Elizabeth E Hespenheide

A pilot study of a thiazolidinedione, troglitazone, in nonalcoholic steatohepatitis

OBJECTIVES:Troglitazone is a thiazolidinedione and peroxisome proliferator–activated receptor gamma (PPARγ) ligand used to treat diabetes mellitus type II. Because hyperinsulinemia may be a factor in nonalcoholic steatohepatitis (NASH), we postulated that troglitazone could have beneficial effects in this disorder. Our study was initiated before reports of idiosyncratic hepatitis induced by this agent and was completed before its recent withdrawal from the market.METHODS:We studied 10 female patients (age 44 ± 16) with histological NASH. All but two were obese (mean body mass index, BMI = 38 ± 6). One had type 2 diabetes, and three had well-compensated cirrhosis with NASH. Troglitazone was given at a dose of 400 mg/day for ≤6 months. Responders (defined as normal ALT at the end of treatment) were rebiopsied. Paired specimens were compared in blinded fashion. Mitochondria were quantitated using ultrathin electron microscopy.RESULTS:Seven of ten patients responded with normal ALT at the end of treatment. One of three nonresponders initially normalized ALT but returned to pretreatment level at 3 months. In this patient, therapy was stopped, and the ALT has remained at the baseline level with no other clinical or laboratory findings. In the responders, ALT fell from 87 ± 38 before to 39 ± 9 at the end of treatment (p = 0.01), and AST decreased from 77 ± 23 to 30 ± 8 (p = 0.002). Biopsy comparisons before and after therapy showed persistent steatohepatitis in all cases, although four of seven showed a one-point improvement in the necroinflammatory grade. Electron microscopy revealed elongation of the mitochondria after therapy.CONCLUSIONS:Normal ALT was seen in 70% of NASH patients at the end of treatment, but this biochemical response was associated with only mild histological improvement, and all follow-up biopsies had evidence of NASH. Normalization of the liver enzymes in patients with NASH who are treated with thiazolidinediones should be viewed with reservation. Follow-up biopsy is essential to evaluate the efficacy of these agents, which, at the histological level, appears to be relatively modest.

Mitochondrial abnormalities in non-alcoholic steatohepatitis

BACKGROUND/AIMS We assessed mitochondrial morphology by electron microscopy and the prevalence of a mitochondrial gene deletion in patients with non-alcoholic steatohepatitis (NASH), alcohol-related liver disease and non-fatty liver diseases. Respiratory chain function using a cytoplasmic hybrid (cybrid) assay was further studied in NASH patients and healthy controls. METHODS Electron microscopy was performed in 26 specimens. Fifteen patients were studied by polymerase chain reaction to detect a 520-bp deletion product of the mitochondrial genome (dmtDNA). Cybrids were created by fusion of platelets with anaerobic neuroblastoma cells in six NASH patients and 12 controls. RESULTS Eight of ten NASH, one of seven alcoholics and two of nine other patients had linear crystalline inclusions in megamitochondria (p<0.05). Three of five patients with alcohol-related liver disease had dmtDNA compared to one of five NASH patients and one of five non-steatohepatitis controls. Cybrid respiratory chain function in platelets was not different from that of controls. CONCLUSIONS Respiratory chain dysfunction, if present in NASH, is not expressed in platelet-derived mitochondria. In contrast to alcohol-related liver disease with active drinking, NASH patients do not commonly express the 5-kb mitochondrial DNA gene deletion in liver tissue. As previously described in early alcohol-related liver disease, crystalline inclusions of unknown composition are seen in hepatic mitochondria in NASH. Their presence suggests either an adaptive process or mitochondrial injury.

Nonalcoholic steatohepatitis and cryptogenic cirrhosis within kindreds

PURPOSE Familial forms of cryptogenic cirrhosis have been described. We have cared for families in which several members were afflicted with cryptogenic cirrhosis as well as the more recently recognized entity of nonalcoholic steatohepatitis. To examine the familial patterns of these disorders, we reviewed patients with nonalcoholic steatohepatitis, with and without cirrhosis, or cryptogenic cirrhosis to assess how frequently their relatives were afflicted with these disorders. SUBJECTS AND METHODS Eighteen members of eight kindreds containing 2 or more afflicted members were studied. Diagnoses were based on histology in all but 3 patients (2 elderly women with liver atrophy and severe cirrhotic ascites diagnosed clinically with cryptogenic cirrhosis and 1 adult man with abnormal serum aminotransferase levels and hepatomegaly that was diagnosed as fatty liver by ultrasound). Other forms of liver disease were excluded by extensive serologic testing. RESULTS There were 8 index patients (1 man, 7 women; 2 with cryptogenic cirrhosis, 4 with nonalcoholic steatohepatitis with cirrhosis, and 2 with nonalcoholic steatohepatitis without cirrhosis) and 10 relatives (4 men, 6 women; 2 with cryptogenic cirrhosis and 8 with nonalcoholic steatohepatitis). Nonalcoholic steatohepatitis and nonalcoholic steatohepatitis with cirrhosis coexisted within four kindreds, one of which also had an afflicted member with cryptogenic cirrhosis. Nonalcoholic steatohepatitis and cryptogenic cirrhosis coexisted within three additional kindreds. Patterns of afflicted patients included mother-daughter, sister-sister, sister-brother, father-daughter, and male-female cousins. Fifteen (83%) of the 18 subjects were obese, and 11 (61%) had type 2 diabetes mellitus. CONCLUSIONS The coexistence of nonalcoholic steatohepatitis with and without cirrhosis and cryptogenic cirrhosis within these kindreds suggests a common pathogenesis and possible genetic risk. These disorders were frequently but not invariably associated with female sex, obesity, and type 2 diabetes.

