Nonalcoholic steatohepatitis (NASH) is often linked with disorders that are clearly associated with insulin resistance (IR): obesity, type 2 diabetes mellitus, and hypertriglyceridemia. We tested the hypotheses that (1) IR is an essential requirement for the development of NASH and (2) a high association between IR and liver disease is relatively specific for NASH. We measured body mass index (BMI), waist/hip ratio, and fasting serum lipid, insulin, C-peptide, and glucose levels in 66 patients with NASH (21 with advanced fibrosis and 45 with mild fibrosis). IR was determined by the homeostasis model assessment (HOMA). We also determined the strength of the association of NASH with insulin resistance syndrome (IRS) as defined by World Health Organization criteria. To assess whether the finding of IR was relatively specific to NASH rather than simply to obesity or liver disease, we compared the results of a subset of 36 patients with less-severe NASH with 36 age-and sex-matched patients with chronic hepatitis C virus (HCV) of comparable fibrotic severity. IR was confirmed in 65 patients (98%) with NASH, and 55 (87%) fulfilled minimum criteria for IRS. IR was found in lean as well as in overweight and obese patients. The IR values and the prevalence of IRS (75% vs. 8.3%) were significantly higher in those with NASH than in comparable cases of HCV. Hyperinsulinemia was attributable to increased insulin secretion rather than decreased hepatic extraction. N onalcoholic steatohepatitis (NASH) is characterized by morphological features indistinguishable from alcoholic liver disease in individuals who do not consume excess alcohol. 1 NASH can progress to cirrhosis, and death from liver failure is now the second-leading cause of death in these patients. 2 Although the prevalence of NASH appears to be increasing, the etiopathogenesis remains poorly understood.Associations with drug toxicity, weight-reducing operations, lipodystrophy, and other uncommon inherited syndromes are well documented but are rarely present in most patients with NASH. [1][2][3][4][5][6][7][8] Rather, attention has been drawn to the increased prevalence of common metabolic disorders in the "typical" patient with NASH. [1][2][3][4][5][6][7] Autopsy data indicate that NASH is at least 6 times more prevalent in obese individuals compared with lean subjects. 7 Type 2 diabetes mellitus or abnormalities of glucose tolerance are present in up to one third of patients with NASH, 8 often with hypertriglyceridemia and/or hypercholesterolemia. 9,10 The above metabolic disorders are also cardiovascular risk factors and often cluster together as syndrome X, which includes impaired glucose tolerance, dyslipidemia, and hypertension. 11 This disease cluster is also referred to as the metabolic or insulin resistance syndrome (IRS); the latter highlights a central role for insulin resistance (IR) in this disorder. 12,13 The expanded formulation of IRS includes central (visceral or truncal) adiposity, lipid abnormalities, hyperuricemia, polycystic ovarian syndrome, and...

There is conflicting evidence regarding inheritance of hemochromatosis gene (HFE) mutations and influence of hepatic iron deposition as cofactors for development of fibrosis in patients with nonalcoholic steatohepatitis (NASH). We studied hepatic iron content (Perls' stain grade), frequency of HFE mutations, and serum iron indices in 93 patients with NASH from a multiethnic background; 59 (63%) were of Anglo-Celtic origin. Data on C282Y mutations were available for all 93 patients and on H63D for 69 patients. Respective controls were 206 (for C282Y, 141 [69%] of whom were Anglo-Celtic) and 180 (for H63D) blood donors. Hyperferritinemia was present in 38 patients (40%) with NASH, but transferrin saturation was increased (>55%) in only 5 (5%). Liver biopsy specimens showed advanced fibrosis in 31 (33%) (cirrhosis in 20%). Altogether, 9 biopsy specimens (10%) showed increased iron: 7 (8%) with grade 2 and 2 (2%) with grade 3 iron staining. Only 1 biopsy specimen with increased iron showed advanced fibrosis. The frequency of C282Y heterozygosity was increased in Anglo-Celtic patients with NASH compared with ethnic blood donor controls (22% vs. 9.2%; P ‫؍‬ .035); there were no C282Y homozygotes in the NASH cohort. Although there was a trend toward higher serum ferritin levels among C282Y heterozygotes with NASH, there were no differences in histologic grades of steatosis, inflammation, or fibrosis between individuals with and without C282Y. The frequencies of compound C282Y/H63D heterozygotes (n ‫؍‬ 1) or H63D heterozygotes (n ‫؍‬ 10) were not increased in NASH. Multivariate analysis identified female sex, diabetes mellitus, and more severe liver inflammation but not HFE mutations, serum ferritin, iron saturation, or hepatic iron staining as independent predictors of hepatic fibrosis. In conclusion, hepatic iron is not a factor linked to hepatic fibrogenesis in patients with NASH. HFE mutations do not confer an additional risk of hepatic fibrosis in this disorder. (HEPATOLOGY 2002;36:142-149.)

Introduction: Cajal like cells (CLCs) in the upper urinary tract have an ability to generate coordinated spontaneous action potentials and are hypothesized to help propel urine from renal pelvis into the ureter. The objective of this review was to describe the variations in the density and distribution of CLCs associated with ureteropelvic junction obstruction (UPJO).Materials and Methods: Studies comparing the density and distribution of CLCs in the human upper urinary tract in patients with UPJO and healthy controls were included in this systematic review. We searched online electronic databases; Ovid MEDLINE, Scopus, PubMed and Cochrane reviews for the studies published before October 31, 2020. A meta-analysis was conducted to compare the density of CLCs at the ureteropelvic junction (UPJ) in patients with UPJO and matched controls.Results: We included 20 and seven studies in the qualitative and quantitative synthesis, respectively. In majority (55%) CLCs were located between the muscle layers of the upper urinary tract. The CLC density in the UPJ gradually increased with aging in both healthy subjects and patients with UPJO. The pooled analysis revealed that the density of CLCs at the UPJ was significantly low in patients with UPJO compared to the controls (SMD = −3.00, 95% CI = −3.89 to −2.11, p < 0.01).Conclusions: The reduction in CLC density at the UPJ in patients with UPJO suggests a contribution from CLCs in the pathogenesis of UPJO. Since age positively correlates with CLC density, it is imperative to carefully match age when conducting case control studies comparing the CLC density and distribution.Protocol Registration Number: CRD42020219882.

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