Significant Steatosis Research Articles

Roles of phosphatidylinositol 3-kinase and osteopontin in steatosis and aminotransferase release by hepatocytes treated with methionine-choline-deficient medium

Feeding mice a methionine and choline-deficient (MCD) diet serves as an experimental animal model for nonalcoholic steatohepatitis (NASH). In the present study we examined the effect of exposing AML-12 hepatocytes to MCD culture medium in regard to mechanisms of steatosis and alanine amino-transferase (ALT) release. Cells exposed to MCD medium developed significant and progressive steatosis from 6 to 24 h and also had significantly increased loss of ALT into the medium at 18 and 24 hours of incubation. No increased oxidative injury or cell death was observed. Osteopontin (OPN) mRNA in cells and protein expression in medium were significantly increased during 6-24 hours of incubation. MCD medium treatment also resulted in activation of PI3-kinase by 30 minutes and its downstream target p-Akt within 1hour of incubation. Steatosis was associated with increased expression of microsomal triglyceride transfer protein (MTTP) mRNA and increased ALT release with over expression of ALT mRNA, all of which were completely prevented by inhibition of PI3-kinase (LY294002). Blocking OPN signaling by treating with anti-OPN or anti-beta3-integrin antibody prevented the increased ALT release while only partially prevented the increased ALT mRNA expression, but had no effect on either steatosis or MTTP expression. In conclusion, incubation of cultured hepatocytes with MCD medium results in cellular steatosis and OPN dependent ALT release. PI3-kinase plays a central role in signaling the MCD medium-induced steatosis and increased OPN expression, whereas OPN appears to play a role in signaling hepatocyte ALT release but not steatosis.

Hepatitis C virus genotype 3 predominates in North and Central India and is associated with significant histopathologic liver disease

Hepatitis C virus (HCV) genotypes help to tailor the treatment response, but their influence on the disease severity and association with hepatic steatosis is not well understood. The prevalence of HCV genotypes and their correlation with the histopathological severity of liver disease and steatosis in Indian patients were studied. HCV-RNA and genotyping was carried out in 398 patients with chronic hepatitis C. Liver biopsy was available in 292 (73.4%) patients. The severity of liver disease was graded on the basis of the histological activity index and the stage of hepatic fibrosis. The patients were categorized as having mild (histological activity index < or =5 and/or fibrosis < or =2) or severe (histological activity index > or =6 and/or fibrosis > or =3) liver disease. Steatosis was graded in 106 patients as 0 (no steatosis), 1 (<33% of hepatocytes affected), 2 (33%-66% of hepatocytes affected), or 3 (>66% of hepatocytes affected). HCV genotype 3 was detected in 80.2% patients (3a:24.4%, 3b:3.3%, 3c:0.5%, 3a/3b:36.7%, and un-subtypable 3:15.3%), genotype 1 in 13.1% (1a:3%, 1b:5.5%, 1a/1b:0.3%, and un-subtypable 1:4.3%), genotype 4 in 3% patients (4a:1.5%, 4b:0.3%, 4a/4c:0.5%, and un-subtypable 4:0.8%), 2 in 2.5% and mixed genotypes (more than one genotype) in 1.3% of patients. The median histological activity index and fibrosis scores were: 5 and 2 in genotype 1; 4 and 2 in genotype 2; 5 and 2 in genotype 3; 7 and 3 in genotype 4; and 5 and 2 in mixed genotypes, respectively. Severe liver disease was present in 17 of 38 (45%) with genotype 1; in 1 of 3 (33%) with genotype 2; in 128 of 236 (54%) with genotype 3; 7 of 10 (70%) with genotype 4; and in 1 of 4 (25%) with mixed genotype. Hepatic steatosis grade > or =2 was found in 28.1% of genotype 3; 23.5% of genotype 1; 20% of genotype 4; and in none of genotype 2 and mixed genotypes. In conclusion, genotype 3 is the most prevalent genotype in patients with chronic hepatitis C in North and Central India and this is associated with significant hepatic steatosis and fibrosis.