Is NASH underdiagnosed among African Americans

OBJECTIVE:Obesity and type 2 diabetes mellitus are considered risk factors for nonalcoholic steatohepatitis (NASH) and cryptogenic cirrhosis. Because obesity and type 2 diabetes are prevalent among African American females by the 5th and 6th decades, one would expect an increased number of African Americans among patients with NASH and cryptogenic cirrhosis.METHODS:We determined the percentage of patients of African American and European American descent among all of the patients in our liver disease registry and those with NASH and cryptogenic cirrhosis. We also assessed the ethnicity of patients in our registry with other common liver diseases including hepatitis C, and we determined the ethnicity of patients seen at our center with type 2 diabetes and a primary diagnosis of obesity over a 4-yr period. Using census data, we compared these results to our local and regional ethnic demographics.RESULTS:Overall, 199 of 2253 patients (9%) in the registry were of African American descent, whereas 1906 were of European American descent (85%). This distribution is similar to the ethnic mix in central Virginia (12% African American, 86% European American) and Albemarle County (12% African American, 83% European American). The prevalence of African American patients among individuals seen at our center for either type 2 diabetes or a primary diagnosis of obesity was over two times the prevalence of African Americans in the county or regional population. In contrast, of 159 NASH patients only one (0.6%) was of African American descent and 154 (97%) were of European American descent (p < 0.001 compared to the total registry, county, or region). Among 206 cryptogenic cirrhosis patients, only two (1%) were of African American descent, whereas 195 (95%) were of European American descent (p < 0.001 compared to the total registry). With regard to other liver diseases, African American patients were slightly overrepresented among hepatitis C patients and markedly overrepresented among patients with hepatic sarcoidosis, similar to previously reported national figures.CONCLUSION:Although there is overrepresentation of African Americans among patients with major risk factors for NASH, individuals of primarily African American descent are infrequently represented among our patients with NASH or cryptogenic cirrhosis. This could result from underrecognition, underreferral, or a true lower prevalence of these disorders among African Americans.

N-2-butyl-cyanoacrylate for bleeding gastric varices: a United States pilot study and cost analysis

OBJECTIVES:N-butyl-2-cyanoacrylate has been reported to be effective for bleeding varices but is not available in the United States. We report the initial US experience with cyanoacrylate in this prospective trial and evaluate its safety, efficacy, and relative costs.METHODS:Patients with active or recent gastric variceal bleeding were eligible. Cyanoacrylate therapy was performed until variceal occlusion was achieved. Rebleeding was assessed at 72 h (acute phase), 6 wk (subacute phase), and 1 yr (chronic phase). Survival was assessed at 3 months and 1 yr. Cost analysis was performed comparing the first 17 patients to historical control patients not treated with cyanoacrylate.RESULTS:A total of 44 patients were enrolled, 37 with cirrhosis and seven with noncirrhotic portal hypertension (NCPH). In cirrhotic patients, rebleeding was seen in two of 37 (5%) at 72 h, one of 30 (3%) at 6 wk, and five of 28 (18%) at 1 yr. Survival without shunt at 3 months was 30 of 34 (88%) and at 1 yr was 24 of 31 (77%). In NCPH patients, rebleeding was seen in two of seven (29%) at 72 h. These patients received definitive therapy for NCPH after diagnosis. Mortality and costs were substantially higher in the non-cyanoacrylate group. The odds of death were greater by 7-fold in the non-cyanoacrylate group than within the cyanoacrylate group (95% CI = 1.18–41.36, p = 0.0318). At 3 months, there was a 3.18-fold difference (95% CI = 1.05–9.64, p = 0.0411) in accrued costs; at 1 yr, the difference was 2.55-fold (95% CI = 0.96–6.94, p = 0.0585). The cost-effective ratio was estimated as

The zonal distribution of megamitochondria with crystalline inclusions in nonalcoholic steatohepatitis

108,237/death averted, reflecting marked cost reduction with improved survival in the cyanoacrylate-treated group. This is believed to result largely from avoidance of shunt interventions.CONCLUSION:Cyanoacrylate treatment of gastric varices is safe, clinically effective, and cost effective.

