Growth hormone deficiency and NAFLD: An overlooked and underrecognized link.

Growth hormone and its mediator insulin-like growth factor-1 exert their effect on different organs and control various physiologic metabolic processes. Adult growth hormone deficiency (AGHD) presents with one or more components of metabolic syndrome and can be associated with nonalcoholic fatty liver disease (NAFLD). AGHD is present in spectrum of hypothalamic/pituitary disorders as well as cranial radiation of brain tumors and often remains underdiagnosed or untreated due to its nonspecific symptoms, relatively difficult diagnosis in some clinical scenarios, and various barriers to treatment. NAFLD usually develops soon after diagnosis of AGHD and might progress rapidly to nonalcoholic steatohepatitis (NASH) with advanced fibrosis, eventually requiring liver transplantation. A timely initiation of growth hormone replacement therapy might be important, although studies so far have demonstrated controversial results on NAFLD, primarily due to small sample size and different diagnostic methods of NAFLD. Increased awareness of the association between AGHD and NAFLD would facilitate early diagnosis of NAFLD and NASH if present. Therefore, a multidisciplinary approach involving hepatology and endocrinology should become a standard of care for these patients.

Nonalcoholic fatty liver disease and obstructive sleep apnea in women with polycystic ovary syndrome.

Nonalcoholic fatty liver disease (NAFLD) and obstructive sleep apnea are frequently associated with polycystic ovary syndrome (PCOS) but remain underrecognized. Women with PCOS have a 2-4 times higher risk of NAFLD independent of body mass index than healthy weight-matched controls. Insulin resistance and hyperandrogenemia together play a central role in the pathogenesis of NAFLD. Timely diagnosis of NAFLD is important because its progression can lead to nonalcoholic steatohepatitis and/or advanced liver fibrosis that can eventually result in liver-related mortality. The presence of NAFLD has also been associated with increased risks of type 2 diabetes, cardiovascular events, overall mortality, and extrahepatic cancers. The treatment of NAFLD in PCOS should include lifestyle interventions. Glucagon-like peptide 1 receptor agonists have shown promising results in patients with PCOS and NAFLD, but future randomized trails are needed to confirm this benefit. Likewise, the use of combined oral estrogen-progestin contraceptives may provide a benefit by decreasing hyperandrogenemia. Sleep disordered breathing is common among women with PCOS and is responsible for a number of cardiometabolic derangements. Obstructive sleep apnea is most often found in overweight and obese women with PCOS, but as is the case with NAFLD, its prevalence exceeds that of women who are of similar weight without PCOS. Left untreated, obstructive sleep apnea can precipitate or exacerbate insulin resistance, glucose intolerance, and hypertension.

Clinical predictors of symptom improvement failure in gastroparesis.

Background: The aim of this study was to determine clinical predictors of gastroparesis outcomes. Methods: Between September 30, 2009 and January 31, 2020, we identified patients with gastroparesis diagnosed based on a 99mTc sulfur-labeled gastric emptying test. The patients who had no symptom improvement at 4 and 12 weeks were considered to have failed to show clinical improvement. Logistic regression was used to compute the association between different factors and clinical outcomes. Results: We identified 320 patients (mean age 47.5±5.3 years, 70.3% female, 71.3% Whites). Failure of clinical improvement was seen in 34.7% patients at 4 weeks and 27.5% at 12 weeks after the gastroparesis diagnosis. At 4 weeks, chronic kidney disease (adjusted odds ratio [aOR] 2.62, 95% confidence interval [CI] 1.31-5.26; P=0.007) and body mass index (BMI) <18.5 kg/m2 (aOR 9.90, 95%CI 2.98-32.93; P<0.001) were associated with a lack of improvement, whereas type 2 diabetes mellitus (T2DM) was associated with better clinical outcomes (aOR 0.50, 95%CI 0.25-0.99; P=0.047). At 12 weeks, subjects who had undergone post-bariatric surgery had no improvement of their gastroparesis symptoms (aOR 2.43, 95%CI 1.01-5.82; P=0.047), whereas T2DM was associated with clinical improvement (aOR 0.46, 95%CI 0.22-0.95; P=0.035). The subgroup analysis showed that BMI <18.5 kg/m2 in non-diabetics and peripheral neuropathy in diabetics were associated with persistent symptoms. Conclusions: Gastroparesis patients with T2DM had significant symptom improvement. A history of bariatric surgery and renal failure were associated with worse clinical improvement. Peripheral neuropathy in diabetics was associated with persistent symptoms.

Diabetes and Hepatocellular Carcinoma: Incidence Trends and Impact of Liver Disease Etiology.

