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doi:10.1111/jgh.12978

H E PAT O L O G Y

Clinical outcomes of cryptogenic compared with non-cryptogenic cirrhosis: A retrospective cohort study Omar Kadhim Mohammed and Sanjiv Mahadeva Division of Gastroenterology, Department of Medicine, Faculty of Medicine, University Malaya, Kuala Lumpur, Malaysia

Key words clinical burden, cryptogenic cirrhosis, metabolic syndrome, non-alcoholic fatty liver disease. Accepted for publication 17 March 2015. Correspondence Dr Sanjiv Mahadeva, Division of Gastroenterology, Department of Medicine, Faculty of Medicine, University Malaya, Kuala Lumpur 50603, Malaysia. Email: [email protected]

Abstract Background and Aim: The consequences of the association between the metabolic syndrome and cryptogenic cirrhosis are uncertain. We aimed to compare the differences in clinical outcomes between cryptogenic and non-cryptogenic cirrhosis. Methods: A retrospective cohort study was conducted in a large, single academic center, over a 5-year duration. Results: Complete data were available in 301 patients with cirrhosis (cryptogenic n = 94, non-cryptogenic n = 207). Compared with non-cryptogenic cirrhosis, patients with cryptogenic cirrhosis were older (mean age 66.4 ± 12.5 vs 60.7 ± 11.3 years, P < 0.0001), had more females (43.6% vs 26.6%, P = 0.003), had less disease severity (Child–Pugh C 8.5% vs 15.9%, P = 0.042), and had a higher prevalence of the metabolic syndrome (83% vs 51.2%, P < 0.0001). During the 5-year period, adults with cryptogenic Child–Pugh A cirrhosis had a longer total hospital admission duration compared with non-cryptogenic cirrhosis (median 7.0 vs 3.0 days, P = 0.035), but this was less evident in patients with more advanced disease. This difference was due to a longer duration of hospitalization for non-liver-related morbidity (median 14.0 days vs 8.0 days, P = 0.04), rather than liverrelated morbidity (median 10.5 days vs 8.0 days, P = 0.34), in patients with cryptogenic compared with non-cryptogenic cirrhosis. Kaplan–Meier survival analysis showed no significant differences in survival between both types of cirrhosis for all grades of severity. Conclusions: Cryptogenic cirrhosis is associated with a longer duration of hospitalization compared with non-cryptogenic cirrhosis at an early stage of the disease. This difference is due to a greater burden of non-liver-related complications in the former.

Introduction Cirrhosis of the liver represents a significant burden to health-care resources both in the United States1 and in the rest of the world.2,3 Health-care costs of US$ 4 billion arising from 150 000 admissions per year have been estimated in the United States,1 with repeated admissions in decompensated cirrhosis contributing to a major component of these costs.4 Apart from liver-related complications, non-liver-associated morbidity is additionally thought to have an impact on clinical outcomes in cirrhosis. Nutritional effects of alcohol in alcohol-induced cirrhosis,5,6 extrahepatic manifestations of hepatitis C (e.g. cryoglobulinemias and glomerulopathies),7 and non-hepatic iron overload in hemochromatosis8 have all been shown to result in non-liver-related morbidity and even mortality in subjects with cirrhosis. Cryptogenic cirrhosis refers to liver cirrhosis that is unexplained by conventional clinical, laboratory, and histological findings.9 It is believed to be associated with the metabolic syndrome, and by inference caused by non-alcoholic fatty liver disease (NAFLD).10

NAFLD and its sequelae non-alcoholic steatohepatitis (NASH) have typical histological features consisting of steatosis, hepatocyte injury, lobular inflammation, and/or fibrosis. Although these histological findings typically disappear after the development of cirrhosis,11 there is increasing recognition that NAFLD is the most likely cause of cryptogenic cirrhosis today.12 NAFLD forms the hepatic component of the metabolic syndrome, and hence is usually associated with other diseases, namely diabetes, hypertension, dyslipidemia, and even coronary artery disease. It is, therefore, anticipated that cryptogenic cirrhosis should have additional morbidity and even mortality from nonhepatic complications, but this has not been demonstrated to date. Liver transplant in Malaysia remains underdeveloped, which provides clinicians an opportunity to study the natural history of cryptogenic cirrhosis without this potential confounder. This study was conducted to compare the morbidity and mortality between cryptogenic and non-cryptogenic cirrhosis over a 5-year duration, specifically to examine for differences between liver and nonliver-related complications.

