Plasma levels and hepatic extraction of renin and aldosterone in alcoholic liver disease.

Arterial plasma levels and hepatic extraction of renin and aldosterone (ALDO) were measured in 24 patients with alcoholic liver disease and in 14 normal subjects being evaluated as prospective kidney donors. Patients with liver disease had higher plasma concentrations and lower fractional hepatic extractions of both renin and ALDO than the normal subjects. The quantity of renin extracted by the liver was highly correlated with plasma renin in both normal subjects and patients. Plasma ALDO concentration was positively correlated with plasma renin (p less than 0.001) but not with serum sodium, potassium or albumin concentration, inferior vena cava pressure, corrected hepatic venous wedge pressure, plasma volume or sulfobromophthalein storage or transport. Sixteen patients were restudied after one month. Six had received 40 mg/day of prednisolone, and the remaining 10 had received a placebo. Neither group had a change in plasma volume, corrected hepatic venous wedge pressure, plasma concentration or hepatic extraction of renin or ALDO. Serum albumin concentration increased and inferior vena cava pressure decreased with prednisolone therapy. These studies document high plasma levels and impaired hepatic extraction of renin and ALDO in patients with liver disease that are not corrected by short-term prednisolone therapy.

Cholestatic hepatitis from erythromycin ethylsuccinate. Report of two cases.

Cholestatic hepatitis developed in two patients while they were receiving erythromycin ethylsuccinate. Both patients had received the drug without apparent problem within two months of the episode of drug-related cholestatic injury. In both, there was complete resolution of the hepatic injury upon withdrawal of the drug. Erythromycin ethylsuccinate should be added to the list of drugs causing cholestatic hepatitis.

Tc-99m human serum albumin: a suitable agent for plasma volume measurements in man.

In 16 patients we have carried out simultaneous plasma-volume measurements with human serum albumins tagged with Tc-99m (Tc-99m HSA) and I-131 (I-131 HSA). The correlation coefficient was 0.987. Tc-99m HSA, prepared from kits that predictably yield high labeling efficiency (and thereby negligible amounts of TCO4-), is clearly a superior agent for repeat plasma volume determinations, because of its shorter half-life and the reduced radiation dose to the subject.

Alcohol-induced liver disease.

Hepatic changes resulting from the regular ingestion of alcohol are many and include fat infiltration, alcoholic hepatitis, and cirrhosis. Only 10% to 15% of chronic alcoholics develop liver disease. Women are more susceptible. An area of considerable importance is the high prevalence of concomitant infection with hepatitis C virus in chronic alcoholics. Patients who have hepatitis C and alcohol-induced liver injury are much more likely to develop progressive liver disease and cirrhosis. Corticosteroid therapy has proven useful in the treatment of patients with severe acute alcoholic hepatitis.

Perspective: preventive isoniazid therapy and the liver.

The preventive use of isoniazid (INH) has been controversial since 1975, but official agencies continue to advocate the procedure. Cost-effectiveness and risk benefit studies of preventive INH use have come to conflicting conclusions. A review of eight such studies indicates an increasing tendency to minimize INH hepatotoxicity and to disregard the declining tuberculosis morbidity and mortality in countries in which INH prophylaxis has not been widely adopted. We report three cases of fatal INH-associated hepatitis that illustrate that this complication of preventive INH use remains a serious problem. Current recommendations that encourage wide use of preventive INH therapy are unwise because they inflict a risk of fatal hepatitis on compliant adults and older children who have little danger of tuberculosis while being difficult to deliver to the alcohol- and drug-addicted persons whose risk is high. Health departments and physicians should severely restrict preventive INH therapy.

Hemodynamic effects of superior mesenteric arterial and intravenous vasopressin infusions in patients with portal hypertension.

Administration of vasopressin (0.4 units/minute) via the superior mesenteric artery (SMA) resulted in a mean 25% reduction in corrected hepatic venous wedge pressure (CHWP) in 9 stable non-bleeding patients with cirrhosis and portal hypertension. There was wide variation of response in individual patients with two of nine showing no decrease in CHWP to vasopressin. Selective intra-arterial infusion did not protect against the systemic effects of vasopressin and resulted in significant elevations in blood pressure (21%) and systemic vascular resistance (39%). A slight decrease in cardiac output (11%) was also observed. In 6 of these patients, vasopressin (0.4 units/minute) was also given intravenously. The resultant decreases in CHWP were similar to those observed with SMA administration.