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) remains the leading cause of cancer-related death among patients with type 2 diabetes mellitus (T2DM). We aimed to assess the independent role of T2DM on HCC risk among patients with different liver disease etiologies. METHODS: We analyzed the United Network for Organ Sharing database of all adults registered for liver transplantation (LT) between February 27, 2002 and December 31, 2017. For initial analyses, patients were divided into four groups: nonalcoholic steatohepatitis (NASH) and all other etiologies with or without T2DM. For additional analyses, we divided them based on underlying etiology. Logistic regression was used to evaluate the impact of T2DM with NASH and other etiologies on HCC risk. RESULTS: Overall, 24,149 (21.6%) of the listed patients had HCC. Of those, 23.9% had T2DM. When compared with nondiabetics, patient with NASH and T2DM had the highest risk of HCC (odds ratio [OR] 1.68; 95% confidence interval [CI] 1.52-1.86), followed by patients with other etiologies and diabetes. After adjusting for other risk factors, these associations remained unchanged. Registrants with T2DM and NASH, cryptogenic cirrhosis, hepatitis C, and alcoholic liver disease were at higher risk of HCC than those without diabetes, but in patients with chronic hepatitis B or primary biliary cholangitis, diabetes did not increase the HCC risk. Between 2004 and 2016, the annual percentage change of HCC incidence increased for all patients with NASH and hepatitis C regardless of their diabetes status. For those with hepatitis B, this trend was significant only for diabetics. CONCLUSIONS: The additive risk of T2DM for HCC development was highest in patients with NASH. HCC risk may vary depending on the underlying etiology.

Acute-on-chronic liver failure in liver transplant candidates with non-alcoholic steatohepatitis.

Non-alcoholic fatty liver disease (NAFLD) has become the most common liver disease worldwide. It is expected that non-alcoholic steatohepatitis (NASH), NASH-related cirrhosis and its decompensated forms will increase further in the next two decades. Acute-on-chronic liver failure (ACLF) is a distinct syndrome characterized by rapid deterioration of liver function in patients with chronic liver disease that is associated with development of one or more organ failures, and carries a very high short-term mortality. There is a paucity of data on ACLF in patients with NASH cirrhosis. Recent studies have shown that although ACLF incidence due to NASH is lower when compared to other etiologies, NASH is the fastest growing liver disease etiology among all ACLF hospitalizations. Higher rates of infections, as a precipitating factor, and circulatory failure were noted in this population. Metabolic derangements such as obesity and diabetes might also play a confounding role in the pathophysiology, clinical course, and prognosis of NASH patients with ACLF. Patients with ACLF due to NASH have shown a lower inpatient mortality despite a longer hospital length-of-stay and a higher 28- and 90-day mortality. Patients with ACLF should be promptly transferred to a transplant center and evaluated for liver transplantation (LT). Optimal prognostic scores, timing of LT, and the best bridge to LT therapy and treatment of post-LT complications need to be elucidated in prospective studies.

A Combination of N-Acetylcysteine and Prednisone Has No Benefit Over Prednisone Alone in Severe Alcoholic Hepatitis: A Retrospective Analysis.

INTRODUCTION: In this study, we assessed whether there were any survival advantages with a combination treatment of intravenous N-acetylcysteine (NAC) and prednisone over prednisone alone in those with severe alcoholic hepatitis [discriminant function (DF) ≥ 32]. PATIENTS AND METHODS: Between January 1, 2013, and February 28, 2019, we identified 68 patients (mean age 47.2 years ± 10.1, 57% women, 65% cirrhosis, MELD score 28.1 ± 6.6) with alcoholic hepatitis, and of those, 21 (31%) received prednisone and 47 (69%) received prednisone + NAC. Lille score ≥ 0.45 was considered a poor response. Renal insufficiency was defined as GFR < 60 ml/min/1.73m2 calculated on two separate occasions. RESULTS: DF (74.2 ± 33.6 vs. 56.9 ± 15.9, p = 0.09) was similar, but MELD (29.2 ± 6.3 vs. 25.5 ± 6.4, p = 0.03) scores were higher in the combination group. The overall 30-day and 90-day mortality was 13.2% (9/68) and 20.6% (14/68), respectively. Women were more likely (OR 4.86, 95% CI 1.62-14.59) to respond to treatment based on Lille score compared to men, but the type of treatment regimen had no effect on Lille score (OR 0.84, 95% CI 0.25-2.78). Treatment regimen had no effect on both adjusted and unadjusted survivals. Multivariate analysis, after adjusting for confounding variables, confirmed these observations. DF + renal insufficiency had the highest AUROC (0.86) to predict mortality. CONCLUSION: The combination treatment of NAC + prednisone is not better than prednisone alone in patients with severe alcoholic hepatitis.

