Relationship between biochemical and virological responses to interferon therapy in chronic hepatitis C infection. Consensus Interferon Study Group.

We have investigated the relationship between serum alanine aminotransferase (ALT) and hepatitis C virus (HCV) RNA in the assessment of responses to interferon (IFN) therapy in chronic HCV infection. Data from 704 patients with HCV infection who were randomized to receive consensus IFN-alpha (CIFN) 3 micrograms (n = 232 patients) or 9 micrograms (n = 232 patients), or IFN-alpha 2b 3 million units (MU) (n = 240 patients), were used for these analyses. All patients were treated three times weekly. Hepatitis C viral RNA (HCV RNA) was determined by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) with a lower limit of detection of 100 copies ml-1. Of patients with normal serum ALT concentrations, 53% (120/225) had undetectable HCV RNA at the end-of-treatment period and 47% (51/109) had undetectable HCV RNA at the end of the post-treatment observation period. In contrast, of the patients with undetectable HCV RNA, 75% (120/161) and 84% (51/61) had normal serum ALT activities at the end-of-treatment and post-treatment observations periods, respectively. The majority of patients with undetectable HCV RNA had normal ALT values. In contrast, only half of the patients with normal ALT values were negative for HCV. End-of-treatment HCV RNA response also better predicted sustained virological response than did end-of-treatment ALT response.

Pharmacokinetics of ondansetron in patients with hepatic insufficiency.

Ondansetron is primarily eliminated via hepatic metabolism; thus, liver disease may affect its clearance. The pharmacokinetics of ondansetron in patients with different degrees of hepatic insufficiency (N = 12 with hepatic impairment, as categorized by Pugh's classification method) were assessed and the results compared with results for age- and gender-matched control subjects with normal liver function (n = 12). A secondary objective was to correlate the Pugh method of assessing hepatic impairment and quantitative metabolic markers used to assess hepatic function (antipyrine clearance and indocyanine green clearance) with changes in the pharmacokinetics of ondansetron. This was an open-label study in which 8 mg ondansetron was given orally and intravenously, following a randomized crossover design. Clearance of ondansetron was lower among patients with hepatic impairment that control subjects. After a single, oral dose of ondansetron, mean absolute bioavailability increased markedly with increased hepatic insufficiency (approaching 100% in the group with severe hepatic impairment versus 66% for control subjects). These data suggest that there is a reduced first-pass effect in patients with liver disease resulting in a higher AUC0-infinity. A correlation existed between clearance of ondansetron and decreased antipyrine clearance; a smaller correlation existed between ondansetron clearance and indocyanine green clearance. Mean percent of ondansetron bound to plasma proteins was significantly lower in patients with liver disease than in control subjects. None of the patients experienced any severe adverse reactions attributed to ondansetron. A reduction in the clearance of ondansetron is associated with increasing degrees of hepatic insufficiency; therefore, patients with severe hepatic impairment (Pugh score of > 9) should have their daily dose of ondansetron limited to 8 mg (or 0.15 mg/kg).

Comparison of quantitative methods to assess hepatic function: Pugh's classification, indocyanine green, antipyrine, and dextromethorphan.

STUDY OBJECTIVES: To compare three quantitative metabolic markers used to assess hepatic function, indocyanine green (ICG), a high-extraction marker; antipyrine, a low-extraction marker; and dextromethorphan, a P-450IID6 marker, with the clinically used Pugh's classification. DESIGN: Comparison of 12 healthy controls with 12 age- and sex-matched patients with different degrees of liver disease. SETTING: Research center in a university-affiliated teaching hospital. PATIENTS: The 12 patients had different degrees of liver disease: 4 mild (Pugh's score 6 or 7); 4 moderate (Pugh's score 8 or 9); and 4 severe (Pugh's score > or = 10). Each level had an equal number of men and women subjects. MEASUREMENTS AND MAIN RESULTS: Clearance of ICG detected mild alterations in hepatic function as efficiently as it did for moderate and severe impairment, but it lacked the specificity to distinguish among the classification groups. In contrast, antipyrine was effective in identifying moderate and severe hepatic impairment; however, its clearance was not reduced in mild liver disease. Pugh's classification appears to be a clinically useful method of assessing the global degree of hepatic impairment in patients with chronic disease, and there was a significant correlation between it and antipyrine clearance (r = 0.67, p = 0.0003) and ICG clearance (r = 0.86, p = 0.0001). Four of eight patients with a Pugh's score greater than 8 had a dextromethorphan metabolic ratio expression reflective of a poor metabolizer phenotype based on 0- to 4-hour urine collection, but only two of those eight patients were classified as poor metabolizers based on 4- to 12-hour urine collection. These percentages of poor metabolizers are substantially higher than for historical controls (8.5-10.4%) and most likely reflect a decrease in the P-450IID6 functional ability with progression of liver disease. However, due to small sample size and lack of knowledge of the patients' genotypes, these data are only suggestive. CONCLUSION: Pugh's classification appears to be a reliable indicator of the degree of chronic liver disease and could be employed as a drug development research classification tool; however, it does not replace quantitative metabolic markers, especially isozyme-specific markers.

