A. Tavill

Nonalcoholic steatohepatitis (NASH) is the term used for a common form of fatty liver presenting in adults with varied clinical manifestations. The most common presentation is asymptomatic elevation of liver enzymes (AST or SGOT and ALT or SGPT), which can be discovered incidentally in the course of an annual checkup, life insurance examination, or as part of surrogate screening before blood donation. At the other end of the clinical spectrum is the patient with complications from cryptogenic cirrhosis, who also shows a lack of evidence of alcohol as an etiological factor in pathogenesis. Clinical associations of probable relevance include gender (female), obesity, diabetes, and hyperlipidemia, but many patients do not conform to any of these stereotypes (e.g., young men of normal weight with normal fasting glucose and lipid levels). Liver biopsy confirms the diagnosis of NASH, the association of steatosis with an inflammatory response being the sine qua non for the condition and &q...

... Such a preparation has been used for the study of gastrointestinal protein loss (Jeejeebhoy, Singh,Mani, and Sanjana, 1965; Jeejeebhoy, Jarnum, Singh, Nadkami, and Westergaard, 1968) in 18 control patients and five patients with protein-losing enteropathy. ...

An integrated approach to normal hepatic iron metabolism requires an understanding of the complex interactions between the dynamic processes of iron uptake, utilization, storage, and release. Lack of knowledge of the specific chemical and physical properties of certain critical compartments of hepatic iron (such as the transit pool and hemosiderin) and of their relative turnover rates has made it extremely difficult to assign precise parameters to their dynamic interactions. With refinement in biochemical and biophysical techniques and with their application to valid biologic models, it should be possible to obtain insights into these areas, which are currently obscure.

JW, a 28-year-old man, was admitted to the hospital on June 13, 1963, complaining of severe muscle pain and weakness, reddish-brown discoloration of the urine and frequent vomiting. Three days previously he had changed his occupation from one that had been relatively ...

The site of synthesis of Hageman factor (HF, Factor XII) has not been previously demonstrated with certainty. We have studied the production and release of HF in the isolated perfused rat liver and have compared rates of synthesis in this system with absolute rates of degradation measured in vivo. Rat livers, perfused for 5 h with a recycling fluid consisting of a perfluorochemical emulsion (Fluosol 43), were used to demonstrate a cumulative increase of HF in the perfusate as measured by a specific and sensitive radioimmunoassay. The rate of increase in the perfusate pool of HF during the final 4 h of perfusion yielded a mean synthetic rate of 3.5 micrograms/h per 100 g body wt, which was approximately 0.2% of the synthetic rate of albumin in the same system. The cumulative appearance of albumin and transferrin was linear after 1 h and calculated rates of synthesis were 2,012 micrograms/h per 100 g and 263 micrograms/h per 100 g body wt, respectively. De novo synthesis of HF was confirmed by demonstrating incorporation of [14C]lysine into specific immunoprecipitates of HF, and by the observations that both specific incorporation of labeled amino acid and net release of immunoassayable HF were inhibited by the administration of cycloheximide. Finally, it was evident that the rates of synthesis observed in the isolated perfused liver agreed closely with absolute rates of degradation of HF measured in vivo with 125I-rat HF (4.0 micrograms/h per 100 g). From these data we conclude that the liver is the principal site of synthesis of HF.

Hepatitis C virus (HCV) has become a major contributor to morbidity and mortality in patients with human immunodeficiency virus (HIV). It is estimated that 30% to 50% of patients with HIV are coinfected with HCV. Advances in antiretroviral therapy and improved life expectancy of HIV patients have resulted in an emergence of HCV-induced liver disease as a leading cause of significant morbidity and death in this population. Clinically, hepatitis C is a more severe disease in HIV-infected individuals, characterized by rapid progression toward end-stage liver disease. Highly active antiretroviral therapy is the mainstay of current acquired immunodeficiency syndrome management. One of the limiting side effects of combination therapy for HIV is hepatotoxicity, which is more common and often more serious in patients with underlying liver disease. Management of coinfected patients has no strict guidelines, but it is generally accepted that HIV infection needs to be treated before HCV. Hepatitis C in coinfected individuals is probably best treated using combination therapy (interferon alpha and ribavirin). It appears that combination therapy can safely be administered to this population and that previous concerns about ribavirin/zidovudine antagonism are unsubstantiated in clinical practice. Although initial results using only interferon alpha showed poor results in HIV coinfected patients, combination therapy seems to be as effective as in the general population. All HIV-HCV coinfected patients should be vaccinated against hepatitis B and hepatitis A; vaccines are safe and effective.