Mesocaval shunts for the control of bleeding esophageal varices.

Results in 44 patients with esophageal bleeding who underwent a mesocaval shunt utilizing a prosthetic graft are presented. Portal hypertension was secondary to alcoholic cirrhosis in 30 patients, to chronic active hepatitis in eight, to primary biliary cirrhosis in four, to cirrhosis secondary to inflammatory bowel disease in one, and to portal vein thrombosis following splenectomy in one. Thirty-six shunts were performed during the emergent or semiemergent time period, and only eight were performed electively. Sixteen of the patients were Child's class A, 16 were class B, and 12 were class C. There were no hospital deaths in the emergency shunt group (of eight patients); there was a 12% mortality rate for patients undergoing semiemergency shunts (two of 17 patients) and a 42% mortality rate for patients who had emergency shunts (eight of 19 patients). Death was related more closely to hepatic reserve, however, than to timing of the shunt. Among the 32 class A and B patients, there were only three deaths in hospital (9%), as compared with seven deaths among the 12 class C patients (58%). Portal-systemic encephalopathy was high in the period immediately after operation (13 of 34 patients, 38%), but it was a chronic problem following discharge from the hospital in only three of 34 patients (9%). The mesocaval shunt is a safe, effective procedure for the control of variceal bleeding in class A and class B patients in any time period, but it carries a high operative mortality risk in the class C patient when it is performed as an emergency operation.

Sclerosing cholangitis: biliary reconstruction with Silastic transhepatic stents.

Because of multiple areas of stricturing and small fibrotic ducts, sclerosing cholangitis has generally not been amenable to direct reconstructive procedures. In reviewing the cholangiograms of 29 patients with sclerosing cholangitis, it became apparent that despite diffuse disease, the hepatic duct bifurcation was often (22 patients) the most severely narrowed area. Because of this finding it was decided to manage patients who have sclerosing cholangitis, persistent jaundice, and hepatic duct bifurcation narrowing with a direct surgical approach. In 11 patients the extrahepatic biliary tree including the bifurcation was resected and the right and left hepatic ducts were dilated. Bilateral 6 mm silicone rubber (Silastic) transhepatic biliary stents were inserted and bilateral hepaticojejunostomy was performed. Eight patients were men, three were women, and the mean age was 41.9 years. At the time of surgery the mean serum bilirubin concentration was 15.3 mg/dl (range 1 to 50 mg/dl). The disease had been present clinically for a mean duration of 3.6 years. There was one hospital death. Nine of the ten remaining patients have responded with a decrease in serum bilirubin concentration to a mean of 2.9 mg/dl. These nine patients have returned to normal activity. The tenth patient has done poorly and awaits liver transplantation. Follow-up ranges from 4 to 36 months (mean 18 months). The stents have been left in position permanently.

A comparison of bumetanide and furosemide in the treatment of ascites. Cooperative study.

In a cooperative study by clinicians in three medical facilities, bumetanide was compared with furosemide in patients presenting with ascites, a complication of chronic liver disease. In an open, parallel, randomized trial, 43 patients received bumetanide and 16 patients received furosemide. They were treated for from one to 28 weeks. Weight loss and decrease in abdominal girth following diuretic action occurred in both groups but was statistically significant only in the bumetanide treated patients. Because of the small number of patients on furosemide, valid statistical analysis could not be obtained. No evidence of hepatic encephalopathy developed during this study, and only one patient on furosemide was discontinued as a result of severe electrolyte imbalance. Differences in changes of electrolytes and uric acid ere not statistically significant in the two groups. The majority of drug-related abnormalities were the result of the pharmacologic activity of the diuretic.

Chromosomal rearrangements in a primary hepatocellular carcinoma.

