Phunchai Charatcharoenwitthaya

Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS Histologic analysis of liver biopsy specimens allows for grading and staging of nonalcoholic fatty liver disease (NAFLD). We performed a longitudinal study to investigate the long-term prognostic relevance of histologic features for patients with NAFLD. METHODS We performed a retrospective analysis of 619 patients diagnosed with NAFLD from 1975 through 2005 at medical centers in the United States, Europe, and Thailand. Patients underwent laboratory and biopsy analyses, and were examined every 3-12 months after their diagnosis. Outcomes analyzed were overall mortality, liver transplantation, and liver-related events. Cumulative outcomes were compared by log-rank analysis. Cox proportional-hazards regression was used to estimate adjusted hazard ratios (HRs). Time at risk was determined from the date of liver biopsy to the date of outcome or last follow-up examination. RESULTS Over a median follow-up period of 12.6 years (range, 0.3-35.1 y), 193 of the patients (33.2%) died or underwent liver transplantation. Features of liver biopsies significantly associated with death or liver transplantation included fibrosis stage 1 (HR, 1.88; 95% confidence interval [CI], 1.28-2.77), stage 2 (HR, 2.89; 95% CI, 1.93-4.33), stage 3 (HR, 3.76; 95% CI, 2.40-5.89), and stage 4 (HR, 10.9; 95% CI, 6.06-19.62) compared with stage 0, as well as age (HR, 1.07; 95% CI, 1.05-1.08), diabetes (HR, 1.61; 95% CI, 1.13-2.30), current smoking (HR, 2.62; 95% CI, 1.67-4.10), and statin use (HR, 0.32; 95% CI, 0.14-0.70). Twenty-six patients (4.2%) developed liver-related events; fibrosis stage 3 (HR, 14.2; 95% CI, 3.38-59.68) and stage 4 (HR, 51.5; 95% CI, 9.87-269.2) compared with stage 0, were associated significantly with the events. Patients with fibrosis, regardless of steatohepatitis or NAFLD activity score, had shorter survival times than patients without fibrosis. CONCLUSIONS In a longitudinal study of patients with NAFLD, fibrosis stage, but no other histologic features of steatohepatitis, were associated independently with long-term overall mortality, liver transplantation, and liver-related events.

The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years.

Objectives: The long-term prognosis of non-alcoholic fatty liver disease (NAFLD) in children remains uncertain. We aimed at determining the long-term outcomes and survival of children with NAFLD. Design: Retrospective longitudinal hospital-based cohort study. Patients: Sixty-six children with NAFLD (mean age 13.9 (SD 3.9) years) were followed up for up to 20 years with a total of 409.6 person-years of follow-up. Results: The metabolic syndrome was present in 19 (29%) children at the time of NAFLD diagnosis with 55 (83%) presenting with at least one feature of the metabolic syndrome including obesity, hypertension, dyslipidaemia and/or hyperglycaemia. Four children with baseline normal fasting glucose developed type 2 diabetes 4–11 years after NAFLD diagnosis. A total of 13 liver biopsies were obtained from five patients over a mean of 41.4 (SD 28.8) months showing progression of fibrosis stage in four children. During follow-up, two children died and two underwent liver transplantation for decompensated cirrhosis. The observed survival free of liver transplantation was significantly shorter in the NAFLD cohort as compared to the expected survival in the general United States population of the same age and sex (log-rank test, p<0.00001), with a standardised mortality ratio of 13.6 (95% confidence interval, 3.8 to 34.8). NAFLD recurred in the allograft in the two cases transplanted, with one patient progressing to cirrhosis and requiring re-transplantation. Conclusions: Children with NAFLD may develop end-stage liver disease with the consequent need for liver transplantation. NAFLD in children seen in a tertiary care centre may be associated with a significantly shorter survival as compared to the general population.

The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: An international collaborative study†‡§

