We characterized 70 consecutive patients with cryptogenic cirrhosis to assess major risks for liver disease. Each patient was reevaluated for past alcohol exposure, scored by the International Autoimmune Hepatitis (IAH) score and assessed for viral hepatitis risks and risks for nonalcoholic steatohepatitis (NASH). The results were compared with 50 consecutive NASH patients, 39 nonalcoholic patients age 50 and over with cirrhosis from hepatitis C, and 33 consecutive patients with cirrhosis caused by primary biliary cirrhosis (PBC). Among the cryptogenic group, 49 (70%) were female, and the mean age was 63 ؎ 11 years. Although ascites and variceal bleeding were common, almost one half lacked major signs of complicated portal hypertension. A history of Type 2 diabetes mellitus and/or obesity was present in 51 (73%). Nineteen (27%) patients had a history of blood transfusions antedating the diagnosis of cirrhosis. No clinical or histological features distinguished this group from the other patients, and 14 (74%) of these had a history of obesity and/or diabetes. Nineteen of the remaining nontransfused patients had indeterminant IAH scores but were histologically and biochemically indistinguishable from the others. Twelve of these (63%) also had a history of obesity and/or diabetes. Both diabetes and obesity were significantly more common in the cryptogenic cirrhotic patients compared with the cirrhotic patients with PBC or hepatitis C. In contrast, the prevalence of obesity and diabetes was similar to the NASH patients who were, on average, a decade younger. Although there is some diversity that indicates more than one cause, our findings suggest that NASH plays an under-recognized role in many patients with cryptogenic cirrhosis, most of whom are older, type 2 diabetic and obese females. (HEPATOLOGY 1999;29:664-669.)

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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.

Severe coagulopathy in fulminant hepatic failure (FHF) is difficult to correct by conventional means. Recombinant activated factor VII (rFVIIa) is an antihemophilic factor that has shown promise in treating coagulopathy in liver disease. Our aim is to review our experience with rFVIIa in treating the coagulopathy of FHF and compare these results with those of conventional therapy. Fifteen patients with FHF who met King's College criteria for orthotopic liver transplantation were studied. All were ascertained from our liver disease registry. Eight consecutive patients were administered fresh frozen plasma (FFP) alone, whereas seven consecutive patients were administered FFP and rFVIIa (40 g/kg intravenous bolus). The two groups, with similar demographic characteristics, were compared in terms of measured parameters of coagulopathy (prothrombin time and international normalized ratio), amount of plasma infused, development of anasarca, ability to undergo intracranial pressure (ICP) transducer placement, bleeding complications, ability to undergo transplantation, and survival. All patients administered rFVIIa (after a single dose) versus none administered FFP alone had temporary (2-to 6-hour) correction of coagulopathy (P < .0002). All patients administered rFVIIa versus 38% administered FFP alone were able to have an ICP transducer placed (P ‫؍‬ .03). The rFVIIa group had less anasarca (P ‫؍‬ .04). An equal number of patients underwent transplantation from each group, but overall survival was slightly better in the rFVIIa group (P ‫؍‬ .04). Five of seven patients in the rFVIIa group were administered one or more subsequent doses of rFVIIa after placement of the ICP monitor (two patients, for additional procedures; three patients, prophylactically in the first 24 hours after ICP transducer placement) at the discretion of the attending physicians. We conclude that rFVIIa is effective in transiently correcting laboratory parameters of coagulopathy in patients with FHF. It facilitates the performance of invasive procedures and is associated with less frequent anasarca compared with conventional therapy. Our preliminary experience supports the need for further studies to define the optimal dosing, safety, and efficacy of rFVIIa in patients with FHF. (Liver Transpl 2003;9:138-143.)

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

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.

Summary 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. Method Injection was performed with enbucrilate and ethiodol (1:1). Eighty patients had portal hypertension and 12 had splenic vein thrombosis. Results In the portal hypertensive group, re‐bleeding from gastric varices was seen in 4 of 80 (5%) from 0 to 72 h, 5 of 76 (6.5%) from > 72 h to 3 months and 9 of 51 (17%) from > 3 months to 1 year. Re‐bleeding and survival were significantly related to the Child‐Pugh class. In the splenic vein thrombosis group (n = 12), there was early rebleeding in 2 (17%) patients from 0 to 72 h, 1 (8%) from > 72 h to 3 months and none in the chronic phase (> 3 months to 1 year) although 1‐year survival in this group was only 6 (50%) due to the underlying malignancy in most. Serious embolization was suspected in 2 patients (2%). Conclusion Enbucrilate offers an important intervention in gastric variceal bleeding which should be further studied in the US. A randomized trial is warranted to compare this intervention to radiological therapy.