Ethane evolution: a new index of lipid peroxidation.

Homogenates of mouse liver and brain at 37 degrees C spontaneously formed lipid peroxides and simultaneously evolved ethane. alpha-Tocopherol, a lipid antioxidant, blocked ethane formation. When mice were injected with carbon tetrachloride (a liquid prooxidant for liver), the animals produced ethane. Ethane evolution in vivo was stimulated by prior administration of phenobarbital and it was diminished by prior injection of alpha-tocopherol. These data suggest that ethane production may be a useful index of lipid peroxidation in tissue homogenates and in intact animals.

Effect of physiologic hyperinsulinemia on glucose and lipid metabolism in cirrhosis.

Insulin secretion and insulin sensitivity were evaluated in eight clinically stable cirrhotic patients and in 12 controls. OGTT was normal in cirrhotics but plasma insulin response was increased approximately twofold compared with controls. Subjects received a three-step (0.1, 0.5, 1.0 mU/kg.min) euglycemic insulin clamp with indirect calorimetry, [6-3H]-glucose, and [1-14C]-palmitate. During the two highest insulin infusion steps glucose uptake was impaired (3.33 +/- 0.31 vs. 5.06 +/- 0.40 mg/kg.min, P less than 0.01, and 6.09 +/- 0.50 vs. 7.95 +/- 0.52 mg/kg.min, P less than 0.01). Stimulation of glucose oxidation by insulin was normal; in contrast, nonoxidative glucose disposal (i.e., glycogen synthesis) was markedly reduced. Fasting (r = -0.553, P less than 0.01) and glucose-stimulated (r = -0.592, P less than 0.01) plasma insulin concentration correlated inversely with the severity of insulin resistance. Basal hepatic glucose production was normal in cirrhotics and suppressed normally with insulin. In postabsorptive state, plasma FFA conc (933 +/- 42 vs. 711 +/- 44 mumol/liter, P less than 0.01) and FFA turnover (9.08 +/- 1.20 vs. 6.03 +/- 0.53 mumol/kg.min, P less than 0.01) were elevated in cirrhotics despite basal hyperinsulinemia; basal FFA oxidation was similar in cirrhotic and control subjects. With low-dose insulin infusion, plasma FFA oxidation and turnover failed to suppress normally in cirrhotics. During the two higher insulin infusion steps, all parameters of FFA metabolism suppressed normally. In summary, stable cirrhotic patients with normal glucose tolerance exhibit marked insulin resistance secondary to the impaired nonoxidative glucose disposal. Our results suggest that chronic hyperinsulinism may be responsible for the insulin resistance observed in cirrhosis.

Hepatic disease in pregnancy.

Liver disease occurring in pregnancy can be categorized into three groups. The first group includes diseases unique to pregnancy and caused by it. Among these are hyperemesis gravidarum, cholestasis of pregnancy, and disorders associated with preeclampsia. Liver involvement may be expected in 50% of patients with hyperemesis gravidarum. Preeclampsia has been associated with both the HELLP syndrome (hemolysis, elevated liver tests, and low platelets), which includes hepatic infarction and rupture, and with acute fatty liver of pregnancy (AFLP). In patients with HELLP syndrome, liver test abnormalities do not correlate with liver injury. Therefore, this and other disorders associated with preeclampsia require aggressive treatment, primarily with delivery. The second group of liver diseases are those exacerbated by pregnancy. Viral infections involving the liver that are usually benign, such as hepatitis E and herpes simplex, are more likely to be exacerbated in pregnant women and are more likely to lead to fulminant hepatic failure. Cholelithiasis and Budd-Chiari syndrome are more prevalent in pregnant women. The third group is comprised of liver diseases that are preexisting in the pregnant patient and includes autoimmune chronic active hepatitis and Wilson's disease. The number of patients in the last group is small, as chronic liver disease is rare in women who are able to bear children.

Primary autoimmune cholangitis. An alternative to antimitochondrial antibody-negative primary biliary cirrhosis.

