treatment. Thus, assessment of early response to IFN treatment is the only practical means of predicting complete response and avoiding prolonged and unnecessary therapy in those with little chance of response.

Hepatitis C RNA in liver of chronic hepatitis C patients before and after interferon alfa treatment.

BACKGROUND: Successful treatment of chronic hepatitis C with interferon alfa is frequently followed by relapse. Because loss of hepatitis C viral RNA (HCV-RNA) in serum is not predictive of sustained response, the loss of HCV-RNA in liver as a predictor of sustained response was investigated. METHODS: Twenty-one patients with chronic hepatitis C treated with recombinant interferon alpha had HCV-RNA sequences determined in frozen liver tissue before and after treatment and in serum at the end of treatment. Reverse double polymerase chain reaction was used to detect sequences to the 5' nontranslated region of the HCV genome using double nested primers. RESULTS: HCV-RNA disappeared in the liver in 10 of 11 (91%) complete responders whereas it remained detectable in the liver or serum of 7 of 8 (87%) nonresponders. Five complete responders relapsed biochemically during 6 month's follow-up; 4 of these had no detectable HCV-RNA in liver at end of treatment. CONCLUSIONS: Disappearance of HCV-RNA in liver correlates with initial clinical outcome, but as previously reported with serum HCV-RNA, this loss does not necessarily allow prediction of a sustained response.

Pathological diagnosis of chronic hepatitis C: a multicenter comparative study with chronic hepatitis B. The Hepatitis Interventional Therapy Group.

BACKGROUND: Hepatic histological responses described in hepatitis C virus (HCV) infection include bile duct damage, lymphoid follicles and/or aggregates in portal tracts, large- and small-droplet fat, Mallory body-like material in hepatocytes, liver cell dysplasia and multinucleation, and activation of sinusoidal inflammatory cells. The specificity of these lesions for HCV infection is uncertain. METHODS: In two multicenter trials of recombinant interferon alfa therapy for chronic hepatitis C and B, the frequency of these eight lesions in pretherapy and posttherapy liver biopsy specimens was examined to determine the set of features, if any, that distinguishes HCV from hepatitis B virus (HBV) infection. The lesions were scored in 317 HCV biopsy specimens and 299 HBV specimens. RESULTS: Stepwise logistic regression determined a set of three features more likely to be seen in HCV than in HBV infection: bile duct damage [odds ratio (OR), 4.7; 95% confidence interval (Cl), 1.8-12.3], lymphoid follicles and/or aggregates (OR, 2.4; 95% Cl, 1.2-4.7), and large-droplet fat (OR, 2.4; 95% Cl, 1.4-4.1). A fourth lesion, Mallory body-like material, was seen only in HCV biopsy specimens (OR, 71.6; 95% Cl, 4.4-996.1). CONCLUSIONS: These four histological lesions are useful pathological parameters in the diagnosis of liver disease caused by HCV.

Detection of hepatitis C virus sequences in liver tissue by the polymerase chain reaction.

Although sensitive assays for serum antibodies to hepatitis C virus (HCV/anti-HCV) have been developed recently, the relation of anti-HCV to HCV infection of the liver has not been clarified. Therefore, we determined the presence of HCV RNA by the reverse transcription-polymerase chain reaction (PCR) in liver biopsy specimens of 21 patients with chronic liver disease and 5 control patients. RNA was extracted from frozen liver tissues by the guanidinium method, HCV cDNA was synthesized by reverse transcription, and core region and NS3 region sequences were amplified by PCR. The sensitivity and specificity of the reaction was significantly enhanced by double PCR with nested primers followed by Southern blotting with an HCV specific oligomer probe. NS3 region sequences were detected in the liver specimens of 12 out of 15 anti-HCV positive patients. Core region sequences were detected in 9 patients, all of whom were also positive for NS3 region sequences. HCV sequences were not detected in 11 anti-HCV negative patients. In all cases, the integrity of the extracted RNA was demonstrated by successful amplification of albumin mRNA as internal control. Our findings demonstrate the feasibility of the reverse transcription-double PCR method followed by Southern blotting for the detection of HCV sequences in liver tissues. In this system, the detection rate of NS3 region sequences is higher than that of core region sequences. There is a statistically significant correlation between high titer anti-HCV antibodies in serum and NS3 region sequences in liver tissue. However, not all anti-HCV positive patients had HCV positive hepatitis. The reverse transcription-polymerase chain reaction for HCV sequences on liver tissue extracts may reveal valuable information on the diagnosis of HCV infection and the pathogenesis of chronic hepatitis C.