The Gastroenterology Core Curriculum published in this issue of Gastroenterology is the product of a 2-year, in-depth analysis of the knowledge and skills desired at the completion of fellowship training in gastroenterology and the specific training process to achieve these goals. This curriculum is a result of the cooperative effort of the American Association for the Study of Liver Diseases,

We prospectively evaluated the ascitic fluid (AF) polymorphonuclear cell (PMN) count, pH, and lactate concentration in single ascitic fluids from 60 patients to determine their relative predictive values for the immediate diagnosis of ascitic fluid infection. Nine of the 60 ascitic fluids were malignant. Of the remaining 51 samples, nine from cirrhotic patients were infected. The mean AF pH, lactate concentration, and PMN count in the infected group were 7.20 +/- 0.19, 80 +/- 51 mg/dl, and 18,199 +/- 19,650 cells/mm3, respectively, and all were significantly different from the corresponding values in noninfected ascites. Mean arterial blood-ascitic fluid (B-AF) pH and lactate gradients in the infected group were 0.23 +/- 0.17 and -46 +/- 31 mg/dl, respectively, and were significantly different from the corresponding values in noninfected ascites (p less than 0.05). Significant differences were not found between infected and malignant ascites, except for the AF PMN count (p less than...

We report a 20-year-old patient with arteriohepatic dysplasia (Alagille's syndrome) who developed progressive renal failure associated with extensive renal lipidosis. A renal biopsy showed diffuse thickening of glomerular basement membrane mimicking idiopathic membranous glomerulonephritis on light microscopy. Electron microscopy, however, demonstrated numerous intramembranous and mesangial lipid deposits, quite similar to those described in familial lecithin cholesterol acyltransferase deficiency. We believe the renal lipidosis developed secondary to hyperlipidemia associated with longstanding intrahepatic cholestasis. This case illustrates that extensive lipid deposition in the glomerular basement membrane may occur in patients with arteriohepatic dysplasia, and it may lead to progressive renal failure.

1. The relation between endogenous urea metabolism and albumin synthesis has been studied in ten patients with chronic renal failure and in four normal subjects, after single intravenous injections of [14-C]urea,[15-N]urea and 125-I-labelled albumin. 2. The rate of urea synthesis was determined from the dynamics of plasma [14-C]urea specific radioactivity and the rate of urea metabolism was estimated from the relative rates of urea synthesis and urea appearance in urine and body water. Deconvolution analysis of plasma [15N]albumin enrichmevt and 125-i-labelled albumin radioactivity yielded the cumulative incorporation of 15-N into total exchangeable albumin and enabled calculation of the absolute rate of urema nitrogen utilization for albumin synthesis. 3. Although the mean absolute rate of urea degradation in uraemic patients (3-7 mmol/h) was higher than in normal subjects (2-3 mmol/h) there was no significant positive correlation between urea degradation and plasma urea concentrat...

A mathematical model was constructed to define the dynamics of incorporation of radioactivity into urea carbon and the guanidine carbon of arginine in plasma albumin after the rapid intraportal-venous administration of Na214CO3 in the isolated perfused rat liver. 2. The model was formulated in terms of compartmental analysis and additional experiments were designed to provide further information on subsystem dynamics and to discriminate between alternative model structures. 3. Evidence for the rapid-time-constant of labelling of intracellular arginine was provided by precursor-product analysis of precursor [14C]carboante and product [14C]urea in the perfusate. 4. Compartmental analysis of the dynamics of newly synthesized urea was based on the fate of exogenous [13C]urea, endogenous [14C]urea and the accumulation of [12C]urea in perfusate water, confirming the early completion of urea carbon labelling, the absence of continuing synthesis of labelled urea, and the presence of a small...