Effect of hypercholesterolemia on experimental colonic anastomotic wound healing in rats

To evaluate the mechanical and biochemical parameters of colonic anastomotic healing in hypercholesterolemic rats. Sixty rats were divided into two groups of 30 each according to their dietary regimens. The test group was fed with a high cholesterol-containing diet for two months while the control group had standard diet. These two groups were further divided into three subgroups consisting of ten rats each. After hypercholesterolemia was established, left colon resection and anastomosis were performed in both groups and samples from liver and abdominal aorta were taken to evaluate the systemic effects of hypercholesterolemia. Anastomotic wound healing, blow-out pressures and tissue hydroxyproline levels were evaluated. The test group had a significant weight gain in two months. Microscopic examination of the abdominal aorta revealed no atherosclerotic change in none of the groups, but liver tissue specimens showed significant steatosis in the test group. Tissue hydroxyproline levels and anastomotic blow-out pressures were significantly lower in the test group than in the controls. Hypercholesterolemia not only increases hydroxyproline levels and blow-out pressures but also worsens anastomotic wound healing.

Peroxisome Proliferator-Activated Receptor α L162V Polymorphism in Nonalcoholic Steatohepatitis and Genotype 1 Hepatitis C Virus-Related Liver Steatosis

BackgroundPeroxisome proliferator-activated receptor α (PPARα) plays important roles in lipid metabolism. A recently discovered L162V polymorphism of the PPARα gene is associated with enhanced transcriptional activity. In this study, the...

Histopathologic Features of Hepatic Steatosis in Patients with Hepatitis C Virus Genotype 3 Infection

Purpose: Steatosis is frequently associated with chronic hepatitis C virus (HCV) infection. Studies have suggested steatosis associated with HCV genotype 3 infection may result from a viral etiology, evidenced by regression of steatosis following successful antiviral therapy. Histopathologic features that may distinguish viral from metabolic steatosis in this setting have not been well characterized. The aim of this study was to identify histopathologic features associated with HCV genotype 3 infection that may be attributable to viral steatosis in contrast to metabolic steatosis. Methods: Liver biopsies from 26 treatment-naïve patients with chronic HCV infection were evaluated, including patients infected with genotypes 1 (n = 8), 2 (n = 10), and 3 (n = 8). Histopathologic features including the type, severity, and zonal distribution of steatosis, lobular inflammation, portal inflammation, and fibrosis in all biopsies were evaluated by a single pathologist who was blind to the clinical status of each patient. Clinical and demographic information was obtained from the medical record. Results: Patient age, gender, race, weight, mean ALT levels, fibrosis stage, and necroinflammatory grade did not differ between genotypes. Genotype 1 patients had higher HCV RNA levels compared with genotypes 2 and 3 (p = 0.003). Overall, 13 patients (genotype 1, n = 4; genotype 2, n = 3; and genotype 3, n = 6) had significant macrovesicular steatosis (grades 2/3 and 3/3). The distribution of steatosis in genotype 3 patients was predominantly centrilobular, involving zones 2 and 3 (5/6, 83%), while steatosis occurring in genotype 1 and 2 patients was nonzonal (7/7, 100%; p = 0.005). Genotype 1 and 2 patients tended to have increased portal inflammation compared with genotype 3 patients (56% vs. 25%, p = 0.06). Increasing ALT levels correlated with lobular inflammation in genotype 3 patients (r = 0.76, p = 0.03) and with portal inflammation in both genotype 2 (r = 0.78, p = 0.01) and genotype 3 patients (r = 0.76, p = 0.03). Conclusions: Patients infected with HCV genotype 3 have a predominantly centrilobular (zones 2 and 3) distribution of steatosis, while steatosis in genotypes 1 and 2 appeared nonzonal. Histopathologic differences in patterns and distribution of steatosis among different HCV genotypes may help in identifying features associated with viral versus metabolic hepatic steatosis.

