Achuthan Sourianarayanane

Risk factors of non-alcoholic fatty liver disease in patients with inflammatory bowel disease

BACKGROUND Metabolic risk factors are associated with non-alcoholic fatty liver disease (NAFLD), but they are less frequent in inflammatory bowel disease (IBD). AIM This study evaluates the frequency of NAFLD and its risk factors among IBD patients including anti-TNF-α therapy. METHODS IBD patients who underwent abdominal imaging from January, 2009 to December, 2010 were analyzed in this nested, case-controlled study. IBD patients with NAFLD by imaging were compared with those who had no evidence of NAFLD (control). RESULTS Among 928 IBD patients, 76 (8.2%) had evidence of NAFLD by imaging, and were compared to 141 patients without NAFLD evaluated (study: control ratio=~1:2). NAFLD patients were older (46.0 ± 13.3 vs. 42.0 ±14.1 years; p=0.018) and had a later onset of IBD compared to the control group (37.2 ± 15.3 vs. 28.7 ± 23.8 years; p=0.002). Metabolic syndrome was present in 29.0% of NAFLD patients, with a median Adult Treatment Panel risk factor of 2 [Interquartile range 1,3]. Patients not receiving anti-TNF-α therapy had a higher occurrence of NAFLD (p=0.048). In multivariate analysis, hypertension (OR=3.5), obesity (OR=2.1), small bowel surgeries (OR=3.7), and use of steroids at the time of imaging (OR=3.7) were independent factors associated with NAFLD. CONCLUSION NAFLD occurred in 8.2% of the IBD population. NAFLD patients were older and had a later onset of IBD disease. IBD patients develop NAFLD with fewer metabolic risk factors than non-IBD NAFLD patients. It is also less common among patients who received anti-TNF-α therapy.

Renin‐angiotensin system and fibrosis in non‐alcoholic fatty liver disease

Therapeutic options are limited for patients with non‐alcoholic fatty liver disease (NAFLD). One promising approach is the attenuation of necroinflammation and fibrosis by inhibition of the renin‐angiotensin system (RAS). We explored whether the risk of fibrosis was associated with the use of commonly used medications in NAFLD patients with hypertension. Specifically, we sought to determine the association between RAS blocking agents and severity of hepatic fibrosis in NAFLD patients with hypertension.

Liver transplantation arrests and reverses muscle wasting

Muscle wasting, sarcopenia, is common in advanced cirrhosis and predicts adverse outcomes while awaiting and following liver transplantation. Frequent post‐transplant worsening of sarcopenia has attracted recent interest. It is unknown whether this serious problem is an expected metabolic consequence of transplantation or results from confounding conditions such as recurrent allograft liver disease or avoidable post‐transplant complications. To clarify this question, we studied pre‐ and post‐transplant muscle mass in a retrospective cohort of 40 patients transplanted for three diseases – alcoholic cirrhosis, non‐alcoholic steatohepatitis cirrhosis, and primary sclerosing cholangitis cirrhosis – in whom allograft disease recurrence was monitored and excluded, and who lacked common post‐transplant muscle wasting complications such as sepsis, renal failure, ischemia, and cholestasis. We measured skeletal muscle index (SMI) using computed tomography before and 12–48 months after transplant. SMI as a categorical variable significantly improved, from 18 patients above the normal cutoff pre‐transplant to 28 post‐transplant (p = 0.008). SMI increases were greatest in patients with the lowest pre‐transplant SMI (p < 0.01). As a continuous variable, mean SMI remained stable, with a non‐significant trend toward improvement. We conclude that after liver transplantation sarcopenia does not progress but is arrested and frequently improves in the absence of confounding conditions.

Clinical spectrum of non-alcoholic fatty liver disease in diabetic and non-diabetic patients

Background While non-alcoholic fatty liver disease (NAFLD) has been well characterised in patients with diabetes mellitus (DM), less is known about NAFLD in non-DM patients. We investigated the clinical characteristics of NAFLD patients with and without DM and accuracy of the NAFLD fibrosis score (NFS) in these two NAFLD groups. Methods Clinical, biochemical and histological variables were evaluated in this prospective cross-sectional study of 503 patients with biopsy proven NAFLD. Comparisons between patients with and without DM were analysed. NFS was correlated with liver histology to assess its robustness in patients with and without DM. Results There were 503 biopsy proven NAFLD patients with 48% of the cohort being diabetic. Relative to patients without DM, patients with DM were older (52 vs. 46 years, p < 0.001), with higher proportion of females (70% vs. 54%, p < 0.001), higher BMI (37 vs. 35, p = 0.009), higher prevalence of hypertension (73% vs. 44%, p < 0.001), higher prevalence of NASH (80.2% vs. 64.4%; p < 0.001) and advanced fibrosis (40.3% vs. 17.0%; p < 0.001). A considerable amount of patients without DM still had NASH (64%) and advanced fibrosis (17%). The clinical utility of the NFS differed between NAFLD patients with and without DM, with sensitivity to exclude advanced fibrosis being 90% of NAFLD patients with DM but only 58% of patients without DM. Conclusion Patients with DM have more severe NAFLD based on histology. However, NASH and advanced fibrosis also occur in a considerable proportion of NAFLD patients without DM. The lower utility of the NFS in NAFLD patients without DM emphasises the heterogeneous nature of the NAFLD phenotype.

