Non-Alcoholic Fatty Liver Disease in Lean and Non-Obese Individuals: Current and Future Challenges.

Non-alcoholic fatty liver disease (NAFLD), which approximately affects a quarter of the world's population, has become a major public health concern. Although usually associated with excess body weight, it may also affect normal-weight individuals, a condition termed as lean/non-obese NAFLD. The prevalence of lean/non-obese NAFLD is around 20% within the NAFLD population, and 5% within the general population. Recent data suggest that individuals with lean NAFLD, despite the absence of obesity, exhibit similar cardiovascular- and cancer-related mortality compared to obese NAFLD individuals and increased all-cause mortality risk. Lean and obese NAFLD individuals share several metabolic abnormalities, but present dissimilarities in genetic predisposition, body composition, gut microbiota, and susceptibility to environmental factors. Current treatment of lean NAFLD is aimed at improving overall fitness and decreasing visceral adiposity, with weight loss strategies being the cornerstone of treatment. Moreover, several drugs including PPAR agonists, SGLT2 inhibitors, or GLP-1 receptor agonists could also be useful in the management of lean NAFLD. Although there has been an increase in research regarding lean NAFLD, there are still more questions than answers. There are several potential drugs for NAFLD therapy, but clinical trials are needed to evaluate their efficacy in lean individuals.

Prevalence of clinically relevant liver fibrosis due to nonalcoholic fatty liver disease in Indian individuals with type 2 diabetes.

BACKGROUND AND AIM: Type 2 diabetes (T2D) in associated with higher prevalence and worse outcomes of nonalcoholic fatty liver disease (NAFLD). However, data regarding the prevalence of clinically relevant liver fibrosis (CRLF) in Indian individuals with T2D are scarce. We investigated the prevalence of, and factors associated with, CRLF in Indians with T2D. METHODS: We conducted a prospective study of 601 consecutive adults with T2D. Steatosis was diagnosed using ultrasonography. Liver stiffness measurement (LSM) by transient elastography of ≥8.0 kPa was taken as cutoff suggesting CRLF. Individuals with LSM > 13.0 kPa underwent dynamic magnetic resonance imaging (MRI) of liver for detecting changes consistent with cirrhosis. RESULTS: The prevalence of steatosis was 84.2%. Higher body mass index (BMI, P = 0.022), alanine aminotransferase (ALT; P = 0.001), and lower high-density lipoprotein (HDL; P = 0.002) were independent factors associated with steatosis. The prevalence of CRLF was 28.2%. Higher BMI (P = 0.001), aspartate aminotransferase (AST; P < 0.0001), gamma-glutamyl transpeptidase (GGT; P < 0.0001), and concomitant hypertension (P = 0.03) were independent factors associated with CRLF. Elevated ALT and AST (≥40 units/L) levels were present in 70.6 and 51.6% individuals with CRLF, respectively. Thirty-one (7.2%) individuals had LSM > 13.0 kPa. Among them, 25 individuals underwent dynamic MRI of liver, which revealed features consistent with cirrhosis in 18 patients. CONCLUSION: CRLF, an established risk factor for cirrhosis and overall mortality, affects at least one out of four (25%) Indians with T2D. These results support screening of all patients with T2D and NAFLD for liver fibrosis.

Low skeletal muscle mass is associated with liver fibrosis in individuals with type 2 diabetes and nonalcoholic fatty liver disease.

BACKGROUND AND AIM: Type 2 diabetes (T2D) and low skeletal muscle mass (SMM) are associated with increased risk of nonalcoholic fatty liver disease (NAFLD). However, data regarding the association between low SMM and NAFLD-related liver fibrosis in individuals with T2D are scarce. Therefore, we aimed to investigate the association between low SMM and liver fibrosis in individuals with T2D and NAFLD. METHODS: Controlled attenuation parameter (CAP) of ≥ 248 dB/m was taken as cutoff suggesting NAFLD. Clinically relevant liver fibrosis and advanced liver fibrosis were defined as liver stiffness measurement (LSM) by transient elastography (TE) of ≥ 8.0 and ≥ 9.6 kPa, respectively. SMM was measured using dual energy X-ray absorptiometry (DEXA). Low SMM was defined as appendicular SMM index of < 7.0 kg/m2 for men and < 5.4 kg/m2 for women. RESULTS: Of the 487 consecutive patients with T2D, 366 (75.1%) had NAFLD. Among individuals with NAFLD, 118 (32.2%) and 64 (17.5%) had clinically relevant liver fibrosis and advanced liver fibrosis, respectively. Low SMM was diagnosed in 78 (21.3%) individuals with NAFLD. Patients with low SMM were older (56.1 vs 52.8 years) and had longer duration of diabetes (10.3 vs 8.1 years). Low SMM was an independent risk factor associated with clinically relevant liver fibrosis (P = 0.002) and advanced liver fibrosis (P ≤ 0.0001). Associations between low SMM and clinically relevant- and advanced liver fibrosis were maintained even after sequential adjustment for confounding variables through the multivariate regression analysis. CONCLUSIONS: Low SMM is independently associated with liver fibrosis in individuals with T2D and NAFLD.