The control of hepatic iron uptake was studied in the perfused liver isolated from rats subjected to nutritional iron deficiency. The total hepatic iron uptake and incorporation into ferritin was found to be higher in iron deficiency and during the 48 h of oral refeeding with iron than in the normal state. Specific incorporation of iron into feritin from a perfusate of normal transferrin iron saturation was enhanced in nutritional iron deficiency as compared to controls after 5 h of perfusion but not after 1 h, suggesting that increased uptake of iron from the perfusate may play a role in stimulating hepatic ferritin synthesis and assembly. This promotion of uptake into ferritin was inhibited by cycloheximide suggesting that enhanced incorporation of iron is dependent upon de novo synthesis of apoferritin. In control, nutritionally iron deficient and iron-refed rats there was a significant, direct correlation between the transferrin-iron saturation of the perfusate at physiological ...

Peroxidative decomposition of cellular membrane lipids is a postulated mechanism of hepatocellular injury in parenchymal iron overload. In the present study, we looked for direct evidence of lipid peroxidation in vivo (as measured by lipid-conjugated diene formation in hepatic organelle membranes) from rats with experimental chronic iron overload. Both parenteral ferric nitrilotriacetate (FeNTA) administration and dietary supplementation with carbonyl iron were used to produce chronic iron overload. Biochemical and histologic evaluation of liver tissue confirmed moderate increases in hepatic storage iron. FeNTA administration produced excessive iron deposition throughout the hepatic lobule in both hepatocytes and Kupffer cells, whereas dietary carbonyl iron supplementation produced greater hepatic iron overload in a periportal distribution with iron deposition predominantly in hepatocytes. Evidence for mitochondrial lipid peroxidation in vivo was demonstrated at all three mean hepatic iron concentrations studied (1,197, 3,231, and 4,216 micrograms Fe/g) in both models of experimental chronic iron overload. In contrast, increased conjugated diene formation was detected in microsomal lipids only at the higher liver iron concentration (4,161 micrograms Fe/g) achieved by dietary carbonyl iron supplementation. When iron as either FeNTA or ferritin was added in vitro to normal liver homogenates before lipid extraction, no conjugated diene formation was observed. We conclude that the presence of conjugated dienes in the subcellular fractions of rat liver provide direct evidence of iron-induced hepatic mitochondrial and microsomal lipid peroxidation in vivo in two models of experimental chronic iron overload.

ABSTRACT Arteriohepatic dysplasia (syndromatic ductular hypoplasia, Alagille syndrome) is a condition of chronic cholestasis dating from infancy accompanied by characteristic facies, pulmonic stenosis, and other somatic abnormalities. The pathologic hallmark of arteriohepatic dysplasia is a paucity or absence of intrahepatic bile ducts, wildely regarded as a congenital deficiency. We present a longitudinal study of six infants and children with arteriohepatic dysplasia, stressing evolution of the characteristic pathology on liver biopsy. All patients were biopsied twice. All five liver biopsies performed during infancy (<6 months old) showed intrahepatic cholestasis and portal inflammation, and two infants had, in addition, giant cell transformation. No infant showed congenital absence of interlobular bile ducts. Three of five infants had normal numbers of interlobular bile ducts (0.5 to 1.0 interlobular bile ducts per triad) and two infants had a paucity of interlobular bile ducts (<0.5 per triad). Three infants showed focal destructive inflammation of interlobular bile ducts. All biopsies performed later in childhood, between 3 and 20 years of age, showed a paucity or absence of interlobular bile ducts. At this time cholestasis and inflammation had largely resolved but some fibrosis persisted. The number of interlobular bile ducts decreased with age in each patient but there was no characteristic age at which interlobular bile ducts disappeared completely. The presence of interlobular bile ducts in infancy followed later in childhood by paucity or absence of interlobular bile ducts, suggests that intrahepatic bile duct deficiency in some patients with arteriohepatic dysplasia is acquired rather than congenital. The mechanism of bile duct disappearance in these patients may have been destructive inflammation of duct epithelium.Histopathologic diagnosis of arteriohepatic dysplasia may be difficult or impossible in infancy since interlobular bile ducts may be present at that time. However, arteriohepatic dysplasia should be considered in the differential diagnosis of all infants with cholestasis and such infants should have careful clinical evaluation for the syndromatic features of arteriohepatic dysplasia. Evaluation of their liver biopsies should include specific morphometric assessment of interlobular bile ducts.