The authors report the clinical and liver biopsy features of nine patients with primary autoimmune cholangitis, a unique form of chronic nonsuppurative destructive cholangitis associated with high-titer serum antinuclear antibodies, including eight women and one man; their median age was 51 years. All patients showed cholestatic hepatic enzyme profiles (median gamma glutamyl transferase and alkaline phosphatase, 800 U/L and 700 U/L, respectively). The median antinuclear antibody titer was 1:1,280 (range, 1:640-1:2,560). All patients' sera were negative for antimitochondrial antibodies; six were also nonreactive for anti-M2 mitochondrial autoantigens. Liver biopsies showed marked paucity of interlobular bile ducts (median percentage of portal tracts containing bile ducts, 11%; range, 0-50%). Granulomatous cholangitis was present in two cases; five livers showed the pattern of bile ductular proliferative piecemeal necrosis. Seven patients were treated with prednisone and azathioprine without clinical benefit. During follow-up of 1 to 5 years, disease has progressed in seven patients, including four who have developed other autoimmune conditions. Although clinically, biochemically, and histopathologically comparable to primary biliary cirrhosis, autoimmune cholangitis abdicates antimitochondrial antibodies in favor of antinuclear antibodies. It represents a distinctive subset of antimitochondrial antibody-negative adult ductopenic disorders, for which conventional immunosuppressive therapy does not appear warranted.

The effects of early treatment of hereditary tyrosinemia type I in infancy by orthotopic liver transplantation.

Two infants with hereditary tyrosinemia secondary to fumarylacetoacetate hydrolase (FAH) deficiency underwent orthotopic liver transplantation at 14 and 16 weeks of age due to poor clinical and biochemical response to medical therapy. Prompt clearance of abnormal metabolites with improved mental alertness and appetite occurred with minimal perioperative complications. Both infants tolerated rapid institution of normal diets and have shown progressive growth and development in the first 36 months after transplantation. Early liver transplantation should be considered as an option for infants with certain inherited metabolic disorders with poor prognosis, such as tyrosinemia type I, who fail to respond to medical therapy.

Management of pediatric liver tumors.

Historically, children with liver tumors were uniformly considered to have a poor prognosis and were approached warily by pediatric surgeons and oncologists. Over the last decade, however, advances in diagnostic imaging technology, discovery of effective chemotherapy, and improved surgical techniques have greatly facilitated the management of children with hepatic tumors. Although orthotopic liver transplantation has emerged as a viable treatment option in the management of hepatic malignancies, including hepatoblastoma and hepatocellular carcinoma, its use is still controversial.

Capturing the semantic relationship between clinical terms with current MeSH bibliographic coding.

This paper compares bibliographic retrieval using current MeSH (Medical Subject Headings) to bibliographic retrieval using explicitly coded semantic relationships between index terms. In a previous study, ten lists of abstracts, each list containing 20-40 papers discussing a specific pair of terms, were analyzed to identify the specific relationship(s) between those terms discussed in each paper. In the present study, we analyze how well current MeSH coding using topical subheadings and check tags, can selectively retrieve those papers discussing each semantic relationship.

Acute hepatic failure at term. Diagnostic problems posed by broad clinical spectrum.

Acute fatty liver of pregnancy presents near term as fulminant hepatic failure, often associated with mild preeclampsia and profound coagulopathy. To protect the life of mother and baby this syndrome must be rapidly diagnosed and differentiated from other conditions that may occur in pregnancy.

Acute hepatic failure in children.

Many diseases may present as acute hepatic failure in the pediatric age group, including viral hepatitis A and B, adverse drug reactions, both toxic and "hepatitic," and inherited metabolic disorders such as tyrosinemia, alpha 1 antitrypsin deficiency, and Wilson's disease. Management is primarily supportive, with care taken to anticipate the known complications of hepatic failure. Few "curative" therapies are known, although attempts at stimulating hepatic regeneration may be helpful.