Chromosome analysis of cells obtained at biopsy from a 65-year-old man with primary hepatocellular carcinoma revealed characteristic abnormalities of chromosomes 1, 5, 6, 9, 13, 16, and 22 in each cell and maintenance of a pseudodiploid chromosome number (46,XY). Five of the chromosomal sites involved in these rearrangements are either in fragile site regions or in regions containing genes that encode cellular oncogenes. Some of the tumor cells manifest mitotic deviations in the form of asynchronies, spiralization, premature centromere division, and non-sister chromatid associations. The significance of these findings to hepatocellular carcinogenesis is discussed.

Cutaneous immunoglobulin deposition in primary biliary cirrhosis.

We studied the skin of six patients with primary biliary cirrhosis (PBC) to determine if there is cutaneous deposition of complement and immunoglobulins in PBC. We also investigated serum samples from these patients for the presence of circulating antibodies against nuclear and cytoplasmic antigens. Three of five patients demonstrated immunoglobulins (IgM or IgG) or complement (C3) deposition at the dermoepidermal junction (DEJ) in clinically normal, light-protected skin. Two of six patients had 2- to 5-mm papular-pustular skin lesions as a manifestation of PBC. Serological studies in these patients disclosed low antinuclear antibody titers in three patients and anti-single-stranded DNA antibody titers in the two patients with skin lesions. These histological, immunofluorescent, and serological findings offer further evidence of the occurrence of circulating immune complexes in at least some patients with PBC.

Surgery in the patient with liver disease.

This article deals with the effects of anesthesia and surgery on the healthy and diseased liver and the preoperative assessment of patients with liver disease. Emphasis is placed on estimating surgical risk. Guidelines for optimal preoperative preparation are discussed.

Hepatic collagen proline hydroxylase activity in alcoholic liver disease.

The activity of hepatic collagen proline hydroxylase was examined in biopsy samples as a factor in collagen synthesis in 77 patients with alcoholic liver disease. The urinary excretion of peptide bound hydroxyproline was also measured in most of the patients, as an index of collagen degradation. The highest activities of collagen proline hydroxylase were found in the patients with alcoholic hepatitis. Enzyme activity was markedly increased in patients with non-specific changes on liver biopsy, whereas, patients with fatty infiltration had only mild elevations, and those with inactive cirrhosis had normal enzyme activity. Urinary hydroxyproline was elevated only in patients with alcoholic hepatitis and inactive cirrhosis. Follow-up determinations in 16 patients with alcoholic hepatitis, after 4 to 5 weeks, revealed a decrease in enzyme activity, but no change in urinary hydroxyproline. We conclude that among the types of alcohol-related liver diseases, alcoholic hepatitis is associated with the greatest turnover of hepatic collagen.

Hepatitis B--an important public health issue.

Hepatitis B is one of the most common infectious diseases in the world. It has been estimated that 350 million people worldwide are chronic hepatitis B virus (HBV) carriers. The global prevalence of chronic HBV infection varies widely, from high ( > 8%, e.g., Africa, Asia and the Western Pacific) to intermediate (2-7% e.g., Southern and Eastern Europe) and low (< 2%, e.g., Western Europe, North America and Australia). The predominant routes of transmission vary according to the endemicity of the HBV infection. In areas of high endemicity, perinatal transmission is the main route of transmission, whereas in areas of low endemicity, sexual contact amongst high-risk adults is predominant. Between one-third and one-quarter of people infected chronically with HBV are expected to develop progressive liver disease (including cirrhosis and primary liver cancer). Although mass vaccination programs have begun to control the spread of HBV infection, therapeutic intervention is the only option for those with established chronic HBV-associated liver disease. Until recently, the only treatment for chronic hepatitis B was the immune modulator, interferon (IFN) alpha. However, IFN alpha treatment has several disadvantages; it is expensive, it must be administered by injection, there are side-effects, and IFN alpha is poorly tolerated. Lamivudine, a nucleoside analogue, is the first effective, and well tolerated, oral treatment for chronic hepatitis B. In conclusion, although we are still some way from eradicating or curing chronic hepatitis B, the advent of lamivudine allows new populations to benefit from therapy and helps to address the global public health problem of hepatitis B.