Genetic and epigenetic disease modifiers: non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD).

Inter-individual and inter-ethnic differences and difference in the severity and progression of liver disease among patients with non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) suggests the involvement of genetic and epigenetic factors in their pathogenesis. This article reviews the genetic and epigenetic modifiers in patients with NAFLD and ALD. Evidence regarding the genetic and epigenetic disease modifiers of NAFLD and ALD was reviewed by searching the available literature. Both genome wide association studies (GWAS) and candidate gene studies pertaining to the pathogenesis in both diseases were included. Clinical implications of the available information are also discussed. Several studies have shown association of both NAFLD and ALD with I148M PNPLA3 variant. In addition to the higher prevalence of hepatic steatosis, the I148M PNPLA3 variant is also associated with severity of liver disease and risk of hepatocellular carcinoma (HCC). TM6SF2 is the other genetic variant shown to be significantly associated with hepatic steatosis and cirrhosis in patients with NAFLD and ALD. The Membrane bound O-acyltransferase domain-containing 7 (MBOAT7) genetic variant is also associated with both NAFLD and ALD. In addition to these mutations, several variants related to the genes involved in glucose metabolism, insulin resistance, lipid metabolism, oxidative stress, inflammatory pathways, fibrosis have also been shown to be the disease modifiers in patients with NAFLD and ALD. Epigenetics involving several micro RNAs and DNA methylation could also modify the disease course in NAFLD and ALD. In conclusion the available literature suggests that genetics and epigenetics are involved in the pathogenesis of NAFLD and ALD which may affect the disease prevalence, severity and response to treatment in these patients.

Nonalcoholic fatty liver disease should be considered for treatment allocation in standard management algorithms for type 2 diabetes.

BACKGROUND AND AIMS: Type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD) often exist together. This is a high-risk population, as presence of T2D promotes the progression of NAFLD to more severe liver pathologies. There are several international guidelines for managing T2D, however guidance for management of NAFLD in individuals with T2D is scarce. In India, there is hardly any screening programme for identification of high-risk NAFLD individuals. METHODS: A literature search was performed with Medline (PubMed), Scopus and Google Scholar electronic databases till October 2020, using relevant keywords (nonalcoholic fatty liver disease; NAFLD; nonalcoholic steatohepatitis; NASH screening and management; metabolic associated fatty liver disease) to extract relevant studies describing screening and management strategies of NAFLD/NASH, especially in patients with T2D. RESULTS: An estimated 12.4 million Indian people are living with coexisting T2D and NAFLD-related advanced liver fibrosis, which is a major determinant of liver-related mortality in these individuals. Several studies have reported screening tools for identification of high risk NAFLD patients with coexisting T2D. The emphasis has been laid on the identification of advanced liver fibrosis and cirrhosis, using noninvasive tests at the primary level. For management, lifestyle measures and appropriate glucose-lowering medication have been proposed that help patients with coexisting T2D and NAFLD. Timely referral to specialists is also critical for preventing complications of cirrhosis. CONCLUSIONS: While current management algorithms for T2D include atherosclerotic cardiovascular disease, kidney dysfunction and obesity as co-morbidities to direct appropriate therapies, NAFLD should be considered as additional pathway to select appropriate treatment.

Pathophysiological mechanisms underlying MAFLD.