Familial intrahepatic cholestasis: an update.

Familial intrahepatic cholestasis is a confusing group of syndromes. Four forms are defined and discussed in detail ("arteriohepatic dysplasia," the Byler syndrome, the THCA syndrome, and Norwegian cholestasis). A comparison of the distinguishing characteristics of these syndromes demonstrates that they share many features, including areflexia, retinal degeneration, and paucity of the intrahepatic bile ducts on biopsy. Alternatively, some traits appear to be specific for a single syndrome: posterior embryotoxon and bony anomalies for arteriohepatic dysplasia, the presence of an abnormal bile acid for the THCA syndrome, and giant cell transformation for Norwegian cholestasis. These syndromes, although rare, merit complete evaluation because, as nature's experiments in bile formation, they represent models of cholestasis and may provide clues to the understanding both of other forms of cholestasis of unknown etiology and of the normal mechanisms of bile formation.

Familial intrahepatic cholestatic syndromes.

This discussion has illustrated the enormous variety found within the category of familial intrahepatic cholestasis. It has also demonstrated how much more there is to learn about these fascinating disorders, which may be examples of experiments in nature on bile formation. This analysis should be recognized to be the author's own, and there is much debate about this classification. For example, some workers in this field contend that North American Indian cholestasis is in reality Byler's syndrome. Such an identity seems unlikely, given the differences between the two syndromes (Table 2). This is a field that is changing rapidly. Recently, a new cholestatic syndrome, bearing some similarities to benign recurrent intrahepatic cholestasis, but dissimilar in several ways, has been reported. There is evidence that cholestasis of pregnancy may be inherited as an autosomal dominant, sex-limited trait. If further studies confirm a genetic etiology, this syndrome would be the most common form of familial intrahepatic cholestasis. The assessment of any individual case remains difficult, particularly early in the course. Table 2 can serve as a guide to the differential diagnosis of these conditions. When faced with a neonate with jaundice, all of the usual causes must be ruled out first. The pattern of bile acids in serum is useful for ruling out Zellweger's syndrome. A good family history and physical examination, particularly of the heart, are important. An ophthalmologic examination by a specialist, often under anesthesia, and a spine radiograph can be useful in confirming a diagnosis of Alagille's syndrome. A liver biopsy, carefully interpreted with input from the clinician, is useful in pointing toward one direction or another. Often a firm conclusion cannot be reached, or is reached prematurely, so the clinician would be advised to inform the parents of all diagnostic possibilities in order to avoid false hopes or unwarranted depression. The diagnostic pitfalls to be avoided in this evaluation are many. No histologic findings are clearly pathognomonic for one syndrome or another. Giant cell transformation and paucity of intrahepatic bile ducts may be found in several syndromes. Biliary atresia, or at least failure to demonstrate a patent biliary tree from the liver to the cystic duct, may be present in patients with Alagille's syndrome. In that syndrome, the eye findings, particularly the posterior embryotoxon, may not be appreciated except on extensive ophthalmologic testing, including gonioscopy. Butterfly vertebrae may not be visible at birth and may be no longer evident in adulthood.(ABSTRACT TRUNCATED AT 400 WORDS)

Contraception and pregnancy after liver transplantation.

1. Libido returns promptly after liver transplantation; patients should be counseled on contraception and avoidance of sexually transmitted diseases. 2. Women after liver transplantation are at increased risk for cancer and should have regularly scheduled screening for cervical and breast cancer. 3. Immunosuppression during pregnancy is not teratogenic and does not lead to congenital anomalies. 4. Pregnancy after liver transplantation is often successful, but must be regarded as high risk, associated with an increased risk for hypertension and preeclampsia, intrauterine growth retardation, and prematurity. It is best delayed until 1 to 2 years after grafting. 5. Close monitoring of immunosuppressant levels in the blood is crucial during pregnancy to avoid inappropriately low levels of immunosuppression.