Subacute liver failure in obese women.

Megamitochondria with crystalline inclusions (MMC) have been previously described in nonalcoholic fatty liver; however, their distribution within hepatic zones is unknown. We sought to determine this distribution from the core liver biopsy specimens of 31 patients: 8 males and 23 females, age range 21 to 72 years. Twenty‐nine showed evidence of nonalcoholic steatohepatitis (NASH) on biopsy with steatosis, inflammation, varying degree of fibrosis, ballooned hepatocytes, and Mallory hyaline, and two patients had cryptogenic cirrhosis thought to represent “burned out” NASH. Identified by transmission electron microscopy, the abundance of MMC was compared between low‐stage (fibrosis stages 1 and 2) and high‐stage (fibrosis stages 3 and 4) groups and between zones with or without difference in fibrosis stage. Regardless of stage, the MMC were distributed equally in all zones and were abundant similarly in low‐ and high‐stage groups. This abundance did not correlate with the degree of oxidative stress (4‐hydroxynonenal staining) or with the abundance of ballooned hepatocytes. Consistent with age as a risk factor for more severe disease, the median age for the low‐stage group was significantly lower than that of the high‐stage group (P = .003). In conclusion, in NASH, the MMC seem to be distributed randomly among zones and without variation in abundance, regardless of the fibrosis stage. The exact function of these structures remains to be defined. In this study, their presence did not seem to correlate with the light microscopic injury pattern represented by ballooned hepatocytes or degree of oxidative stress defined by immunostaining for 4‐hydroxynonenal. (HEPATOLOGY 2004;39:1423–1429.)

Enbucrilate for gastric varices: extended experience in 92 patients

OBJECTIVES:Steatosis or steatohepatitis, common conditions associated with obesity, are usually considered to be stable or only slowly progressive. We have encountered a small number of patients with a history of obesity and a subacute course of liver failure over a period of 4–16 wk from the onset of symptoms. The patients had findings suggestive of an acute exacerbation of previously unrecognized nonalcoholic steatohepatitis (NASH).METHODS:The patients were ascertained from our liver disease registry, which, at the time of the study, contained 2380 patients: 167 had NASH and 215 had cryptogenic cirrhosis. Five of these patients were identified with a subacute course of their illness.RESULTS:The patients were female, aged 41–65 yr, and obese (BMI >30, mean 41 ± 9, range 32–52). One patient had type 2 diabetes treated by diet alone and one had a history of glucose intolerance. None had known prior liver disease and two had no prior medical problems. All five presented with fatigue and lethargy. Over 4–16 wk, the patients developed frank encephalopathy, ascites, jaundice, and multiorgan failure. An extensive evaluation revealed no clear etiology of their disease, although initial imaging studies consistently showed evidence of previously unrecognized cirrhosis. Four patients died from complications of liver failure and the fifth patient underwent OLT. Histology revealed cirrhosis with variable numbers of balloon cells in all five patients, frank steatohepatitis in three, necrosis in two, and microvesicular (with macrovesicular) steatosis in one.CONCLUSIONS:These patients, all obese and middle-aged women with no history of liver disease, had previously unrecognized cirrhosis and sudden deterioration of uncertain cause. We speculate, based on the clinical and histological findings, that these patients had undiagnosed NASH with silent progression to cirrhosis followed by subacute liver failure. We propose that obesity-related liver disease may infrequently present as severe, subacute illness.

CASE REPORT: Myositis, Microvesicular Hepatitis, and Progression to Cirrhosis from Troglitazone Added to Simvastatin

Aim We assessed N‐2‐butyl‐cyanoacrylate (enbucrilate) in 92 patients with gastric variceal bleeding under an FDA‐approved investigation. These results extend our prior report of the first 44 patients.

Imaging and clinical characteristics of focal atrophy of segments 2 and 3 in primary sclerosing cholangitis

A 68-year-old woman, with type 2 diabetes mellitus, hypercholesterolemia, and prior long-term simvastatin therapy, self-resumed troglitazone after running out of metformin. She developed an acute severe hepatitis with microvesicular steatosis and mysositis. There was subsequent resolution of the myositis but progression of the hepatitis to symptomatic cirrhosis over a period of 12 weeks. Both troglitazone and simvastatin are metabolized by cytochrome P-450 3A4. Troglitazone typically induces metabolism of drugs metabolized by this cytochrome so that simple simvastatin toxicity seems less likely to have been involved. The association with myositis, the severity of the hepatitis with progression to cirrhosis, and the presence of microvesicular steatosis suggests altered mitochondrial metabolism, which has been described with each agent, as the underlying pathogenic mechanism. Although troglitazone (Rezulin) has been withdrawn from the market, other similar agents are available for therapy of type 2 diabetes mellitus. Increased awareness of a potential interaction between these two classes of drugs is warranted.