Systemic Therapy for Advanced Hepatocellular Carcinoma: An Update of a Rapidly Evolving Field.

Hepatocellular carcinoma (HCC) incidence and mortality have shown an unfavorable upward trend over the last two decades, especially in developed countries. More than one-sixth of the patients have advanced HCC at presentation. Systemic therapy remains the treatment of choice for these patients. Current options include tyrosine kinase inhibitors (TKIs) and immunotherapy. This review aims to summarize current knowledge on the rapidly evolving field of systemic therapy with several newly approved medications over the last year. Sorafenib remains one of the first-line treatment choices for patients with hepatitis C etiology, intermediate to advanced HCC stage, and Child-Pugh class A. Lenvatinib is the other first-line drug that might have better efficacy in non-hepatitis C etiologies and advanced HCC without portal vein thrombosis. Patients intolerant to first-line therapy might benefit from immunotherapy with nivolumab or pembrolizumab. In those who fail first-line therapy, the choice should be based on the side effects related to previous treatment, performance status, and underlying liver dysfunction. Ongoing studies are investigating immunotherapy alone or immunotherapy in combination with TKIs as first-line therapy. Several second-line options for combination systemic therapy and systemic plus local-regional treatment are under investigation. Future studies should focus on identifying reliable biomarkers to predict response to therapy and to better stratify patients at high risk for progression. Multidisciplinary approach is pivotal for successful outcomes in patients with advanced HCC.

Autoimmune hepatitis: Current and future therapeutic options.

Autoimmune hepatitis (AIH) is a rare immune-mediated liver disease with few major advances in treatment options over the last several decades. Available options are effective in most patients albeit are imprecise in their mechanisms. Novel and more tolerable induction regimens and alternative options for management of patients intolerant or with suboptimal response to traditional therapies including in the post-transplant setting remain an important unmet need. This review aims to summarize recent data on pharmacological options and investigational drugs in development for patients with AIH. Standard therapy using prednisone with or without azathioprine remains the mainstay of therapy and is effective in most patients. Budesonide may be considered for induction in early disease and in those with mild fibrosis, but has not been approved for maintenance therapy. Mycophenolate mofetil (MMF) in combination with steroids might be an alternative first-line therapy, but results from a randomized trial are awaited. MMF as a second-line maintenance agent has moderate efficacy though more frequent adverse events in patients with cirrhosis may be seen. Tacrolimus may be an equally effective second-line option particularly in non-responders, but data remain limited. Management of recurrent AIH post-liver transplantation remains controversial with insufficient data to support long-term steroid use. Moving forward, expanding the scope of therapeutic options to include biologics including B-cell depleting agents may be a promising step. Recent insights in understanding the pathogenesis of AIH could serve as a basis for future therapies, including the elucidation of different immunoregulatory pathways and the potential role of the intestinal microbiome.

Nonalcoholic Steatohepatitis is the Most Rapidly Increasing Indication for Liver Transplantation in Young Adults in the United States.

GOALS: To analyze the frequency and trend of liver transplantation (LT) for nonalcoholic steatohepatitis (NASH) cirrhosis in young adults aged 18 to 40 years and to assess post-LT outcomes in this age group. BACKGROUND: NASH is currently the fastest-growing indication for LT in US adults. It is believed that NASH is a rare indication for LT among young adults. STUDY: Using the United Network for Organ Sharing database, we performed a retrospective cohort analysis of all LTs in young adults between 2002 and 2012. Incidence rate ratio was calculated for each indication. RESULTS: A total of 5157 young adults underwent LT over the study period-54% were male, 23% obese. Mean (±SD) age and body mass index were 31.6±6.7 years and 26.3±6.1 kg/m, respectively. The incidence of LTs performed for NASH cirrhosis increased from 0.53% in 2002 to 4.46% in 2012. NASH was the most rapidly growing indication for LT among all other etiologies with a 14% increment per year (incidence rate ratio, 1.14; 95% confidence interval, 1.09-1.20, P<0.001). The 5-year post-LT outcomes were comparable between NASH and non-NASH recipients, but graft survival was lower and retransplantation cumulative rates were higher in NASH recipients compared with those with other metabolic liver diseases (63.5% vs. 81.4%, P=0.003 and 12.7% vs. 4.2%, P=0.046, respectively). CONCLUSIONS: NASH is the fastest-growing indication for LT among young US adults aged 18 to 40 years and now accounts for almost 5% of all LTs in this age group.