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Methods

glycemic control), respiratory disease (respiratory tract infections), and surgical problems unrelated to cirrhosis complications.

Study design. A retrospective cohort study was conducted at a large, teaching hospital, following approval by the local institutional review board. All patients receiving treatment at the University of Malaya Medical Centre (UMMC, a 1200 bedded hospital serving a population catchment area of close to two million people in urban Malaysia) from 2008 onwards were selected for the study. Subjects were identified from a computerized patient database in the medical records department, and cases that matched the ICD 10 classification for a diagnosis of cirrhosis were reviewed for the study. Information regarding all clinic visits and hospital admissions was obtained from these medical records. To ensure completeness of data, phone calls were made to patients who did not appear to have current ongoing treatment at the hospital to obtain the following information: status of the patients at the time of the study (i.e. alive or dead) and any additional hospitalizations not in the UMMC. Differences in (i) hospital admission days and (ii) mortality between cryptogenic and non-cryptogenic cirrhosis were the main outcomes for this study. Study patients and definitions. Patients with a diagnosis of liver cirrhosis were eligible for inclusion in the study. Cirrhosis was diagnosed by either liver biopsy or with a combination of clinical, biochemical, and imaging modalities. The criteria for diagnosis without a liver biopsy were as follows: (i) presence of portal hypertension, (ii) radiological features of cirrhosis, and (iii) absence of portal or splenic vein thrombosis. All patients with cirrhosis had to have a comprehensive screen for the underlying etiology as follows: viral hepatitis B and C serology (hepatitis B surface antibody, surface antigen, and hepatitis C Antibody), iron studies (ferritin, iron, total iron binding capacity), ceruloplasmin levels, antinuclear antibody titers, anti-smooth muscle antibody, anti-mitochondrial antibody titers, and α1-antitrypsin levels. Alcoholic cirrhosis was diagnosed based on a history of consuming alcohol above the accepted safe limits (Asian standards: < 14 units alcohol per week in men and < 7 units per week alcohol in women) prior to the diagnosis of cirrhosis. Patients with a diagnosis of cirrhosis without a complete etiological screen were excluded from the study. Cryptogenic cirrhosis was defined as the absence of any positive blood screen (as above) and with no history of alcohol consumption above the safe limit. Metabolic syndrome was considered to be present if any of its components, that is diabetes, hyperlipidemia, and/or hypertension, were documented (i.e. with medical therapy) at the time of diagnosis of cirrhosis. Central obesity was intentionally not included for this retrospective review as patients with decompensated cirrhosis would have ascites or edema, confounding this measurement. Liver-related admissions were defined as any hospital admission for any of the following indications: ascites, upper gastrointestinal tract (GIT) bleeding, spontaneous bacterial peritonitis, hepatocellular jaundice, hepatic encephalopathy, and hepatocellular carcinoma-related issues. Non-liver-related admissions were defined as any hospital admission due to one of the following indications: non-hepatic infection (e.g. cellulitis, urinary tract infections, etc.), cardiovascular disease (e.g. acute coronary syndrome), neurological disease (cerebrovascular accidents), renal disease (chronic kidney disease), endocrine complications (poor 1424

Statistical analysis. All data were entered into a standard statistical software program, SPSS version 21.0 (SPSS Inc., Chicago, IL, USA). Continuous data were expressed as means ± SD or medians with interquartile range, and analyzed with a Student’s t-test or Mann–Whitney U-test where appropriate. Categorical data were analyzed using the chi-squared test. Survival analysis was calculated according to the Kaplan–Meier method. Sample size for the study was calculated using a computerized statistical program.13 Based on an estimated 20% difference in comorbidity between cryptogenic and non-cryptogenic cirrhosis,14 we calculated that a sample size of 249 patients (83 cases and 166 controls) would have a power of 85% to detect a difference in clinical outcome between both groups at an α level of 0.05. Statistical significance was assumed at a P-value of < 0.05.