Treatment of chronic hepatitis C with recombinant alpha-interferon. A multicentre randomized, controlled trial. The Hepatitis Interventional Therapy Group.

To assess the efficacy of therapy with the antiviral agent interferon in chronic hepatitis C (non-A, non-B hepatitis), we randomly assigned 166 chronic hepatitis C patients to treatment with either 3 million or 1 million units of recombinant interferon alfa-2b three times weekly for 24 weeks, or to no treatment. The probability of normalization or near normalization of the serum alanine aminotransferase levels after 6 months of interferon therapy was 46% in patients treated with 3 million units of interferon (p less than 0.001) and 28% in those treated with 1 million units (p less than 0.02), but only 8% in untreated patients. Serum alanine aminotransferase levels became completely normal in 22 of the 26 patients (85%) who responded to treatment with 3 million units of interferon and 9 of the 16 patients (56%) who responded to treatment with 1 million units. The patients who received 3 million units of interferon had histological improvement because of the regression of lobular and periportal inflammation. Relapse within 6 months after the completion of treatment occurred in 51% of the patients treated with 3 million units of interferon and 44% of those treated with 1 million units. We conclude that a 24-week course of interferon therapy is effective in controlling disease activity in many patients with hepatitis C, although relapse after the cessation of treatment is common.

Treatment of chronic hepatitis C with recombinant interferon alfa. A multicenter randomized, controlled trial.

Chronic hepatitis C (non-A, non-B hepatitis) is a common and often progressive viral liver disease. To assess the efficacy of therapy with the antiviral agent interferon alfa, we randomly assigned 166 patients with chronic hepatitis C to treatment with either 3 million or 1 million units of recombinant interferon alfa three times weekly for 24 weeks, or to no treatment. The probability of normalization or near normalization of the serum alanine aminotransferase levels after six months of interferon therapy was 46 percent in patients treated with 3 million units of interferon (P less than 0.001) and 28 percent in those treated with 1 million units (P less than 0.02), but only 8 percent in untreated patients. The serum alanine aminotransferase level became completely normal in 22 of the 26 patients (85 percent) who responded to treatment with 3 million units of interferon and 9 of the 16 patients (56 percent) who responded to treatment with 1 million units. The patients who received 3 million units of interferon had histologic improvement because of the regression of lobular and periportal inflammation. Relapse within six months after the completion of treatment occurred in 51 percent of the patients treated with 3 million units of interferon and 44 percent of those treated with 1 million units. We conclude that a 24-week course of interferon therapy is effective in controlling disease activity in many patients with hepatitis C, although relapse after the cessation of treatment is common.

A prospective, randomized controlled trial of chronic esophageal variceal sclerotherapy.

The results of a prospective, randomized controlled trial of chronic esophageal variceal sclerotherapy conducted over a 38-month period are presented. One-hundred twenty patients were randomized following variceal bleeding, 63 to esophageal variceal sclerotherapy and 57 to control. Mean follow-up was similar in both groups (esophageal variceal sclerotherapy, 12.5 +/- 8.8 months; control, 14.9 +/- 6.6 months). Twenty-one percent of the patients in each group were lost to follow-up. Esophageal variceal sclerotherapy decreased rebleeding as evidenced by a decrease in the mean bleeding risk factor, transfusion requirement and by an increase in bleeding free interval; differences between the treated and control groups in these parameters were especially significant after variceal obliteration. A high incidence of asymptomatic ulceration and low frequency of strictures were notable effects of esophageal variceal sclerotherapy. Cumulative life table analysis revealed no differences in survival between esophageal variceal sclerotherapy and control groups. However, when patients who received portal-systemic shunt surgery (esophageal variceal sclerotherapy, 6%; control, 28%) were removed from the analysis at the time the shunt surgery was performed (defining the shunt as an endpoint, a significant difference in survival (p less than 0.05, F ratios) in favor of esophageal variceal sclerotherapy was observed.