Liver transplantation outcomes using donors after cardiac death

Purpose of review Livers from non-heart-beating donors are a small but increasing component of organs used for transplantation. This review describes the current status and considers potential developments in this area. Recent findings The use of non-heart-beating donors in liver transplantation is largely confined to ‘controlled’ donors with short warm ischemic times, with outcomes which are comparable to transplantation from heart-beating donors. Reports of liver transplantation from ‘uncontrolled’ non-heart-beating donors, with much longer warm ischemia periods, suggest a much poorer outcome. Summary Livers retrieved with short warm ischemia times from controlled non-heart-beating donors can be considered an acceptable source of livers for transplantation. Careful donor selection requires an age limit (preferably <60 years), discarding organs with significant steatosis, minimizing cold ischemia (<8 hours) and selection of stable recipients. With longer warm ischemia times from uncontrolled non-heart-beating donor, the risk of primary non-function is still unacceptably high. The results obtained to date do not justify widespread clinical application and use of uncontrolled non-heart-beating donors should probably be restricted to carefully controlled clinical trials. To realise the much greater potential of uncontrolled non-heart-beating donor, new techniques of resuscitation, preservation and viability assessment will be needed.

Effect of Significant Histologic Steatosis or Steatohepatitis on Response to Antiviral Therapy in Patients With Chronic Hepatitis C

Treatment of chronic hepatitis C (CHC) results in an average sustained viral response (SVR) rate of 54%-63%. Most previous studies have not separately reported SVR rates for patients who have CHC and concomitant significant hepatic steatosis (>33%) or histologic evidence of steatohepatitis (SH). The aim of this study was to evaluate SVR in patients with CHC plus steatosis or SH on biopsy examination, compared with a group of controls with CHC and no significant steatosis or SH. Our surgical pathology database and clinical files were queried for CHC between 1997 to 2002. Biopsy specimens with both CHC and significant steatosis (>33%) or SH were categorized as group 1. Of the patients treated with antiviral therapy, information on either SVR (hepatitis C virus [HCV] RNA negative at 6 months posttreatment) or lack of SVR (nonresponse as early as 12 weeks into therapy and relapsers) with either interferon (IFN)/ribavirin or pegylated IFN/ribavirin was found in 84 patients. A control group (group 2) of 231 CHC patients was identified by using a 2-year database (January 2000-June 2001) of patients without evidence of greater than 33% steatosis or SH. The overall SVR was 28% in group 1, compared with 44% for group 2 ( P = .001). For HCV genotype 1, the SVR was 23% vs 34% for group 2 ( P = .19). For HCV genotypes 2 and 3, the SVR was 42% vs 78% for groups 1 and 2 ( P = .008), respectively. Overall SVR for patients with HCV and significant steatosis or SH is considerably lower than for HCV and steatosis less than 33% and no SH.

Mice Heterozygous for a Defect in Mitochondrial Trifunctional Protein Develop Hepatic Steatosis and Insulin Resistance

Little is known about the role of mitochondrial beta-oxidation in development of nonalcoholic fatty liver disease (NAFLD). Mitochondrial trifunctional protein (MTP) catalyzes long-chain fatty acid oxidation. Recently, we generated a mouse model for MTP deficiency and reported that homozygous (MTPa-/-) mice suffer neonatal death. In this study, we investigated effects of heterozygosity for the MTP defect on hepatic oxidative stress, insulin resistance, and development of NAFLD in mice. We evaluated liver histopathology, serum alanine aminotransferase (ALT), glucose, fatty acids, and insulin levels in MTPa+/- and MTPa+/+ littermates. Insulin resistance was evaluated using glucose tolerance test (GTT) and insulin tolerance test (ITT). Liver tissues were used to measure triglyceride and fatty acid content, activity of superoxide dismutases (SOD) and glutathione peroxidase (GPx), glutathione (GSH), and cytochrome P-450 2E1 expression. Aging but not young MTPa+/- mice developed hepatic steatosis with elevated ALT, basal hyperinsulinemia, and increased insulin area under curve (AUC) on GTT compared with MTPa+/+ littermates. In response to insulin challenge, aging MTPa+/- mice had slower rate of glucose disappearance and increased glucose AUC. Significant hepatic steatosis and insulin resistance developed concomitantly in the MTPa+/- mice at 9-10 months of age. Aging MTPa+/- mice had higher antioxidant activity of total SOD and GPx, lower GSH, and increased expression of cytochrome P-450 2E1, consistent with increased hepatic oxidative stress. Heterozygosity for beta-oxidation defects predisposes to NAFLD and insulin resistance in aging mice. Impairment of mitochondrial beta-oxidation may play an important role in pathogenesis of NAFLD.