Results Between January 2008 and July 2013, 479 patients with a diagnosis of cirrhosis were identified. A final 301 (62.8%) patient records were eligible for analysis—see Figure 1. Of the 301 study patients, n = 134 (44.5%) were alive, while n = 132 (43.9%) were deceased, and n = 35 (11.6%) were lost to follow-up at the time of data collection. The etiologies of cirrhosis in all patients were as follows: cryptogenic n = 94 (31.2%), hepatitis B alone n = 74 (24.6%), alcohol alone n = 65 (21.6%), hepatitis C alone n = 42 (14.0%), autoimmune n = 11 (3.7%), alcohol + viral hepatitis

Figure 1 Flow diagram of data acquisition in this study. ICD, International Classification of Diseases.

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(B/C) n = 6 (2.0%), hepatitis B/C coinfection n = 4 (1.3%), and drug-induced n = 4 (1.6%). The overall Child–Pugh grade distribution was as follows: grade A = 129 (42.9%), grade B = 131 (43.5%), and grade C = 41 (13.6%). Cirrhosis was confirmed by histology in 69 patients with Child–Pugh A disease, while the remaining 232 cases were diagnosed with cirrhosis based on clinical criteria (see Methods). Table 1 illustrates the demographic and clinical parameters of patients with and without cryptogenic cirrhosis. Patients with cryptogenic cirrhosis were significantly older (mean age 66.4 ± 12.5 years vs 60.7 ± 11.3 years, P < 0.0001) and had a greater proportion of females (43.6% vs 26.6%, P = 0.003) compared with those with non-cryptogenic cirrhosis. With regard to liver disease severity, patients with cryptogenic cirrhosis had less advanced disease compared with those with non-cryptogenic cirrhosis (Child–Pugh’s C 8.5% vs 15.9%, P = 0.042). In terms of comorbidities, patients with cryptogenic cirrhosis were found to have a greater prevalence of components of the metabolic syndrome. There was a higher prevalence of diabetes mellitus (70.2% vs 39.6%), hypertension (56.4% vs 39.1%), ischemic heart disease (16% vs 4.3%), and dyslipidemia (18.1% vs 8.2%) in cryptogenic compared with non-cryptogenic cirrhosis. The prevalence of metabolic syndrome was significantly higher in cryptogenic versus non-cryptogenic cirrhosis (83% vs 51.2%, P < 0.0001). In addition, patients with cryptogenic cirrhosis were found to have a higher proportion of chronic kidney disease (19.1% vs 7.2%), which may have been due to the greater prevalence of metabolic syndrome in these patients.

rhosis had a longer duration of hospitalization (for all causes), particularly in those with Child–Pugh grade A cirrhosis. The differences in hospitalization duration between cryptogenic and noncryptogenic cirrhosis was most evident for non-liver-related problems, again particularly in patients with Child–Pugh grade A disease (median 14.0 vs 8.0 days, P = 0.04). Table 3 demonstrates the details of liver and non-liver-related admissions in both groups of patients across all grades of cirrhosis. The main differences in admission days between patients with cryptogenic and noncryptogenic cirrhosis were observed for neurological (median 27 vs 14 days), cardiovascular (median 30 vs 9 days), and endocrine (median 45 vs 5 days) diseases. Due to the demographic differences between patients with and without cryptogenic cirrhosis (Table 1), the relationship between cryptogenic cirrhosis, age, gender, and non-liver-related admissions was explored in a linear regression model. Adjusting for age and gender, cryptogenic cirrhosis was shown to have a significant association with non-liverrelated admission days (t = 2.96, P = 0.003). Figure 2 illustrates the Kaplan–Meier survival curves for survival in patients with Child–Pugh grades A–C. The median survival for cirrhotic patients with Child–Pugh A (cryptogenic 40.0 vs non-cryptogenic 39.5 months, log–rank statistic 0.24), Child– Pugh B (cryptogenic 25.0 vs non-cryptogenic 24.0 months, log–rank statistic 0.85), and Child–Pugh C (cryptogenic 19.0 vs non-cryptogenic 12.0 months, log–rank statistic 0.94) was not significantly different between both groups of patients.