BACKGROUND AND AIMS: The pathophysiology underlying metabolic associated fatty liver disease (MAFLD) involves a multitude of interlinked processes, including insulin resistance (IR) underlying the metabolic syndrome, lipotoxicity attributable to the accumulation of toxic lipid species, infiltration of proinflammatory cells causing hepatic injury and ultimately leading to hepatic stellate cell (HSC) activation and fibrogenesis. The proximal processes, such as IR, lipid overload and lipotoxicity are relatively well established, but the downstream molecular mechanisms, such as inflammatory processes, hepatocyte lipoapoptosis, and fibrogenesis are incompletely understood. METHODS: A literature search was performed with Medline (PubMed), Scopus and Google Scholar electronic databases till June 2020, using relevant keywords (nonalcoholic fatty liver disease; metabolic associated fatty liver disease; nonalcoholic steatohepatitis; NASH pathogenesis) to extract relevant studies describing pathogenesis of MAFLD/MASH. RESULTS: Several studies have reported new concepts underlying pathophysiology of MAFLD. Activation of HSCs is the common final pathway for diverse signals from damaged hepatocytes and proinflammatory cells. Activated HSCs then secrete excess extracellular matrix (ECM) which accumulates and impairs structure and function of the liver. TAZ (a transcriptional regulator), hedgehog (HH) ligands, transforming growth factor-ß (TGF-ß), bone morphogenetic protein 8B (BMP8B) and osteopontin play important roles in activating these HSCs. Dysfunctional gut microbiome, dysregulated bile acid metabolism, endogenous alcohol production, and intestinal fructose handling, modify individual susceptibility to MASH. CONCLUSIONS: Newer concepts of pathophysiology underlying MASH, such as TAZ/Ihh pathway, extracellular vesicles, microRNA, dysfunctional gut microbiome and intestinal fructose handling present promising targets for the development of therapeutic agents.

Effect of Empagliflozin on Liver Fat in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial (E-LIFT Trial).

OBJECTIVE: Sodium-glucose cotransporter 2 (SGLT-2) inhibitors have been shown to reduce liver fat in rodent models. Data regarding the effect of SGLT-2 inhibitors on human liver fat are scarce. This study examined the effect of empagliflozin (an SGLT-2 inhibitor) on liver fat in patients with type 2 diabetes and nonalcoholic fatty liver disease (NAFLD) by using MRI-derived proton density fat fraction (MRI-PDFF). RESEARCH DESIGN AND METHODS: Fifty patients with type 2 diabetes and NAFLD were randomly assigned to either the empagliflozin group (standard treatment for type 2 diabetes plus empagliflozin 10 mg daily) or the control group (standard treatment without empagliflozin) for 20 weeks. Change in liver fat was measured by MRI-PDFF. Secondary outcome measures were change in alanine transaminase (ALT), aspartate transaminase (AST), and γ-glutamyl transferase (GGT) levels. RESULTS: When included in the standard treatment for type 2 diabetes, empagliflozin was significantly better at reducing liver fat (mean MRI-PDFF difference between the empagliflozin and control groups -4.0%; P < 0.0001). Compared with baseline, significant reduction was found in the end-of-treatment MRI-PDFF for the empagliflozin group (16.2% to 11.3%; P < 0.0001) and a nonsignificant change was found in the control group (16.4% to 15.5%; P = 0.057). The two groups showed a significant difference for change in serum ALT level (P = 0.005) and nonsignificant differences for AST (P = 0.212) and GGT (P = 0.057) levels. CONCLUSIONS: When included in the standard treatment for type 2 diabetes, empagliflozin reduces liver fat and improves ALT levels in patients with type 2 diabetes and NAFLD.

Cytomegalovirus infection in living donor liver transplant recipients significantly impacts the early post-transplant outcome: A single center experience.

BACKGROUND: Cytomegalovirus (CMV) is the most common viral infection in liver transplant recipients that influences the outcomes of liver transplantation. However, its impact on early outcomes following living donor liver transplantation (LDLT) is not fully defined in the Indian subcontinent. This study was done to assess the impact of CMV infection on early post-transplant outcomes in LDLT recipients. METHODS: Out of 272 LDLTs performed from January 2012 to April 2013, 151 recipients underwent CMV viral load analysis in plasma within 90 days post LDLT based on clinical suspicion. Patients with CMV infection (n = 55) were compared with those without CMV infection (n = 96). RESULTS: The median time interval of CMV infection from LDLT was 25 days (range 2-90 days). The mean age of study population was 48.92 years. About 116 (76.8%) of the patients were male. Hepatitis C virus (HCV) (39.1%)-related chronic liver disease (CLD) was most common indication for liver transplant. No statistically significant difference was observed in etiology of liver disease (P = .38), Chid-Turcotte-Pugh (CTP) (P = .41), and Model for End-stage Liver Disease (MELD) (P = .12) scores between the groups. Patients with CMV infection had significantly higher incidence of acute cellular rejection (16.1% vs 5.4%, P = .02); longer ICU stay (P = .01); and a higher overall 90-day mortality (24.2% vs 6.7%, P = .001). Bacteremia and fungemia were significantly more common in the CMV infection group. CONCLUSION: Cytomegalovirus infection significantly influences the early post LDLT outcomes and contributes to increased overall mortality.