Histological Changes in the Liver of Morbidly Obese Patients: Correlation with Metabolic Parameters

Obesity is a major risk factor for fatty liver disease. The purpose of this study was: 1) to determine the degree of steatosis, inflammation and fibrosis in liver biopsies of morbidly obese patients in relation to their body fat distribution and metabolic status, and 2) to examine the course of liver enzyme changes with surgically-induced weight loss. The study population included 179 morbidly obese bariatric surgical patients (82% female, 18% male, mean age 39+/-0.7 (SEM) years, BMI 52+/-0.6 kg/m2, excess body weight 80+/-1.8 kg). All patients tested negative for hepatitis and HIV. Liver biopsies were taken intra-operatively. Hepatic enzyme activities were measured along with lipid parameters, fasting glucose, insulin and leptin. Liver biopsies showed that 47% of morbidly obese females and 85% of males had >30% of hepatocytes filled with fat droplets. Clinically significant hepatic steatosis was associated (P<0.01) with: a) metabolic aberrations, i.e.hyperlipidemia, hyperglycemia, b) male gender, c) abdominal adiposity, and d) elevated hepatic aminotransferase activities. Hepatic inflammation was found in 47% of females and 55% of males, and 'moderate' fibrosis occurred in 12% of males and 6% of females. Postoperatively, the activity of hepatic aminotransferases declined after an initial increase in response to weight loss, with normalization of values occurring at an excess weight loss of 50% (P<0.0001). The majority of morbidly obese patients have >30% steatosis of the liver. The incidence of steatosis is higher for males than females, possibly due to their visceral obesity and associated metabolic aberrations.

Prevention and treatment of HCV recurrence after liver transplantation

Prevention and treatment of HCV recurrence after liver transplantation

Arterialized partial orthotopic liver transplantation in the mouse: A new model and evaluation of the critical liver mass

The availability of a model of partial orthotopic liver transplantation (OLT) in the mouse would be an important tool for studying injuries associated with transplantation. The goals of this study were three-fold: (1) to develop a model of partial OLT in the mouse, (2) to determine the minimal graft volume in this model, and (3) to define the injury associated with small volume incompatible with animal survival. Putative grafts of 30% and 50% were prepared. Their weight was 30 ± 5% and 45 ± 10%, respectively. Subsequently, 30% and 45% syngeneic partial liver grafts were orthotopically transplanted into C57BL/6 mice. Each recipient receiving a 45% graft survived permanently, whereas those receiving only a 30% graft volume died within 2 to 4 days of surgery. Serum transaminase levels normalized in the 45% graft group within 14 days after surgery. In this group, small foci of necrosis and mild steatosis were noted on histology at postoperative day 2, but no abnormalities were noted after 14 days and 100 days. In contrast, recipients who underwent transplantation with a 30% graft volume showed a comparable amount of necrosis and significant microvesicular steatosis in most hepatocytes 2 days after surgery. Hepatocyte proliferation was reduced in this group when compared with animals who underwent transplantation with a 45% graft volume. In conclusion, partial liver transplantation is feasible in the mouse with a critical graft volume ranging between 30% and 45%. Small liver grafts develop massive microvesicular steatosis and impaired regeneration rapidly leading to animal death. (Liver Transpl 2003;9:789-795.)

Dual-echo, chemical shift gradient-echo magnetic resonance imaging to quantify hepatic steatosis: Implications for living liver donation

In living liver donation, a fatty liver poses risks for both recipient and donor. Currently, liver biopsy is the standard for assessing the presence and extent of steatosis. The goals of this study were to correlate a steatosis index derived from magnetic resonance imaging (MRI) to the histologic grade on biopsy as well as to determine the topographic distribution of steatosis within the liver. We examined the ability of dual-echo, chemical shift gradient-echo MRI to predict the degree of steatosis on liver biopsy. A total of 22 subjects received both a liver biopsy and detailed MRI evaluation. These individuals included 15 potential living donors and 7 patients with nonalcoholic fatty liver disease. MRI steatosis index was then compared with histologic grade on liver biopsy. The topographic distribution of hepatic steatosis was determined from those subjects in whom MRI detected hepatic steatosis. The steatosis index had a positive correlation with grade of steatosis on liver biopsy (correlation coefficient, 0.84). There was no significant variation in the degree of steatosis among segments. A steatosis index of >0.2 had good positive and negative predictive value for the presence of significant steatosis (>15%) on biopsy. Our quantitative MRI protocol can predict the degree of hepatic steatosis when it is minimal to moderate, and may obviate the need for liver biopsy for the purpose of quantification of steatosis in living donors. Fat saturation added to the MRI protocol may further improve diagnostic accuracy. This technique may be applicable to the larger population with hepatic steatosis. (Liver Transpl 2003;9:851-856.)