Information on the long‐term prognosis of nonalcoholic fatty liver disease (NAFLD) is limited. We sought to describe the long‐term morbidity and mortality of patients with NAFLD with advanced fibrosis or cirrhosis by prospectively studying 247 such patients from four international centers (in Australia, USA, UK and Italy). Their natural history was then compared with 264 patients with HCV infection who were either naïve or non‐responders to treatment. Both cohorts were Child‐Pugh class A and had advanced fibrosis (stage 3) or cirrhosis (stage 4) confirmed by liver biopsy at enrollment. In the NAFLD cohort, followed up for a mean of 85.6 months (range, 6‐297), there were 48 (19.4%) liver‐related complications and 33 (13.4%) deaths or liver transplants. In the HCV cohort, followed up for 74.9 months (mean; range, 6‐238), there were 47 (16.7%) liver‐related complications and 25 (9.4%) deaths or liver transplants. When adjusting for baseline differences in age and gender, the cumulative incidence of liver‐related complications was lower in the NAFLD than the HCV cohort (P = 0.03), including incident hepatocellular cancer (6 versus 18; P = 0.03), but that of cardiovascular events (P = 0.17) and overall mortality (P = 0.6) were similar in both groups. In the NAFLD cohort, platelet count, stage 4 fibrosis, lowered platelet count, and lowered serum cholesterol and alanine aminotrasferase (ALT) levels were associated with liver‐related complications; an aspartate aminotransferase/ALT ratio >1 and older age were associated with overall mortality, and higher serum bilirubin levels and stage 4 fibrosis were associated with liver‐related mortality. Conclusions: Patients with NAFLD with advanced fibrosis or cirrhosis have lower rates of liver‐related complications and hepatocellular cancer than corresponding patients with HCV infection, but similar overall mortality. Some clinical and laboratory features predict liver‐related complications and other outcomes in patients with NAFLD. (HEPATOLOGY 2011;54:1208–1216)

Utility of serum tumor markers, imaging, and biliary cytology for detecting cholangiocarcinoma in primary sclerosing cholangitis

There is limited information on test performance for detecting cholangiocarcinoma in primary sclerosing cholangitis (PSC), particularly when used sequentially. This study aimed to characterize diagnostic performance of serum carbohydrate antigen 19‐9 (CA 19‐9), ultrasonography, computed tomography, magnetic resonance imaging, cholangiography, and biliary cytologic techniques for detecting cholangiocarcinoma in PSC. All consecutive patients with PSC were screened and followed for development of cholangiocarcinoma from 2000 through 2006. Of 230 patients, 23 developed cytopathologically confirmed cholangiocarcinoma with an annual incidence of 1.2%. The optimal cutoff value for serum CA 19‐9 was 20 U/mL, which yielded a sensitivity of 78%, specificity of 67%, positive predictive value (PPV) of 23%, and negative predictive value (NPV) of 96%. Serum CA 19‐9 combined with either ultrasonography, computed tomography, or magnetic resonance imaging provided a sensitivity of 91%, 100%, and 96%, specificity of 62%, 38%, and 37%, PPV of 23%, 22%, and 24%, and NPV of 98%, 100%, and 98%, respectively, if at least one method was positive. Subsequent cholangiographic examinations in these patients increased specificity to 69% and PPV to 42% while maintaining sensitivity of 91% and NPV of 96%. Following this group, conventional cytology, aneuploidy detection by digital imaging analysis, and aneusomy detection by fluorescence in situ hybridization in brushing samples of biliary strictures had a sensitivity of 50%, 57%, and 86%, specificity of 97%, 94%, and 83%, PPV of 86%, 89%, and 80%, and NPV of 83%, 74%, and 88%, respectively, for detecting cholangiocarcinoma. Conclusion: Tumor serology combined with cross‐sectional liver imaging may be useful as a screening strategy and cholangiography with cytologic examination is helpful for the diagnosis of cholangiocarcinoma in patients with PSC. (HEPATOLOGY 2008.)

Nonalcoholic fatty liver disease increases risk of death among patients with diabetes: a community-based cohort study.

OBJECTIVES:The significance of nonalcoholic fatty liver disease (NAFLD) among patients with diabetes is unknown. We sought to determine whether a diagnosis of NAFLD influenced mortality among a community-based cohort of patients with type II diabetes mellitus.METHODS:A total of 337 residents of Olmsted County, Minnesota with diabetes mellitus diagnosed between 1980 and 2000 were identified using the Rochester Epidemiology Project and the Mayo Laboratory Information System, and followed for 10.9±5.2 years (range 0.1–25). Survival was analyzed using Cox proportional hazards modeling, with NAFLD treated as a time-dependent covariate.RESULTS:Among the 337 residents, 116 were diagnosed with NAFLD 0.9±4.6 years after diabetes diagnosis. Patients with NAFLD were younger, and more likely to be female and obese. Overall, 99/337 (29%) patients died. In multivariate analysis to adjust for confounders, overall mortality was significantly associated with a diagnosis of NAFLD (hazard ratio (HR) 2.2; 95% confidence interval (CI) 1.1, 4.2; P=0.03), presence of ischemic heart disease (HR 2.3; 95% CI 1.2, 4.4), and duration of diabetes (HR per 1 year, 1.1; 95% CI 1.03, 1.2). The most common causes of death in the NAFLD cohort were malignancy (33% of deaths), liver-related complications (19% of deaths), and ischemic heart disease (19% of deaths). In adjusted multivariate models, NAFLD was borderline associated with an increased risk of dying from malignancy (HR 2.3; 95% CI 0.9, 5.9; P=0.09) and not from cardiovascular disease (HR 0.9; 95% CI 0.3, 2.4; P=0.81).CONCLUSIONS:The diagnosis of NAFLD is associated with an increased risk of overall death among patients with diabetes mellitus.