Increasing Burden of Chronic Liver Disease Among Adolescents and Young Adults in the USA: A Silent Epidemic.

BACKGROUND AND AIMS: Chronic liver disease (CLD) starts or becomes established in the adolescent and young adult (AYA) age group. This study aimed to estimate trends in CLD prevalence among US AYAs and to assess factors associated with CLD. METHODS: Cross-sectional data from 14,547 AYAs (population-weighted N = 68,274,386) aged 15-39 years enrolled in the National Health and Nutrition Examination Survey from 1988 to 2012 were used. Nonalcoholic fatty liver disease (NAFLD) was defined as elevated alanine aminotransferase (>19 U/L for females and >30 U/L for males) in subjects with BMI ≥ 25 kg/m2; alcoholic liver disease (ALD) as excessive alcohol use (≥3 drinks/day for men and ≥2 drinks/day for women) and elevated aminotransferases after excluding alternative etiologies. Participants were considered hepatitis C virus (HCV) positive if antibody to HCV and HCV-RNA was positive. RESULTS: There was a sharp increase in the prevalence of CLD from 12.9% in 1988-1994 to 28.5% in 1999-2004 that remained stable after that (27.7%). NAFLD was the most common etiology accounting for 22% of all CLD in the later period. The prevalence of ALD has been steadily increasing throughout the years, while HCV has been decreasing. On multivariate analysis, being overweight/obese, Mexican-American ethnicity, later study period, older age, and male gender, were associated with higher odds of having CLD. CONCLUSION: More than one quarter of US AYAs might be affected by CLD. CLD prevalence in this age group has more than doubled over the past three decades mainly due to rise in NAFLD prevalence.

Nonalcoholic fatty liver disease in adolescents and young adults: The next frontier in the epidemic.

Nonalcoholic fatty liver disease (NAFLD) is a significant health burden in adolescents and young adults (AYAs) which has substantially risen in prevalence over the last decades. The occurrence of NAFLD parallels high rates of obesity and metabolic syndrome in this age group, with unhealthy lifestyle also playing an independent role. Genetic factors, sex, and ethnicity should be considered in a risk stratification model. NAFLD and nonalcoholic steatohepatitis (NASH) in AYAs often go unrecognized and, if untreated, can progress eventually to cirrhosis requiring liver transplantation (LT) before the age of 40. Recently, NASH has increased as an indication for LT in this age group. Important knowledge gaps include the feasibility of noninvasive diagnostic tests and imaging modalities as well as uncertainty about unique histological features and their predictive value. Future clinical trials focused on AYAs are needed to determine effectiveness of therapies. Tools for increasing awareness and prevention of NAFLD in AYAs are greatly needed. (Hepatology 2017;65:2100-2109).

De Novo Malignancies After Transplantation: Risk and Surveillance Strategies.

De novo malignancies are one of the leading causes of late mortality after liver and kidney transplantation. Nonmelanoma skin cancer is the most common malignancy, followed by posttransplant lymphoproliferative disorder and solid organ tumors. Immunosuppression is a key factor for cancer development, although many other transplant-related and traditional risk factors also play a role. In this review, the authors summarize risk factors and outcomes of frequently encountered de novo malignancies after liver and kidney transplantation to stratify recipients at highest risk. Future efforts in prospectively validated, cost-effective surveillance strategies that improve survival of these complex patients are greatly needed.

The Intestinal Microbiome and the Liver Transplant Recipient: What We Know and What We Need to Know.

The intestinal microbiome and immune system are in close symbiotic relationship in health. Gut microbiota plays a role in many chronic liver diseases and cirrhosis. However, alterations in the gut microbiome after liver transplantation and the implications for liver transplant recipients are not well understood and rely mainly on experimental animal studies. Recent advances in molecular techniques have identified that increased intestinal permeability, decreased beneficial bacteria, and increased pathogenic species may play important roles in the early posttransplant period. The associations between microbiota perturbation and postliver transplant infections and acute rejection are evolving. The link with metabolic syndrome, obesity, and cardiac disease in the general population require translation into the transplant recipient. This review focuses on our current knowledge of the known and potential interaction of the microbiome in the liver transplant recipient. Future human studies focused on microbiota changes in liver transplant patients are warranted and expected.

Effect of weight loss on magnetic resonance imaging estimation of liver fat and volume in patients with nonalcoholic steatohepatitis.