Nonalcoholic fatty liver disease in patients investigated for elevated liver enzymes.

Nonalcoholic fatty liver disease (NAFLD) is a common diagnosis among patients referred to gastroenterology and hepatology clinics for the evaluation of elevated liver enzymes. The diagnosis of NAFLD is supported by blood work to exclude other liver diseases, and by ultrasound evidence of fat in the liver in patients without a significant history of alcohol intake. The gold standard, however, is a liver biopsy to show the typical histological features of NAFLD, which are almost identical to those of alcohol-induced liver damage and can range from mild steatosis to cirrhosis. A variety of retrospective series have linked NAFLD to obesity, diabetes, hyperlipidemia, total parenteral nutrition, jejunoileal bypass surgery and certain medications. A subset of patients with NAFLD that had an initial presentation of elevated liver enzymes was studied. Two hundred and two patients were reviewed, of whom 49 met the inclusion criteria including a liver biopsy. Patients were excluded if insufficient data were available, if the patients had a significant history of ethanol intake or if they had other coexisting liver disease. These patients were seen between 1996 and 2000 in gastroenterology and hepatology clinics in two community hospitals and one regional liver transplant centre in Edmonton, Alberta. NAFLD was associated with a spectrum of changes in the liver ranging from mild steatosis to more significant steatosis with inflammation and fibrosis. Cases of NAFLD with steatosis and mixed inflammatory infiltration but lacking ballooning degeneration or fibrosis were prevalent in young (20 to 40 years of age) patients with no other significant medical history except for obesity. NAFLD with biopsies showing significant fibrosis and ballooning cell degeneration was associated with obesity, diabetes and older age. It was concluded that, in this predominantly outpatient setting, age over 40 years and diabetes at any age are risk factors for both nonalcoholic steatohepatitis and nonalcoholic steatohepatitis with cirrhosis. It is therefore recommended that patients with raised liver enzymes and suspected NAFLD be targeted for liver biopsy in their evaluation.

Liver damage in obese patients.

Hepatic steatosis, nonalcoholic steatohepatitis and cryptogenetic cirrhosis are frequent in an obese population. Therefore, it is wise to submit all obese patients with significant alterations in hepatic function tests to transparietal liver biopsy. The aim of this study is to determine the hepatic conditions of morbidly obese patients during bariatric surgery by means of a wedge liver biopsy, to avoid any eventual hepatic damage being ascribed to the surgical procedure. This prospective study entails 216 consecutive patients, whose work-up included liver function tests, before undergoing vertical gastroplasty and wedge liver biopsy. Histology was assessed for hepatic steatosis, necroinflammatory activity and liver fibrosis/cirrhosis. Abnormal preoperative liver function tests were detected in 65 patients, in 52 unexpectedly. Histologically, significant steatosis was found in 168 patients (77.8%); necroinflammatory activity in 13 (6.0%); liver fibrosis in 46 (21.3%), 5 of whom (2.3%) were found to have an asymptomatic and unknown liver cirrhosis. In morbidly obese patients, the incidence of histological liver damage is very high, despite acceptable liver function tests. In addition to steatosis, however, a "second hit" to induce necrosis and inflammation, favoring the development of significant fibrosis, is not essential. Being obese is an independent risk factor for liver damage and could contribute to liver fibrosis either alone or in association with other insulting factors. The identification of obese patients with septal fibrosis/cirrhosis, at surgery, is of considerable interest in clinical practice, mainly under the aspect of prognosis and liability.

Parenteral nutrition with lipid or glucose suppresses liver growth and response to GH in adolescent male rats.