Nonalcoholic Steatohepatitis in Children: A Multicenter Clinicopathological Study

Nonalcoholic fatty liver disease (NAFLD) may have distinct histological features in children and adults, but to date limited data are available on the spectrum and significance of histological lesions in pediatric patients. We conducted a multicenter study of children with well‐characterized, biopsy‐proven NAFLD to (1) assess the presence and significance of a constellation of histological lesions and (2) identify clinical and laboratory predictors of disease severity. One hundred thirty children with NAFLD seen from 1995 to 2007 in five centers in the United States and Canada were studied. Clinical and laboratory data were collected. Slides stained with hematoxylin‐eosin and trichrome were evaluated by two liver pathologists. The NAFLD activity score (NAS) and the pattern of liver injury (type 1 or adult versus type 2 or pediatric nonalcoholic steatohepatitis [NASH]) were recorded. Fibrosis was staged using a published 7‐point scale. The median age was 12 years (range, 4‐18 years); 63% were boys, and 52% were Caucasian. Fibrosis was present in 87% of patients; of these, stage 3 (bridging fibrosis) was present in 20%. No patient had cirrhosis. The median NAS was 4. Overlapping features of both type 1 (adult pattern) and type 2 (pediatric pattern) NASH were found in 82% of patients. Compared with patients with no or mild fibrosis, those with significant fibrosis were more likely to have higher lobular and portal inflammation scores (P < 0.01), perisinusoidal fibrosis (P < 0.001), and NAS ≥5 (P < 0.005). Serum aspartate aminotransferase levels were the only clinical or laboratory data that independently predicted severity of fibrosis (P = 0.003). Conclusion: Our results highlight the limitations of published proposals to classify pediatric NAFLD, and identified histological lesions associated with progressive disease. (HEPATOLOGY 2009.)

Long‐term survival and impact of ursodeoxycholic acid treatment for recurrent primary biliary cirrhosis after liver transplantation

The recurrence of primary biliary cirrhosis (PBC) in the hepatic allograft may impact patient and graft survival with long‐term follow‐up. The efficacy of ursodeoxycholic acid (UDCA) for treatment of recurrent PBC after liver transplantation (LT) remains less well known. The aims of this study were as follows: 1) to determine the significance of recurrent PBC on overall survival among PBC patients who underwent LT, and 2) to determine the efficacy of UDCA treatment after LT in patients with recurrent PBC. A retrospective cohort study was conducted of 154 PBC patients who underwent LT with at least 1 yr of follow‐up after transplantation from 1985 through 2005. A total of 52 patients with recurrent PBC were identified. After adjusting for age and gender, recurrent PBC was not associated with death or liver retransplantation (hazard ratio, 0.97, 95% confidence interval, 0.41–2.31; P = 0.9). A total of 38 patients with recurrent PBC received UDCA at an average dose of 12 mg/kg/day for a mean duration of 55 months. Over a 36‐month period, an estimated 52% of UDCA‐treated patients experienced normalization of serum alkaline phosphatase and alanine aminotransferase compared to 22% of untreated patients. There was no significant difference in the rate of histological progression between subgroups. UDCA did not influence patient and graft survival. In conclusion, the development of recurrent PBC has little impact on long‐term survival or need for retransplantation. While UDCA therapy is associated with biochemical improvement, its role in delaying histologic progression remains unknown. In this short period of treatment, UDCA was not associated with improved patient and graft survival compared to untreated patients. Liver Transpl 13:1236–1245, 2007.

Low Circulating Levels of Dehydroepiandrosterone in Histologically Advanced Nonalcoholic Fatty Liver Disease