Discussion Clinical outcomes in cryptogenic versus noncryptogenic cirrhosis. Table 2 highlights the hospital admission data for all cirrhosis patients during the study duration, stratified by the Child–Pugh grade. Patients with cryptogenic cir-

Table 1

This study has highlighted several novel observations about the natural history of cryptogenic cirrhosis in relation to other causes of cirrhosis. One of the main advantages we have in conducting this type of study is that liver transplant in Malaysia remains

Demographic and clinical parameters in patients with cryptogenic and non-cryptogenic cirrhosis

Parameter

Cryptogenic cirrhosis n = 94

Non-cryptogenic n = 207

P-value

Age (mean ± SD) years Gender Male Female Ethnicity Malay Chinese Indian Others Child–Pugh score A B C Comorbidity Diabetes mellitus Hypertension Ischemic heart disease Dyslipidemia Metabolic syndrome Chronic kidney disease

66.4 ± 12.5

60.8 ± 11.3

< 0.0001

53 (56.4%) 41 (43.6%)

152 (73.4%) 55 (26.6%)

0.003

53 (37.2)% 27 (28.7)% 29 (30.9)% 3 (3.2)%

58 (28)% 72 (34.8)% 69 (33.3)% 8 (3.9)%

0.440 0.446 0.234 0.121

37 (39.4%) 49 (52.1%) 8 (8.5%)

92 (44.4%) 82 (39.6%) 33 (15.9%)

0.07 0.04 0.042

70.2% 56.4% 16% 18.1% 83% 19.1%

39.6% 39.1% 4.3% 8.2% 51.2% 7.2%

< 0.0001 0.005 0.001 0.012 < 0.0001 0.002

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Table 2 Duration of hospitalization for cryptogenic and non-cryptogenic cirrhosis patients between 2008 and 2013 based on severity of disease (Child–Pugh grade) Child–Pugh A Cryptogenic n = 37 Total admission days (median; IQR) Liver-related admission days (median; IQR) Non-liver-related admission days (median; IQR)

Child–Pugh B

Child–Pugh C

Non-cryptogenic n = 92

P

Cryptogenic n = 49

Non-cryptogenic n = 82

P

Cryptogenic n=8

Non-cryptogenic n = 33

P

7.0 (2.0–21.0)

3.0 (0.0–9.0)

0.035

13.0 (4.5–26.0)

12.5 (5.8–23.0)

0.94

11.5 (7.0–40.5)

9.0 (5.0–21.0)

0.45

10.5 (3.5–23.5)

8.0 (3.5–18.0)

0.34

18.0 (7.0–40.0)

13.0 (7.0–23.5)

0.17

14.0 (7.0–46.0)

9.0 (5.0–26.0)

0.19

14.0 (7.0–35.0)

8.0 (2.0–19.0)

0.04

18.0 (9.0–48.0)

19.0 (10.8–32.0)

0.72

86.0 (46.0–86.0)

16.0 (5.0–42.0)

0.11

IQR, interquartile range.

Table 3

Admission days based on indications for hospitalization for all grades of cirrhosis Cryptogenic cirrhosis n = 94

Liver related (median; IQR days) Ascites Anemia SBP Jaundice Hepatic encephalopathy HCC Non-liver-related (median; IQR days) Infection-related Neurology Respiratory Cardiovascular Renal Endocrine Surgical

22 (9–42) 22 (11.5–37.5) 35 (21–42) 19 (7.7–35.5) 30 (13–54) 13 (2–21) 18 (10−42) 27 (6.5−32.5) 34 (24.5–61) 30 (7.5–42) 35.5 (30–41) 45 (5.3–101.3) 21 (14–54)

Non-cryptogenic cirrhosis n = 207

P-value

14.5 (7.5–27.7) 13 (7–27) 22 (14–38.5) 13 (5–24) 16 (10–32) 10.5 (2.8–19.3)

0.33 0.32 0.62 0.36 0.25 0.43

17 (9–30) 14 (12–16) 12.5 (8.3–35) 9 (3–22) 26 (5–61) 5 (4–13) 19 (4.8–33)