Our aim was to investigate the effects of modifying the carbohydrate-to-lipid ratio of parenteral nutrition (PN) on body composition and the anabolic actions of insulin-like growth factor I (IGF-I) and growth hormone (GH). Adolescent male Sprague-Dawley rats were randomized to receive 7 days of GH, IGF-I (3.5 mg. kg(-1). day(-1) for both) or placebo while receiving high-carbohydrate PN (CHO-PN), high-lipid PN (L-PN), or an oral diet (chow) (the PN protocols were isonitrogenous and isocaloric). PN impaired muscle growth, which was reversed by GH in the CHO-PN group only (P < 0.03). PN increased carcass lipid (P < 0.02), the effect being greater in the L-PN than in the CHO-PN group (P < 0.001). Visceral lean tissue growth was significantly impaired by PN (P < 0.001). IGF-I reversed this impairment, but GH had no effect. PN impaired the normal increase in hepatic protein and DNA (P < 0.001) and produced liver steatosis (P < 0.001). However, this steatosis was less in L-PN than in CHO-PN (P < 0.001). Serum IGF-I and the acid-labile subunit (ALS) were decreased by PN (P < 0.001) and were not affected by GH during PN treatment. However, GH significantly increased serum ALS concentrations in the chow-fed rats (P = 0.032). In conclusion, modifying the CHO-to-L ratio of PN had no significant effect on IGF-I action, but CHO-PN increased the peripheral effect of GH. L-PN increased carcass lipid significantly and decreased hepatic steatosis. Nevertheless, PN caused significant liver steatosis and profound impairment of hepatic cell growth, which was associated with relative hepatic GH resistance.

The effect of taurine depletion by beta-alanine treatment on the susceptibility to ethanol-induced hepatic dysfunction in rats.

Alcohol was administered chronically to female Sprague-Dawley rats in a nutritionally adequate totally liquid diet for 28 days. This resulted in significant hepatic steatosis and lipid peroxidation. Beta-alanine, when co-administered with alcohol, seemed to increase hepatic steatosis, as assessed histologically, but decreased triglyceride levels as measured biochemically. In addition, beta-alanine and especially alcohol co-administered with beta-alanine, significantly increased homocysteine and cysteine excretion into urine throughout the 28-day period of ethanol administration. Serum homocysteine levels were significantly higher in alcohol- and alcohol plus beta-alanine-treated animals compared to pair-fed control animals. Alcohol did not affect the urinary excretion of taurine, except after 21 days, when levels were reduced. Levels of liver taurine were markedly depleted in animals receiving alcohol and particularly alcohol plus beta-alanine, compared to pair-fed controls. Liver and serum taurine levels were also markedly depleted in animals receiving beta-alanine and alcohol plus beta-alanine, compared to non-beta-alanine-treated animals. There was evidence of slight cholestasis in animals treated with alcohol and more so with alcohol plus beta-alanine, as indicated by raised serum alkaline phosphatase and bile acids. These in vivo findings demonstrate for the first time that animals treated with beta-alanine may be more susceptible to ethanol-induced hepatic dysfunction, possibly as a result of taurine depletion.

CHOLESTASIS AND ALCOHOLIC LIVER DISEASE

Histologic cholestasis and clinical jaundice may be seen in all stages of alcoholic liver disease. In rare cases, isolated cholestasis without significant steatosis, hepatitis, or cirrhosis is identified in an alcoholic patient. The mechanisms of ethanol-induced cholestasis are not well studied but may involve compression of intrahepatic biliary radicals or interference with basolateral uptake and intracellular transport of bile acids. In the evaluation of the jaundiced alcoholic patient, clinical, biochemical, and radiologic data are usually sufficient to distinguish alcohol-induced liver disease from extrahepatic biliary obstruction. In cases where the diagnosis is not readily apparent, more invasive studies such as liver biopsy or ERCP may be necessary. The risk of these invasive studies is directly related to the degree of underlying hepatic dysfunction.

Idiopathic neonatal hepatitis presenting as neonatal hepatic siderosis and steatosis.