The biological basis of variability in histological progression of nonalcoholic fatty liver disease (NAFLD) is unknown. Dehydroepiandrosterone (DHEA) is the most abundant steroid hormone and has been shown to influence sensitivity to oxidative stress, insulin sensitivity, and expression of peroxisome proliferator‐activated receptor alpha and procollagen messenger RNA. Our aim was to determine whether more histologically advanced NAFLD is associated with low circulating levels of DHEA. Serum samples were obtained prospectively at the time of liver biopsy in 439 patients with NAFLD (78 in an initial and 361 in validation cohorts) and in controls with cholestatic liver disease (n = 44). NAFLD was characterized as mild [simple steatosis or nonalcoholic steatohepatitis (NASH) with fibrosis stage 0‐2] or advanced (NASH with fibrosis stage 3‐4). Serum levels of sulfated DHEA (DHEA‐S) were measured by enzyme‐linked immunosorbent assay. Patients with advanced NAFLD had lower plasma levels of DHEA‐S than patients with mild NAFLD in both the initial (0.25 ± 0.07 versus 1.1 ± 0.09 μg/mL, P < 0.001) and validation cohorts (0.47 ± 0.06 versus 0.99 ± 0.04 μg/mL, P < 0.001). A “dose effect” of decreasing DHEA‐S and incremental fibrosis stage was observed with a mean DHEA‐S of 1.03 ± 0.05, 0.96 ± 0.07, 0.83 ± 0.11, 0.66 ± 0.11, and 0.35 ± 0.06 μg/mL for fibrosis stages 0, 1, 2, 3, and 4, respectively. All patients in both cohorts in the advanced NAFLD group had low DHEA‐S levels, with the majority in the hypoadrenal range. The association between DHEA‐S and severity of NAFLD persisted after adjusting for age. A relationship between disease/fibrosis severity and DHEA‐S levels was not seen in patients with cholestatic liver diseases. Conclusion: More advanced NAFLD, as indicated by the presence of NASH with advanced fibrosis stage, is strongly associated with low circulating DHEA‐S. These data provide novel evidence for relative DHEA‐S deficiency in patients with histologically advanced NASH. (HEPATOLOGY 2008;47:484–492.)

Colon Neoplasms Develop Early in the Course of Inflammatory Bowel Disease and Primary Sclerosing Cholangitis

BACKGROUND & AIMS Colon cancer surveillance guidelines for patients with inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC) suggest annual colonoscopy once the diagnosis of concomitant disease is made, but there is little evidence to support this recommendation. We conducted a retrospective review of patients with colonic neoplasms (colon cancer or dysplasia) to test this guidelines validity and determined when colonic neoplasms occurred in the population. METHODS Records were retrospectively reviewed from 54 patients with IBD, PSC, and colonic neoplasia for dates of diagnosis of IBD, PSC, and colon neoplasia and descriptive information about the colon neoplasms that developed. RESULTS The occurrence of colon neoplasms within 2 years of diagnosis of IBD and PSC (21.5 per 100 patient years of follow-up) was similar to the occurrence within 8 to 10 years from diagnosis of IBD and PSC (20.4 per 100 patient years of follow-up). The colonic neoplasms that developed in this population were spread throughout the colon. CONCLUSIONS Patients with IBD and PSC have a risk of developing colonic neoplasms soon after the coexistence of the 2 diseases is discovered. This finding supports the current colon cancer surveillance guideline recommendations of yearly colonoscopies for this patient population, beginning at the time of diagnosis of PSC in patients with IBD or with the diagnosis of IBD in patients with PSC.

Relations of steatosis type, grade, and zonality to histological features in pediatric nonalcoholic fatty liver disease.

Background: The relations between hepatic steatosis and histological features of hepatocyte injury in children with nonalcoholic fatty liver disease have yet to be examined. The aims of the present study were to establish associations between steatosis amount, type, and distribution in a well-characterized group of children with biopsy-proven nonalcoholic fatty liver disease (NAFLD). Patients and Methods: One hundred eight children with NAFLD seen in 5 centers were studied. Clinical and laboratory data were collected. Hematoxylin-eosin and Masson trichrome stains were evaluated by 2 expert liver pathologists. Steatosis grade (0–3), type (macrovesicular, microvesicular, or mixed), and zone (1, 3, azonal, or panacinar) were determined. The NAFLD activity score and fibrosis stage were determined. Results: Median patient age was 12 years and median body mass index was 31 kg/m2. Fibrosis was present in 87%. The median NAFLD activity score was 4. Mild, moderate, and severe steatosis were present in 42%, 34%, and 24% of biopsies, respectively. Macrovesicular steatosis was present in 81% and mixed steatosis was present in 19%. Panacinar distribution of steatosis was most frequent (40%), followed by azonal (27%). Steatosis grade positively correlated with portal inflammation (P = 0.018). Azonal distribution positively correlated with presence of hepatocyte ballooning (P = 0.03). Biopsies with mixed steatosis were approximately 20 times more likely to have megamitochondria than those with macrovesicular steatosis alone (95% confidence interval 2.3–204.9). There was no relation between steatosis amount, type, or distribution to fibrosis stage. Conclusions: Specific histological patterns of steatosis in children are associated with histological markers of steatohepatitis. Ballooning and portal inflammation correlated well with features of steatosis.