0.78 0.02 0.50 0.05 0.45 0.10 0.11

IQR, interquartile range; HCC, hepatocellular carcinoma; SBP, spontaneous bacterial peritonitis.

underdeveloped, with very few adults having the opportunity to undergo this treatment within the country. Previous national statistics have revealed that most liver transplants for Malaysian adult patients had been conducted abroad, that is privately.15 Most of the patients attending the UMMC are of a middle or lower income socioeconomic group, and liver transplant abroad remains unaffordable. Furthermore, most patients had maintained their clinical follow-up at the same institution following their initial diagnosis, with only 11.6% of cases lost to follow-up. Our study has shown that adults with cryptogenic cirrhosis were older at the time of their initial diagnosis, compared with those with non-cryptogenic cirrhosis. Furthermore, patients with cryptogenic cirrhosis had a significantly higher proportion of the metabolic syndrome (83% vs 51.2%), including various disease components of the metabolic syndrome, that is type 2 diabetes, hyperlipidemia, and hypertension. We intentionally did not include assessment of obesity in this study due to the potential confounder of ascites and peripheral edema in patients with decompensated cirrhosis. Nevertheless, our observations support a strong correla1426

tion for the assumption that most, if not all, cases of cryptogenic cirrhosis have developed from NAFLD.16 The casual relationship between NASH and cryptogenic cirrhosis was first suggested by Caldwell et al., who noticed that patients with cryptogenic cirrhosis were similar to patients with NASH in sharing the high prevalence of obesity and diabetes,16 and this was supported by a subsequent case–control study.17 Further demographic differences between cryptogenic and noncryptogenic cirrhosis observed in this study need clarification. We found a higher proportion of females in patients with cryptogenic cirrhosis compared with non-cryptogenic cirrhosis. This may be explained by the greater proportion of hepatitis B and alcoholrelated cirrhosis in the non-cryptogenic group, which are characteristically male-predominant diseases in this country.18,19 From an ethnic distribution perspective, no significant differences were observed in the group with cryptogenic cirrhosis. This is somewhat surprising, as both metabolic syndrome and NAFLD have a clear ethnic predeliction in Malaysia. In a nationwide population survey of 17 211 adults in Malaysia, Rampal et al. had demonstrated that

Journal of Gastroenterology and Hepatology 30 (2015) 1423–1428 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd

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Figure 2 (a) Kaplan–Meier survival curves for Child–Pugh grade A cirrhosis patients from 2008 to 2013. (b) Kaplan–Meier survival curves for Child–Pugh grade B cirrhosis patients from 2008 to 2013. (c) Kaplan– Meier survival curves for Child–Pugh grade C cirrhosis patients from ) no, ( ) yes. 2008 to 2013. Cryptogenic: (