Radiologic-histological correlation of hepatocellular carcinoma treated via pre-liver transplant locoregional therapies.

BACKGROUND Locoregional therapies (LRTs) are treatments to achieve local control of hepatocellular carcinoma (HCC). Correlation between radiologic response to LRT and degree of induced tumor necrosis is not well understood. The aim of this study was to evaluate different levels of radiologic response after pre-liver transplant (LT) LRT and its correlation with percentage of tumor necrosis on explanted histopathology. METHODS Institutional Review Board approved LT database was queried for treated HCC in patients undergoing LT. Radiologic response was evaluated to predict tumor necrosis in the explanted liver. Tumor response was evaluated 1 to 3 months after LRT with computed tomography or MRI via Response Evaluation Criteria in Solid Tumors (RECIST), and European Association for the Study of the Liver (EASL) guidelines. LRT was repeated as needed until time of LT. Histological tumor necrosis was graded as complete (100%), partial (50%-99%), or poor (<50%). RESULTS Between 2002 and 2011, 128 patients (97 men and 31 women) received pre-LT LRT including transarterial therapy (93), radiofrequency ablation (20), or combination of both (15). The mean age of the patients was 58+/-9 years. Their mean follow-up was 35+/-27 months. The median waitlist time was 55 days. One hundred (78%) patients had HCC within the Milan criteria at the initial radiologic diagnosis. Nineteen (15%) of the patients had complete tumor necrosis on histopathology analysis. Fifty (39%) of the patients exhibited partial necrosis, 52 (41%) showed poor or no necrosis and 7 (5%) showed progressive disease. The overall pre-LT radiologic staging was correlated with explant pathology in 73 (57%) of the patients. Underestimated tumor stage was noted in 49 (38%) patients, and overestimated tumor stage in 6 (5%) patients. The post-LT 3-year overall survival and disease free survival were 82% and 80%, and the rates for complete and partial tumor necrosis were 100% vs 78% (P=0.02) and 100% vs 75% (P=0.03), respectively. CONCLUSIONS In the current era, interpretation of radiologic response after LRT for HCC does not correlate accurately with histologic tumor necrosis. Total tumor necrosis is the goal of LRT; therefore, evolution in its performance is needed. Similarly, ways to predict therapy induced tumor necrosis via radiological investigation need to be improved.

The development of a non-invasive model to predict the presence of non-alcoholic steatohepatitis in patients with non-alcoholic fatty liver disease.

Non‐alcoholic steatohepatitis (NASH) is an advanced and aggressive form of non‐alcoholic fatty liver disease (NAFLD), which remains difficult to diagnose without a liver biopsy. Hyperferritinemia has increasingly been associated with the presence of NASH. Hence, we sought to explore the relationship between ferritin and NASH and to develop a composite model based on ferritin to predict the presence of NASH.

Loco-regional therapy in patients with Milan Criteria-compliant hepatocellular carcinoma and short waitlist time to transplant: an outcome analysis

OBJECTIVES Liver transplantation (LT) in Milan Criteria (MC) hepatocellular carcinoma (HCC) has excellent outcomes. Pre-transplant loco-regional therapy (LRT) has been used to downstage HCC to meet the MC. However, its benefit in patients with a brief waiting time to transplant remains unclear. This study evaluated outcomes in patients with short waitlist times to LT for MC-compliant HCC. METHODS Patients undergoing LT for MC HCC at either of two transplant centres between 2002 and 2009 were retrospectively evaluated for outcome. Patients for whom post-transplant follow-up amounted to <12 months were excluded. RESULTS A total of 225 patients were included, 93 (41.3%) of whom received neoadjuvant LRT. The median waiting time to transplant was 48 days. Mean post-transplant follow-up was 32.2 months. Overall and disease-free survival at 1 year, 3 years and 5 years were 93.1%, 82.4% and 72.6%, and 91.3%, 79.3% and 70.6%, respectively. There was no difference in overall (P= 0.94) and disease-free survival (P= 0.94) between groups who received and did not receive pre-LT LRT. There were also no disparities in survival or tumour recurrence among categories of patients (with single tumours measuring <3 cm, with single tumours measuring 3-5 cm, with multiple tumours). CONCLUSIONS Loco-regional therapy followed by rapid transplantation in MC HCC appears not to have an impact on post-transplant outcome.