Hyperemesis gravidarum.

Hyperemesis gravidarum is a poorly understood disorder and one for which many physicians have little sympathy, perhaps because we find it difficult to understand its pathogenesis and to treat. It may be associated with dysfunction in a variety of organs, including the thyroid and liver. Many theories, prominently including psychological or behavioral abnormalities, have been proposed to explicate this syndrome. On examination, however, no single theory seems to provide an adequate explanation for hyperemesis gravidarum. Treatment for hyperemesis gravidarum includes fluid and electrolyte supplementation, nutritional support, and total parenteral nutrition, as well as psychological and behavioral therapies and, in selected cases, pharmacotherapy.

Inherited liver diseases in adults.

Important inherited disorders causing acute and chronic liver disease include hemochromatosis, Wilson's disease, alpha 1-antiprotease (antitrypsin) deficiency, and cystic fibrosis. The detection of an index case has implications for screening family members. A normal life span can be expected with treatment in asymptomatic patients with Wilson's disease and hemochromatosis. We present a clinical approach to disease recognition, investigation, and screening.

Liver disease in cystic fibrosis.

Because of improved survival in the past two decades, liver disease has assumed greater importance in patients with cystic fibrosis. Clinical detection has been difficult thus far. In recent years, advances in our understanding of pathogenesis as well as increasing experience in therapeutic modalities have been accomplished. For these reasons, it is relevant to review this topic.

Acute fatty liver of pregnancy: the hepatologist's view.

Acute fatty liver of pregnancy is a rare clinical entity unique to pregnancy that can lead to hepatic failure and encephalopathy and, if the diagnosis is delayed, to death for the baby and the mother. The characteristic histological picture demonstrates microvesicular fatty infiltration of hepatocytes. Acute fatty liver of pregnancy is a disease of the third trimester of pregnancy. The most significant clinical findings are nausea or vomiting, abdominal pain, jaundice, hepatic encephalopathy, increased transaminase levels, decreased platelet count, increased prothrombin time, and renal failure. Hypertension and proteinuria are common. Liver biopsy is not always necessary for diagnosis but may be useful in atypical cases. The primary therapy is early delivery and supportive care. Both the obstetric team and the medical consultants must have a high index of suspicion for this disease because early delivery is lifesaving and has transformed the prognosis for the mother and the baby. Collaboration between obstetricians and gastroenterologists is necessary to make the diagnosis and also to improve our understanding of this disease of unknown etiology.

Baking powder pica mimicking preeclampsia.

We report a case of baking powder pica during pregnancy that was associated with maternal hypertension, hypokalemia, and elevated liver function tests. After discontinuation of baking powder ingestion and correction of electrolyte abnormalities, the blood pressure and the liver function tests normalized.

Insulin resistance in noncirrhotic idiopathic portal hypertension.

To explore further the pathogenesis of glucose intolerance and insulin resistance observed in patients with cirrhosis and portal hypertension, we studied a 35-year-old woman with presinusoidal portal hypertension without cirrhosis due to nodular regenerative hyperplasia of the liver. After oral glucose ingestion, glucose tolerance remained normal; however, this occurred at the expense of a markedly hyperinsulinemic plasma response, suggesting the presence of insulin resistance. To examine this question more directly, we performed a stepwise euglycemic insulin clamp study in combination with an infusion of [6-3H]glucose and [1-14C]palmitate and indirect calorimetry. The ability of insulin to promote total body (primarily muscle) glucose uptake was markedly impaired, whereas its effect to suppress hepatic glucose production was normal compared with results obtained in nine healthy subjects. Moreover, insulin failed to normally suppress plasma free fatty acid turnover and oxidation in this patient. This informative case demonstrates that portal hypertension alone, without hepatic dysfunction from cirrhosis, is associated with impaired insulin-mediated glucose and plasma free fatty acid metabolism and may also play a predominant role in the development of insulin resistance in many cirrhotic patients.