Uncommon cause of dysphagia: paraneoplastic achalasia.

Achalasia secondary to underlying neoplasm is a rare entity. Early recognition of secondary achalasia is important as its treatment involves management of underlying malignancy, while treatment of primary achalasia mainly involves lowering the lower oesophageal sphincter pressure with pneumatic dilatation or Heller's myotomy. We discuss an interesting case of achalasia secondary to non-Hodgkin's lymphoma.

Revisiting chronic rejection following living donor liver transplantation in the tacrolimus era: A single center experience.

BACKGROUND AND AIMS: Chronic rejection (CR) is an uncommon but important cause of graft dysfunction, leading to graft loss and often requires retransplantation. This study evaluates the incidence and outcome of the patients with CR at a large living donor liver transplant (LDLT) center. METHODS: Data of patients with CR were retrospectively analyzed in 1232 adult (age >18 years) LDLT on tacrolimus (mainly)-based immunosuppression. Sirolimus/everolimus (mammalian target of rapamycin [mTOR] inhibitors) was added to baseline immunosuppression as rescue therapy in patients with CR. Data are shown as median (interquartile range [IQR]). RESULTS: Twenty-three patients (22 males), aged 42 (IQR 45-56) years, had biopsy-proven chronic rejection at 21 (8-44) months after liver transplantation. The incidence of chronic rejection was 1.9% in this cohort. The patients with CR (n = 23) had a significantly higher incidence of cytomegalovirus (CMV) viremia, acute cellular rejection, and history of anastomotic biliary strictures as compared to patients without CR. Five patients were noncompliant with immunosuppression before the diagnosis of CR. Twelve patients (52%) responded to addition of mTOR inhibitors, whereas 11 did not respond and had poor outcome. CONCLUSION: The incidence of chronic rejection is low in LDLT. Treatment with mTOR inhibitors can reverse graft dysfunction in approximately half of the patients.

Nutritional status using subjective global assessment independently predicts outcome of patients waiting for living donor liver transplant.

BACKGROUND: Malnutrition is an important risk factor for adverse outcomes in patients awaiting liver transplant. Living donor liver transplant, being an elective procedure, allows nutritional rehabilitation and optimization of these patients before transplant. AIM: This paper aimed to evaluate the outcome of end-stage liver disease (ESLD) patients with various degrees of malnutrition waiting for living donor liver transplant. METHODS: Nutritional status was assessed using subjective global assessment (SGA) in patients who were evaluated for a liver transplant at our center from January 2015 to September 2015. All the data were collected prospectively. Predictive factors for mortality were analyzed using logistic regression and survival was obtained using Kaplan-Meier curves. RESULTS: One hundred and seventeen patients were grouped based on their nutrition status into normal, mild-moderate, and severe malnutrition. The groups were comparable in terms of age, sex, etiology of liver disease except alcoholic liver disease. Graft recipient weight ratio was comparable among groups. There was no significant difference in hospital stay. However, severe malnourished patients had higher incidence of sepsis (p=0.005) and death due to sepsis (p=0.01). Nutritional status was the only independent predictor of mortality on multivariate analysis. CONCLUSION: Nutritional status measured with SGA independently predicts short-term outcome of ESLD patients waiting and after living donor liver transplant.

(D+10) MELD as a novel predictor of patient and graft survival after adult to adult living donor liver transplantation.