Idiopathic neonatal hepatitis (INH) is a heterogeneous disease of undetermined cause. We report a retrospective histologic reevaluation of INH. Sixty patients with INH were reviewed along with 32 biliary atresia (BA) patients. Histologic findings, iron and fat deposits, giant cell transformation, portal fibrosis, and bile duct proliferation were semiquantitatively graded from 0 to 4+. Significant histologic findings were defined as > or =2+. Frequencies of patients with significant histologic findings in the INH group were compared with those of the BA group. Among the patients with significant histologic findings, those in the INH group had significantly less iron deposits (P < 0.01), portal fibrosis (P < 0.01), and bile duct proliferation (P < 0.01) than those of the BA group. A combination of significant hepatic macrovesicular steatosis and siderosis was observed in 10 INH patients but not in any BA patient (10/60 vs 0/32, P < 0.05). Without extensive treatment, the 10 INH patients all recovered, and hepatic abnormalities normalized by the age of 12 months. In conclusion, the present study showed that the recognition of hepatic siderosis is helpful to distinguish BA from INH and that in a subset of INH patients hepatic macrovesicular steatosis and siderosis occurs.

Graft function and outcome of older (> or = 60 years) donor livers.

Livers from donors > or = 60 years of age are often considered inadequate for transplantation by many centers. With waiting times exceeding 1 year in our region, we have aggressively used livers from this donor age group. Between 1990 and 1994, 209 patients received 223 liver grafts at our institution. Of these, 29 (13%) were from donors > or = 60 years of age (group A) and 194 (87%) were from donors < 60 years of age (group B). The two groups were matched for recipient diagnosis and severity of disease. Group A and B donors had similar liver, renal, and hematologic studies prior to donation. Weight, sex, race and vasopressor requirement were also similar. Postoperative alanine aminotransferase, aspartate aminotransferase,and prothrombin time were not significantly different over the first 10 postoperative days. Group A grafts were significantly more cholestatic than group B grafts on postoperative days 6-10. The retransplantation rate for primary graft nonfunction was not significantly different from group A (6.7%) and group B (3.4%; P=0.04). Patient and graft survival rates at 1 year were 58.6 % and 44.8% for group A and 79.2% and 74.5% for group B (P<0.001 for both). Four of 12 deaths in the first year in group A were completely unrelated to graft function. If these are excluded, patient and graft survival rates were 68% and 52%, which are better but still significantly less than in group B. Initial graft function of older donor livers are similar to that of the matched younger group. However, patient and graft survival rates were significantly worse for the older donors, even when corrected for unrelated deaths. Livers should not be discarded based on age alone without inspection and/or biopsy to rule out significant steatosis. Prompt retransplantation for primary graft nonfunction of older donors are generally more cholestatic than those from the younger donor age group; however, many of them function quite well. At the present time, given the inability to identify donor variables associated with decreased recipient survival, we recommend cautious use of older liver grafts in healthier recipients.

Fatal neonatal liver failure and mitochondrial cytopathy (oxidative phosphorylation deficiency): a light and electron microscopic study of the liver.

Mitochondrial cytopathies are multisystemic disorders of extremely variable expression due to a deficiency in oxidative phosphorylation. Cases have recently been reported in which fatal liver failure with neonatal onset was the major clinical and biochemical syndrome. In this series we reviewed the liver histology of 10 such patients who died in the first weeks of life (from 3 days to 6 mo). In six cases the diagnosis was confirmed by study of the mitochondrial respiratory chain in the muscle, liver or both; in the other four, appropriate tests were not available for diagnosis but symptoms were identical and all other diagnoses were ruled out. In all 10 cases we noted significant steatosis, mostly microvesicular; widespread hepatocytic, canalicular and bile duct cholestasis with bile thrombi and cholangiolar proliferation; and different degrees of hepatosiderosis and glycogen depletion. Fibrosis took varying forms: perisinusoidal, periportal with the formation of septa, even precirrhosis. In the two cases of infants who died, one at 5 and one 6 mo, micronodular cirrhosis was also present. Mitochondria, either densely or loosely packed, were abnormal-pleiomorphic with few or no cristae and a granular fluffy matrix. Dense, large granules were seen in two cases. The association of neonatal liver failure and hyperlactacidemia should lead to immediate examination of the respiratory chain. The expression of this mitochondrial cytopathy can be lethal, associated with severe liver damage due to the deficiency in oxidative phosphorylation.