Endoscopy in gastrointestinal disease. Procedures that offer an alternative to surgery.

Today, endoscopic procedures are available to treat many diseases of the gastrointestinal tract that just a few years ago would have required surgery. These procedures have proved to be safe and effective and are well accepted by patients. When considering such a procedure, the primary care physician needs to be aware of its advantages and limitations and the nearest center where it can be obtained. Many new endoscopic surgical procedures are undergoing evaluation, and undoubtedly some will soon be incorporated into the armamentarium of the gastroenterologist. Until more data on their efficacy and safety are available, however, these procedures should remain within the realm of the clinical investigator.

Chest pain and dysphagia in patients with prolonged peristaltic contractile duration of the esophagus.

Dysphagia and chest pain are well-described symptoms in subjects with achalasia, diffuse esophageal spasm (DES), and high-amplitude peristaltic contractions, a subset of nonspecific motor disorders (NEMD). We observed a high incidence of chest pain and dysphagia in a different NEMD subgroup characterized by prolonged peristaltic contractile duration (PPCD) and normal contractile amplitude. We compared the manometric characteristics of patients with PPCD to healthy controls and compared the clinical profile of PPCD patients to that of patients with achalasia, DES, and high-amplitude peristalsis. In 20 patients with PPCD, mean contractile duration was 7.4 +/- 0.3 sec, significantly greater than healthy controls (3.7 +/- 0.1 sec) (P less than 0.001). PPCD was associated with an 85% incidence of chest pain and 65% incidence of dysphagia. These symptoms were similar to those observed in patients with achalasia, DES, and high-amplitude peristalsis. In PPCD patients, chest pain was more frequently of long duration in comparison to achalasia and DES. PPCD was encountered more frequently than either achalasia or DES in patients referred to our laboratory. This study suggests that in symptomatic NEMD patients, abnormal duration of peristaltic contractions, rather than abnormal amplitude, may be a distinguishing manometric feature.

Chest pain, dysphagia, and high amplitude esophageal peristalsis: a clinical and manometric study.

Recent literature has called attention to an esophageal motor abnormality characterized by high amplitude peristaltic contractions (HAPC). We characterized symptoms, manometric characteristics, and radiographic findings of 19 such patients and compared them to patients with other nonspecific esophageal motor disorders (NEMD). In the HAPC group, mean amplitude was 254 +/- 14 mm Hg, which was significantly higher than that of control subjects (94 +/- 8.9 mm Hg) and of those with other NEMD (116 +/- 10.8 mm Hg). Contractile duration of the HAPC and NEMD groups was 6.9 +/- 0.5 sec and 5.9 +/- 0.4 sec, respectively, both being significantly higher than normal. Results of esophagograms were frequently abnormal in both groups, but there was no specific abnormality separating the two groups. There was a high incidence of chest pain and dysphagia in the HAPC group. These data suggest that HAPC may represent a distinct subgroup of primary esophageal motor disorders.

Granular cell schwannoma of the extrahepatic biliary system.

We report the case of a woman who presented with a typical picture of cholelithiasis and choledocholithiasis. A percutaneous transhepatic cholangiogram revealed instead a concentric narrowing of the common bile duct and at operation she was found to have a rare, benign tumor of the extrahepatic biliary tree, a granular cell schwannoma.

Gastric xanthoma: histologic similarity to signet ring cell carcinoma.

Gastric xanthomas (GX) are pale yellow nodules or plaques, usually less than 3 mm in size, in the gastric mucosa. They are frequently found in groups, most often along the lesser curvature and pyloric regions. They consist of liquid-laden histiocytes in the lamina propria occasionally extending into the submucosa. There is no correlation between GX and hypercholesterolemia. The lesion is of little significance, except as it may be misdiagnosed as carcinoma. We present two cases of GX, one initially thought histologically to be a signet ring cell carcinoma. With the paucity of reports of GX in the medical literature and the potential for incorrect diagnosis, we emphasize the importance of recognition and accurate histologic diagnosis of GX.