Rocky Mountain spotted fever mimicking acute cholecystitis.

Rocky Mountain spotted fever can present with predominantly abdominal symptoms including nausea, vomiting, diarrhea, and abdominal pain. Two elderly patients presented with an acute febrile illness and abdominal symptoms. Rash was not present initially. Workup disclosed cholelithiasis in one, and a thickened gallbladder wall surrounded by a sonolucent zone suggesting a pericholecystic abscess was found by ultrasonography in the other. Both patients underwent emergency laparotomy, with cholecystectomy in both and appendectomy in one. Both patients died several days postoperatively. Pathologic specimens reviewed later showed that multiple blood vessels of the gallbladder and the appendix were infected with Rickettsia rickettsii, and there was focal vascular thrombosis and hemorrhage. These documented direct rickettsial infections and lesions in the blood vessels of abdominal viscera suggest the basis for the abdominal symptoms in Rocky Mountain spotted fever.

Hepatobiliary disease that precedes ulcerative colitis.

There is a variable temporal relationship between the presenting symptoms of inflammatory bowel disease and associated hepatic disease: hepatobiliary disease may precede, occur with, or occur many years after the onset of the bowel disease. We describe six patients in whom hepatobiliary disease of initially obscure origin preceded the development of inflammatory bowel disease. The colitis which subsequently developed in these patients was symptomatically mild. In our series, there was a high prevalence of sclerosing cholangitis. We conclude that in patients with chronic hepatobiliary disease of obscure origin, evaluation should include detailed questioning about bowel symptoms and routine sigmoidoscopy to screen for subclinical colitis. If a diagnosis of colitis is made in such a patient, endoscopic retrograde cholangiography may be indicated to evaluate the biliary tree for sclerosing cholangitis.

Isolated duodenal varix: an unusual cause of gastrointestinal hemorrhage.

We have reported an unusual case of upper gastrointestinal hemorrhage due to an isolated varix involving the second portion of the duodenum. The varix originated directly from the inferior vena cava and did not communicate with the portal venous system. The diagnosis was made preoperatively by upper gastrointestinal endoscopy. Surgical resection of the varix and the involved portion of the duodenal wall proved curative.

Fatal herpetic hepatitis in pregnancy.

Disseminated herpetic infections are becoming more commonly reported during pregnancy. Such infections almost always occur in the third trimester and are usually associated with a primary infection, which serves as a portal of entry. Because of the high fetal and maternal mortality associated with this condition, early diagnosis and treatment are essential. Disseminated herpesvirus infection must be considered whenever a pregnant patient has herpetic mucocutaneous lesions, vague systemic symptoms, or evidence of massive hepatic dysfunction.

Chronic hepatitis in patients with hemophilia A: histologic studies in patients with intermittently abnormal liver function tests.

Recent studies in multiply transfused patients with hemophilia A and persistent liver function abnormalities have shown a high incidence of chronic active hepatitis. The purpose of the present study was to determine the severity of liver disease in multiply transfused patients with intermittent liver enzyme abnormalities. Fifteen patients with elevated enzymes on two or three out of four determinations at 6-mo intervals were studied. None had signs or symptoms of chronic liver disease. Thirteen had serologic evidence of prior exposure to the hepatitis B virus. Liver biopsy performed on these patients after replacement therapy with factor VIII showed chronic persistent hepatitis or other mild forms of liver disease in 14 of the 15 patients. Patients with chronic persistent hepatitis had significantly higher mean liver enzymes at time of biopsy than patients with milder forms of hepatic inflammation, but there was no relationship between liver histology and hepatitis B serology or the amount of factor VIII used in the 6 mo preceding biopsy. These findings support the continued use of factor VIII concentrates in patients with hemophilia.