Clinical outcomes of cirrhosis

the prevalence of metabolic syndrome was 27.5%, and ethnic Indians had the highest prevalence compared with all other ethnic groups.20 In another cross-sectional study of 469 young Malaysian adults, Chan et al. had observed an inordinately high prevalence of NAFLD among ethnic Indians and Malays, compared with ethnic Chinese.21 A possible explanation for the lack of ethnic predilection among our group of cryptogenic cirrhosis cases may be due to the demographics of patients seeking health care at the UMMC, with recent surveys showing a disproportionate number of ethnic Chinese patients attending the gastroenterology outpatient services.22 In patients with early/compensated cirrhosis (i.e. Child–Pugh grade A), this cohort study has demonstrated a greater duration of non-liver-related admissions in adults with a cryptogenic compared with a non-cryptogenic cirrhosis etiology. This resulted in an increased median number of hospital admission days for cases with cryptogenic cirrhosis, indicating the greater clinical burden associated with this disease compared with other types of cirrhosis at an early stage of disease. The lack of difference in non-liverrelated admissions for more advanced grades of cirrhosis may have been due to (i) the smaller number of patients in this category or (ii) the greater impact of liver-related complications in advanced disease. The specific types of non-liver-related diseases that contributed to longer admissions appeared to be stroke and cardiovascular diseases, both of which are known to be associated with NAFLD.23,24 Although no formal costing analysis was performed, it would be logical to assume that direct costing calculations (i.e. costings related to health care only) would have demonstrated a greater economic burden associated with cryptogenic cirrhosis, compared with non-cryptogenic cirrhosis. To the best of our knowledge, this important observation has not been described before. A recent report from the United States was able to demonstrate that patients with NASH/cryptogenic cirrhosis were more likely to be denied liver transplant compared with hepatitis C cirrhosis cases due to a greater proportion of comorbid illness.14 However, the authors were not able to clarify the type of comorbidity associated with cryptogenic cirrhosis as they had used a retrospective database. Despite the documented differences in morbidity, our survival analysis revealed no significant difference in mortality between patients with and without cryptogenic cirrhosis. This finding is in agreement with other studies that have examined survival of cirrhosis patients in a non-transplant setting. Yatsuji et al. had compared 68 patients with cirrhotic NASH with 69 cases of hepatitis C cirrhosis in Japan.25 The authors found that cirrhotic NASH had a similar 5-year survival rate as hepatitis C cirrhosis patients, together with a similar liver-related morbidity, including hepatocellular carcinoma. In Sri Lanka, Senanayake et al. demonstrated that cryptogenic cirrhosis patients had a similar survival rate to cases with alcoholic cirrhosis.26 The main cause of mortality in both cryptogenic and alcohol-related cirrhosis was liver-related in this cohort of Sri Lankan patients. However, in our cohort of Malaysian patients, we were not able to obtain information about the cause of mortality in those with cryptogenic cirrhosis. There are several limitations to this study. With its retrospective design, there may have been missing data due to recall bias among patients who were contacted by telephone. The presence of metabolic syndrome may have been underestimated as we did not strictly adhere to international criteria due to missing data on prior

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central obesity and impaired glucose tolerance. Furthermore, a sizeable proportion of initial medical records screened did not fulfill our inclusion criteria and hence may have been inadvertently excluded. Nevertheless, our study sample size was sufficiently powered for the research query, and we had a low rate of poor follow-up data (11.6%). Lead time bias in a retrospective study of survival in cirrhosis may have influenced our survival analysis. Some patients were only diagnosed when they presented with features of decompensation, whereas others may have been detected earlier during surveillance of asymptomatic chronic liver disease. However, it is reassuring to note that other studies examining survival in cryptogenic cirrhosis have obtained similar results to ours. This study has confirmed previous observations that cryptogenic cirrhosis is associated with the metabolic syndrome and likely to result from NAFLD. Cryptogenic cirrhosis at an early stage has a longer duration of hospitalization due to non-liverrelated morbidity, compared with non-cryptogenic cirrhosis. However, the survival of cryptogenic cirrhosis patients appears to be similar to non-cryptogenic cirrhosis. Data from this study provide further information on the clinical burden of cryptogenic cirrhosis, which largely results from NAFLD.

References 1 Kim WR, Brown RS Jr, Terrault NA et al. Burden of liver disease in the United States: summary of a workshop. Hepatology 2002; 36: 227–42. 2 Coltorti M, Del Vecchio-Blanco C, Caporaso N et al. Liver cirrhosis in Italy. A multicentre study on presenting modalities and the impact on health care resources. National Project on Liver Cirrhosis Group. Ital. J. Gastroenterol. 1991; 23: 42–8. 3 Fagan KJ, Zhao EY, Horsfall LU et al. The burden of decompensated cirrhosis and ascites on hospital services in a tertiary care facility: time for change? Intern. Med. J. 2014; 44: 865–72. 4 Volk ML, Tocco RS, Bazick J et al. Hospital readmissions among patients with decompensated cirrhosis. Am. J. Gastroenterol. 2012; 107: 247–52. 5 Mezey E. Alcoholic liver disease: roles of alcohol and malnutrition. Am. J. Clin. Nutr. 1980; 33: 2709–18. 6 Alvarez MA, Cirera I, Sola R et al. Long-term clinical course of decompensated alcoholic cirrhosis: a prospective study of 165 patients. J. Clin. Gastroenterol. 2011; 45: 906–11. 7 Mayo MJ. Extrahepatic manifestations of hepatitis C infection. Am. J. Med. Sci. 2003; 325: 135–48. 8 Ellervik C, Tybjaerg-Hansen A, Grande P et al. Hereditary hemochromatosis and risk of ischemic heart disease: a prospective study and a case-control study. Circulation 2005; 112: 185–93. 9 Czaja AJ. Cryptogenic chronic hepatitis and its changing guise in adults. Dig. Dis. Sci. 2011; 56: 3421–38.