Serum amino acids following human orthotopic liver transplantation.

Our findings indicate that serum amino acid changes after OLT are complex and influenced by multiple factors including sepsis and use of parenteral hyperalimentation with exogenous amino acids. Additional factors which may influence the rate of normalization of amino acids after OLT include the presence of malnutrition (frequently observed before OLT) and the extent of pretransplant portal-systemic shunting. Our results demonstrate that the presence of septic complications and the use of CPN are important determinants of the postoperative levels of several amino acids, including the BCAA/AAA ratio. Our logistic regression model using the BCAA/AAA ratio predicted the occurrence of sepsis after OLT 77% of the time. Prospective assessment and validation of this model is under way.

Chronic hepatitis.

Evaluation, management and treatment of patients with chronic inflammation of the liver is an important task for the clinician. Almost every ongoing liver injury has an element of inflammation. In those disorders grouped as chronic hepatitis, the brunt of the liver injury is borne by the hepatocyte and continues until either the stimulus is removed or the inflammatory response is blunted. Chronic viral infection is by far the most important cause of chronic hepatitis. Hepatitis B and hepatitis C infections are both frequent causes and may result in cirrhosis. Interferon therapy has proven useful in the treatment of some patients with bone disorders. Idiopathic autoimmune chronic hepatitis is an important contributor to the diagnosis of chronic hepatitis and usually responds to corticosteroid therapy. Because of the availability of effective therapy, Wilson's disease, which is a quite rare but important cause of chronic hepatitis, should be considered. Even more rarely, an ongoing reaction to the continued administration of a therapeutic drug leads to chronic hepatitis. Advances in diagnosis, increased understanding of the courses followed by each of the major disorders, and the availability of effective treatment for many patients has heightened interest in the syndrome of chronic hepatitis.

A model for a managed care education approach to increase hepatitis awareness: Part I.

Morbidity and mortality associated with viral hepatitis, especially hepatitis C, are expected to increase rapidly over the next 2 decades. Many MCOs view hepatitis as a high-cost disease with a relatively low incidence; the incentive to develop education or awareness programs for hepatitis is correspondingly low. The American Gastroenterological Association, the American Society for Gastrointestinal Endoscopy, and the American Association for the Study of Liver Diseases have, through the American Digestive Health Foundation, developed a unique, proactive, and flexible educational initiative for managed care. After providing an overview of hepatitis, this paper describes the four phases of this program designed to increase hepatitis awareness among managed care providers and members.

A model for a managed care education approach to increase hepatitis awareness: Part. II.

In last month's issue, the authors described a unique partnership that led to the development of an educational program on hepatitis C for managed health care plans. Part II and the conclusion addresses the implementation of the program in managed health plans.

Alcoholic hepatitis: pathogenesis and approaches to treatment.

Alcoholic hepatitis is a necrotizing, often inflammatory, process that is an important precursor to the development of cirrhosis. Acetaldehyde, which is derived from alcohol by the action of alcohol dehydrogenase, is apparently the most important factor leading to alcohol-induced liver injury. Other factors of importance in determining the appearance and rate of progression of liver diseases in patients who are chronic alcoholics include sex, nutritional status, and various immunologic reactions. In addition, there is an incompletely understood genetic predisposition to the development of alcoholic hepatitis. Several histologic features found in patients with alcoholic hepatitis have been evaluated in efforts to determine which are of prognostic value. The predominance of the alcohol-induced injury in zone III of the hepatic lobule; deposition of collagen, IgA, and fibronectin in the space of Disse; defenestration of endothelial cells; and transformation of lipocytes and myofibroblasts to fibroblasts have been investigated. Prolongation of the prothrombin time and marked elevation of serum bilirubin levels are indicators of a subgroup of patients with alcoholic hepatitis who have a poor prognosis, especially if there is also evidence of hepatic encephalopathy. Supportive care and abstinence from alcohol are the foundations of therapy. Corticosteroid therapy appears to decrease the number of early deaths in patients with severe alcoholic hepatitis. Other experimental approaches to therapy include the use of propylthiouracil, anabolic-androgenic steroids, and insulin and glucagon.