We modified the previously described D-MELD score in deceased donor liver transplant, to (D+10)MELD to account for living donors being about 10 years younger than deceased donors, and tested it on living donor liver transplantation (LDLT) recipients. Five hundred consecutive LDLT, between July 2010 and December 2012, were retrospectively analyzed to see the effect of (D+10)MELD on patient and graft survival. Donor age alone did not influence survival. Recipients were divided into six classes based on the (D+10)MELD score: Class 1 (0-399), Class 2 (400-799), Class 3 (800-1199), Class 4 (1200-1599), Class 5 (1600-1999), and Class 6 (>2000). The 1 year patient survival (97.1, 88.8, 87.6, 76.9, and 75% across Class 1-5, P=.03) and graft survival (97.1, 87.9, 82.3, 76.9, and 75%; P=.04) was significantly different among the classes. The study population was divided into two groups at (D+10)MELD cut off at 860. Group 1 had a significantly better 1 year patient (90.4% vs 83.4%; P=.02) and graft survival (88.6% vs 80.2%; P=.01). While donor age alone does not predict recipient outcome, (D+10)MELD score is a strong predictor of recipient and graft survival, and may help in better recipient/donor selection and matching in LDLT.

Good outcome of living donor liver transplantation in drug-induced acute liver failure: A single-center experience.

INTRODUCTION: Drug-induced acute liver failure (ALF) is associated with high mortality. There is limited literature on results of living donor liver transplantation (LDLT). MATERIAL AND METHODS: The study was conducted at a tertiary care center in North India. All patients who received LDLT for drug-induced ALF were included. The data are shown as median (IQR). RESULTS: A total of 18 patients (15 females and three males), aged 34 (25-45) years, underwent LDLT for drug-induced liver injury (DILI)-related ALF. Etiology of ALF was antitubercular medications (n=14), orlistat (n=1), flutamide (n=1), and complementary alternative medications (n=2). The baseline parameters were as following: bilirubin 17.7 (16.3-23.8) mg/dL, INR 3.3 (2.5-4.0), jaundice encephalopathy interval 6 (3-17.5) days, arterial ammonia 109 µmol/L (73-215), Model for End-Stage Liver Disease (MELD) 24 (18-33), grade of encephalopathy 2 (1-4), which progressed to grade 3 (3-4) before transplantation. All patients underwent right lobe LDLT; hospital stay was 17 (13-22) days, and ICU stay was 5 (5-7) days. Two patients died in the first month after liver transplantation due to sepsis and multi-organ failure; the rest of the patients are alive and doing well at a follow-up of 50 (4-82 months). CONCLUSION: Good outcomes can be obtained by LDLT for drug-induced ALF.

Hepatocellular Carcinoma Presenting as Dyspnea at Rest due to Innumerable Lung Metastasis.

Hepatocellular carcinoma (HCC) the most common primary tumor of the liver usually develops in the setting of chronic liver disease. The presentation is usually due to worsening of chronic liver disease or being detected incidentally on imaging. Rarely metastasis to distant organ becomes the presentation. The authors describe a case of a 70-year-old woman who presented with dyspnea of 2 weeks duration. She was diagnosed as having HCC and extensive multiple pulmonary metastases. She was symptomatic only for the pulmonary metastasis with only 2 lesions in the liver. Because of advanced nature of disease, no specific therapy for the tumor was possible.

Lower relapse rates with good post-transplant outcome in alcoholic liver disease: Experience from a living donor liver transplant center.

INTRODUCTION: Post-transplant relapse is a major factor influencing the long-term outcome in alcoholic liver disease (ALD) patients. AIMS: The aim of this study was to evaluate the relapse rates following living donor liver transplantation (LDLT) in patients with ALD in the Indian context with strong family support. METHODS: Of 458 patients who underwent LDLT for ALD, 408 were included in the study. Post-transplant relapse was determined by information provided by the patient and/or family by means of outpatient and e-mail questionnaire, supported by clinical/biochemical parameters/liver histopathology. RESULTS: All except one were males, with a mean age of 46.9 ± 8.5 years. The overall rate of relapse was 9.5 % at 34.7 months (interquartile range (IQR) 15-57.6), lower than that reported in the literature from the West. The relapse rate was higher in patients with a shorter duration of pre-transplant abstinence (17.4 % and 15.4 % for recipients with pre-transplant abstinence of <3 and <6 months, respectively, p < 0.05). The overall survival was 88.5 % at 3 years. Of 39 patients with relapse, 16 (41 %) were occasional drinkers, 14 (35.8 %) were moderate drinkers, and 9 (23 %) were heavy drinkers. All the heavy drinkers presented with features of graft dysfunction. CONCLUSIONS: Good results can be obtained following LDLT for ALD, with significantly lower relapse rates in our setup as compared to the West.