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10 Tellez-Avila FI, Sanchez-Avila F, Garcia-Saenz-de-Sicilia M et al. Prevalence of metabolic syndrome, obesity and diabetes type 2 in cryptogenic cirrhosis. World J. Gastroenterol. 2008; 14: 4771–5. 11 Caldwell SH, Lee VD, Kleiner DE et al. NASH and cryptogenic cirrhosis: a histological analysis. Ann. Hepatol. 2009; 8: 346–52. 12 Clark JM, Diehl AM. Nonalcoholic fatty liver disease: an underrecognized cause of cryptogenic cirrhosis. JAMA 2003; 289: 3000–4. 13 Dupont WD, Plummer WD. PS power and sample size program available for free on the Internet. Control. Clin. Trials 1997; 18: 274. 14 O’Leary JG, Landaverde C, Jennings L et al. Patients with NASH and cryptogenic cirrhosis are less likely than those with hepatitis C to receive liver transplants. Clin. Gastroenterol. Hepatol. 2011; 9: 700–704 e1. 15 Hooi LS, Mansor LY. 7th Report of the National Transplant Registry. Kuala Lumpur: National Transplant Registry, 2010; 3–12. 16 Caldwell SH, Oelsner DH, Iezzoni JC et al. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology 1999; 29: 664–9. 17 Poonawala A, Nair SP, Thuluvath PJ. Prevalence of obesity and diabetes in patients with cryptogenic cirrhosis: a case-control study. Hepatology 2000; 32: 689–92. 18 Qua CS, Goh KL. Liver cirrhosis in Malaysia: peculiar epidemiology in a multiracial Asian country. J. Gastroenterol. Hepatol. 2011; 26: 1333–7. 19 Tai ML, Goh KL, Mohd-Taib SH et al. Anthropometric, biochemical and clinical assessment of malnutrition in Malaysian patients with advanced cirrhosis. Nutr. J. 2010; 9: 27. 20 Rampal S, Mahadeva S, Guallar E et al. Ethnic differences in the prevalence of metabolic syndrome: results from a multi-ethnic population-based survey in Malaysia. PLoS ONE 2012; 7: e46365. 21 Chan WK, Bazar N, Razlan H et al. Non-alcoholic fatty liver disease in a young multiracial Asian population: a worrying predilection in Malay and Indian males. Hepatol. Int. 2014; 8: 121–7. 22 Mahadeva S, Goh KL. Clinically significant endoscopic findings in a multi-ethnic population with uninvestigated dyspepsia. Dig. Dis. Sci. 2012; 57: 3205–12. 23 Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N. Engl. J. Med. 2010; 363: 1341–50. 24 Sookoian S, Pirola CJ. Non-alcoholic fatty liver disease is strongly associated with carotid atherosclerosis: a systematic review. J. Hepatol. 2008; 49: 600–7. 25 Yatsuji S, Hashimoto E, Tobari M et al. Clinical features and outcomes of cirrhosis due to non-alcoholic steatohepatitis compared with cirrhosis caused by chronic hepatitis C. J. Gastroenterol. Hepatol. 2009; 24: 248–54. 26 Senanayake SM, Niriella MA, Weerasinghe SK et al. Survival of patients with alcoholic and cryptogenic cirrhosis without liver transplantation: a single center retrospective study. BMC Res. Notes 2012; 5: 663.

Journal of Gastroenterology and Hepatology 30 (2015) 1423–1428 © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd

Clinical outcomes of cryptogenic compared with non-cryptogenic cirrhosis: A retrospective cohort study.

The consequences of the association between the metabolic syndrome and cryptogenic cirrhosis are uncertain. We aimed to compare the differences in cli...
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