Cirrhosis, variceal bleeding, and distal splenorenal shunt in hemophilia A.

Chronic liver disease has become a significant complication of the therapy of hemophilia disorders. We describe two patients with hemophilia A and hepatitis B virus hepatitis who progressed to cirrhosis with bleeding esophageal varices. Each underwent distal splenorenal shunt under plasma concentrate therapy without difficulty. One patient died 19 months after operation and unsuspected hepatocellular carcinoma was found at autopsy. These cases illustrate the potential severity of liver disease in hemophilia and the ability to safely perform surgery for portal hypertension if required.

Medical complications of hemophilia.

The modern, comprehensive care of patients with hemophilia requires an awareness that complications other than those caused by acute hemorrhage can occur. The use of newer, more potent plasma concentrates has been accompanied by an increased incidence of liver disease in transfusion-requiring hemophiliacs. The progression to chronic active hepatitis and cirrhosis are particularly ominous developments in these patients. There is also a high incidence of urinary tract abnormalities in hemophiliacs, though the long-term consequences of these abnormalities are unknown. Furthermore, it must be remembered that urinary tract disorders unrelated to hemorrhage, such as nephrolithiasis, tumors, and nephritis, can occur in patients with hemophilia and may be mistaken for hemorrhage. Finally, hypertension occurs more frequently in patients with hemophilia than in the general population and may in part contribute to the occurrence of bleeding within the central nervous system. Methods for evaluating and treating these various disorders are discussed. Greater awareness of these potentially treatable medical complications will improve further the quality of care in hemophilia.

Liver-spleen imaging in patients with subacute hepatic necrosis and chronic hepatitis.

Tc-99m-sulfur colloid reticuloendothelial images and percutaneous liver biopsies are correlated in 54 patients who presented with signs and symptoms of subacute hepatic necrosis or chronic active hepatitis. The scored Tc-99m-sulfur colloid scan is compared to the histological severity of disease. Serial scans and biopsies are compared. In patients with significant hepatocellular disease, the liver-spleen scan did not correlate well with the histological severity of disease. Changes in the spleen-to-liver ratio are more common than those in the liver or increased bone marrow activity, and appear earlier. In serial studies, changes in the Tc-99m-sulfur colloid scans correlate weakly with changes in histology.

Treatment of alcoholic hepatitis with encephalopathy. Comparison of prednisolone with caloric supplements.

A previous report from this institution demonstrated significant improvement of caloric intake and survival in patients with alcoholic hepatitis and hepatic encephalopathy given prednisolone when compared with placebo. The purpose of this study was to compare the effects of prednisolone with a regimen of 1600 calories per day without prednisolone. Fourteen patients with alcoholic hepatitis and encephalopathy were studied. All 7 on caloric supplementation and 2 of 7 given prednisolone died (p less than 0.01). These results suggest that prednisolone therapy reduces the mortality of those patients with alcoholic hepatitis and hepatic encephalopathy. This effect does not appear to be related to total caloric intake.

Fatal hepatic necrosis after halothane anesthesia in a boy with juvenile rheumatoid arthritis: a case report.

Hepatitis from halothane is usually diagnosed by excluding other possible causes. Whether preexisting hepatic damage, which can occur in certain autoimmune disorders, contraindicates the use of halothane has yet to be proven. The case of a 14-year-old boy with early-onset juvenile rheumatoid arthritis who developed fatal hepatic necrosis 13 days after halothane anesthesia is presented.

Liver biopsy in hemophilia A.

Hepatitis is a significant complication of the treatment of hemophilia A with factor VIII concentrates. Chronic liver disease in these patients is infrequently documented in the literature. The results of percutaneous liver biopsy, under the coverage of glycine-precipitated factor VIII, in six patients with hemophilia A who had the persistence of abnormal liver-function tests for at least 6 months, are described. Three patients had chronic active hepatitis, and three had chronic persistent hepatitis. No complications were encountered as a result of the biopsy procedure. These results suggest that percutaneous liver biopsy should be considered in patients with hemophilia A with continuously abnormal liver-function tests to establish a histologic diagnosis and to guide further therapy.