Diabetes Mellitus, Insulin, Sulfonylurea and Advanced Fibrosis in Non- Alcoholic Fatty Liver Disease

Background & aims: Diabetes mellitus is a risk factor for advanced fibrosis in non-alcoholic fatty liver disease. However, not all non-alcoholic fatty liver disease patients with diabetes develop advanced fibrosis. We hypothesised that prescription medications used by these patients influence the development of advanced fibrosis. We investigated the association of commonly used medications and advanced fibrosis in non-alcoholic fatty liver disease patients with diabetes. Methods: Clinical information including demographics, medical history, medication history, biochemical and histologic variables were ascertained in 459 patients with biopsy proven non-alcoholic fatty liver disease. We compared characteristics of patients with and without diabetes and explored potential associations between classes of drugs as risk factors and advanced fibrosis among the diabetic patients with NAFLD. Results: Presence of diabetes was an independent risk factor for advanced fibrosis. In diabetic patients, age (OR 1.09; 95%CI 1.04-1.15, p=0.000) and grade of ballooning (OR 5.59; 95%CI 2.69-11.61, p=0.000) had a positive relationship with advanced fibrosis. The use of insulin (OR 4.95; 95%CI 1.65-14.88, p=0.004) and sulfonylurea (OR 5.07; 95%CI 1.87-13.75, p=0.001) were positively associated while statin use (OR 0.31; 95%CI 0.12-0.78, p=0.013) was negatively associated with advanced fibrosis. Conclusion: Among non-alcoholic fatty liver disease patients with diabetes, the prevalence of advanced fibrosis was higher in patients treated with insulin and sulfonylurea, but lower in patients on statins. These findings provide support for a greater role of statin use in non-alcoholic fatty liver disease patients with diabetes while limiting the use of insulin and sulfonylurea.

Nonalcoholic steatohepatitis recurrence and rate of fibrosis progression following liver transplantation

Background Nonalcoholic steatohepatitis (NASH) is known to recur following liver transplantation (LT). Metabolic risk factors increase with immunosuppression. However, the rate of fibrosis progression following LT for NASH while on immunosuppression is less clear. Aim The incidences of steatosis, NASH, and fibrosis following LT for NASH were quantified and compared with those transplanted for alcoholic liver disease (ALD). Patients and methods Records of all NASH patients and 1 : 2 match with ALD transplant recipients between 2001 and 2006 were reviewed retrospectively. Patients without liver biopsies beyond 2 months following LT were excluded. Results NASH patients (n=77) were older (P=0.0006) and less likely male (P<0.001) than ALD patients (n=108). The incidence of steatosis, NASH, and fibrosis stage increased at 1, 3, and 5 years in both groups. Although steatosis and nonalcoholic fatty liver disease activity scores were higher, fibrosis was lower in NASH compared with ALD (0.43 vs. 1.0 stage/year; P=0.0045). The incremental increase in the rate of fibrosis was faster in the first year compared with 4–5 years (0.8 vs. 0.04 stage/year) following LT. The rate of fibrosis progression during 4–5 years was decreased in NASH compared with ALD recipients (0.04 vs. 0.33 stage/year; P=0.015). NASH etiology was associated with reduced rate of fibrosis progression (odds ratio=0.67) on multivariate analysis. Conclusion Despite having more steatosis and inflammation, progression of fibrosis was slower in NASH compared with ALD recipients. Fibrosis progression slows with time following LT on immunosuppression and approximates the pretransplant progression rate by year 5.

Role of Transplantation in the Treatment of Benign Solid Tumors of the Liver: A Review of the United Network of Organ Sharing Data Set

IMPORTANCE The role of orthotopic liver transplantation for the treatment of benign solid liver tumors (BSLT) is not well defined. OBJECTIVE To analyze outcomes in the United Network of Organ Sharing data set of patients with a diagnosis of BSLT who underwent transplantation. DESIGN, SETTING, AND PARTICIPANTS A retrospective analysis of the United Network of Organ Sharing data set was performed for all (N = 87,280) patients who underwent transplantation for BSLT in the United States from October 1, 1988, through January 31, 2013. MAIN OUTCOMES AND MEASURES Demographics, clinicopathological characteristics, distribution of the procedures by region and state, and overall survival rates. RESULTS During the study period, 147 liver transplants (0.17%) were to treat BSLT. Sixty-two patients (42.2%) had adenomas, 29 (19.7%) had focal nodular hyperplasia, 25 (17.0%) had hemangiomas, 11 (7.5%) had hepatic epithelioid hemangioendotheliomas, and 20 (13.6%) were classified as having unknown benign tumors. The overall 1-, 3-, and 5-year survival rates were 90.9%, 85.2%, and 81.8%, respectively. Using multivariable analysis, we found that age was the only independent factor associated with patient survival. The overall 5-year survival rate for patients older than 50 years was 88% compared with 91% in younger individuals (95% CI, 148-384; P = .005). Region 3 (Alabama, Arkansas, Florida, Georgia, Louisiana, Mississippi, and Puerto Rico) contributed the maximum number (33 [22.4%]) of these transplants. CONCLUSIONS AND RELEVANCE Although liver transplantation cannot be considered a first-line treatment, it is a valid therapeutic option in selected patients who are not amenable to resection. Only 0.17% of the transplants in the United States are performed for this indication, with satisfying long-term results. Age was an independent predictor of patient survival. Further studies are needed to better understand the role of liver transplantation in the treatment of BSLT.