The polymeric immunoglobulin receptor on rat hepatocytes binds dimeric IgA on the sinusoidal surface and mediates its transport to the canaliculus, where the complex of dimeric IgA and secretory component, the cleaved extracellular domain of polymeric immunoglobulin receptor, is secreted into bile. This process is unique in that disulfide bonds are formed between dimeric IgA and polymeric immunoglobulin receptor during transcytosis, permanently preventing their dissociation. Here we present three lines of evidence that disulfide bonding between dimeric IgA and polymeric immunoglobulin receptor occurs predominantly in a late transcytotic compartment and that hepatic transcytosis can proceed in the absence of disulfide bond formation. First, throughout the course of transcytosis the percentage of intracellular dimeric IgA disulfide bonded to polymeric immunoglobulin receptor is less than half that in bile, suggesting that disulfide bond formation is a late event in transcytosis. Second, dimeric IgA that recycles from early endocytotic compartments into the circulation is mostly noncovalently bound to secretory component. Finally, the rate of transcytosis of dimeric IgA and its appearance in bile are not affected when disulfide bond formation with polymeric immunoglobulin receptor is inhibited by blocking of free thiol groups on dimeric IgA with iodoacetamide. These results are consistent with other findings in the literature and indicate that the main physiological role of disulfide bond formation between dimeric IgA and polymeric immunoglobulin receptor is not to facilitate transcytosis but, rather, to stabilize the dimeric IgA-secretory component complex after its release into external secretions such as bile and intestinal secretions.

A study of urea and albumin metabolism was carried out in a patient with the stagnant loop syndrome and in a control subject using radioisotopic and stable isotopic techniques. The patient had a higher rate of urea synthesis, urea hydrolysis in the gut, and of incorporation of recycled urea nitrogen into albumin. Although only a small proportion (0.4%) of the urea nitrogen available was used for albumin synthesis and this constituted only 0.8% of the daily nitrogen requirement for this purpose, the reutilization of nitrogen was relatively much greater than was observed in the control study.

The control of hepatic iron uptake was studied in the perfused liver isolated from rats subjected to nutritional iron deficiency. The total hepatic iron uptake and incorporation into ferritin was found to be higher in iron deficiency and during the 48 h of oral refeeding with iron than in the normal state. Specific incorporation of iron into feritin from a perfusate of normal transferrin iron saturation was enhanced in nutritional iron deficiency as compared to controls after 5 h of perfusion but not after 1 h, suggesting that increased uptake of iron from the perfusate may play a role in stimulating hepatic ferritin synthesis and assembly. This promotion of uptake into ferritin was inhibited by cycloheximide suggesting that enhanced incorporation of iron is dependent upon de novo synthesis of apoferritin. In control, nutritionally iron deficient and iron-refed rats there was a significant, direct correlation between the transferrin-iron saturation of the perfusate at physiological transferrin concentrations and total hepatic iron uptake after 5 h perfusion. A significant positive correlation was found between the hepatic total and ferritin iron uptake and the transferrin synthetic rate measured in the same liver. It is proposed that in the liver the negative feedback of iron supply on transferrin synthesis may be linked with a positive feedback on ferritin synthesis. The time-course of these reciprocal responses suggests a role for hepatic ferritin and/or a component of the non-haem, non-ferritin iron pool in the regulation of transferrin synthesis.

The role of iron supply in the regulation of hepatic transferrin synthesis by the isolated perfused rat liver was studied using nutritional iron deficiency as the experimental model. The increased transferrin release encountered in iron deficiency could be equated with enhanced de novo synthesis as evidenced by the inhibitory effects of cycloheximide and measurements of intrahepatic protein pools before and after perfusion. Refeeding with iron, sufficient to restore plasma iron and hepatic ferritin iron but before correction of anaemia, promoted a reduction towards normal in the transferrin synthetic rate. This effect was not produced by transfusional correction of the anaemia, suggesting a specific response to iron supply. Phenobarbitone treatment, which produced a marked fall in hepatic ferritin iron concentration but no change in haemoglobin or plasma iron concentrations, promoted a specific enhancement of transferrin synthesis in both control and iron deficient livers. The concentration of liver iron stores appears to be a major regulatory factor in the control of hepatic transferrin synthesis.