BACKGROUND & AIMS: Little is known about how weight loss affects magnetic resonance imaging (MRI) of liver fat and volume or liver histology in patients with nonalcoholic steatohepatitis (NASH). We measured changes in liver fat and liver volume associated with weight loss by using an advanced MRI method. METHODS: We analyzed data collected from a previous randomized controlled trial in which 43 adult patients with biopsy-proven NASH underwent clinical evaluation, biochemical tests, and MRI and liver biopsy analyses at the start of the study and after 24 weeks. We compared data between patients who did and did not have at least 5% decrease in body mass index (BMI) during the study period. RESULTS: Ten of 43 patients had at least a 5% decrease in BMI during the study period. These patients had a significant decrease in liver fat, which was based on MRI proton density fat fraction estimates (18.3% ± 7.6% to 13.6% ± 13.6%, P = .03), a relative 25.5% reduction. They also had a significant decrease in liver volume (5.3%). However, no significant changes in levels of alanine aminotransferase or aspartate aminotransferase were observed with weight loss. Thirty-three patients without at least 5% decrease in BMI had insignificant increases in estimated liver fat fraction and liver volume. CONCLUSIONS: A reduction in BMI of at least 5% is associated with significant decrease in liver fat and volume in patients with biopsy-proven NASH. These data should be considered in assessing effect size in studies of patients with nonalcoholic fatty liver disease or obesity that use MRI-estimated liver fat and volume as end points.

Effect of metformin on ballooning degeneration in nonalcoholic steatohepatitis (NASH): when to use metformin in nonalcoholic fatty liver disease (NAFLD).

The key histologic feature of nonalcoholic steatohepatitis (NASH) is hepatocellular ballooning (HB). It plays an important role in NASH progression and is an independent predictor of liver mortality. In this review, we identified all studies using metformin in the treatment of nonalcoholic fatty liver disease (NAFLD) that included pre- and post-treatment liver biopsies. We specifically reviewed the effects of metformin on HB. Improved HB was noted in pediatric populations and in those adult patients who were able to lose weight and improve or normalize transaminases during therapy. Previous studies have supported the beneficial effects of metformin in reduction of body weight, improvement of insulin resistance, prevention of complications related to diabetes and chemo-preventive benefits in reducing hepatocellular carcinoma. All these effects make it an attractive treatment consideration for patients with diabetes, and prediabetes who have co-existing NAFLD. Future studies are warranted in order to confirm this effect of metformin on HB and its association with improving long-term outcomes in patients with NAFLD.

Serum γ-glutamyltranspeptidase predicts all-cause, cardiovascular and liver mortality in older adults.

BACKGROUND: Serum γ-glutamyltranspeptidase (GGT), a marker of fatty liver disease (FLD), predicts mortality in young adults. However, the association between serum GGT and mortality in older adults is unclear. OBJECTIVES: To examine if elevated serum GGT predicts all-cause, cardiovascular (CVD), and liver mortality in community-dwelling older adults. DESIGN AND SETTING: A prospective cohort study including 2364 participants (mean-age 70 yr, BMI-24.5 kg/m2, 54% women) from the Rancho Bernardo Study who attended a research visit in 1984-87 when multiple metabolic covariates were ascertained including serum GGT. They were followed for a mean (± standard deviation) of 13.7 (±6.2) years. MEASUREMENT: Multivariable-adjusted Cox-proportional hazards analyses were conducted to examine the association between elevated serum GGT (>51 U/L in men and > 33 U/L in women) and all-cause, CVD, and liver mortality. RESULTS: In these older men and women, cumulative mortality was 56.2% (n=1329) with CVD and liver mortality accounting for 49.4% and 2.3% of all deaths, respectively, over 32,387 person-years of follow-up. In multivariate analyses (adjusted for age, sex, alcohol use, body-mass-index, total cholesterol, HDL cholesterol, serum triglyceride, smoking status, systolic blood pressure, diabetes mellitus, serum interleukin-6, and c-reactive protein), serum GGT elevation was significantly associated with all-cause (HR, 1.55, 95% CI, 1.21-1.98), CVD (HR, 1.51, 95% CI, 1.04-2.17), and liver mortality (HR, 9.10, 95% CI, 3.42-24.26). CONCLUSIONS: In community-dwelling older adults, serum GGT is an independent predictor of all-cause, CVD, and liver mortality.

Prognostic implication of liver histology in patients with nonalcoholic fatty liver disease in diabetes.

Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) frequently coexist due to shared risk factors. Their rising prevalence parallels the growing epidemic of obesity and insulin resistance (IR). In patients with T2DM and biopsy-proven NAFLD, a significantly higher prevalence of nonalcoholic steatohepatitis (NASH) (63-87%), any fibrosis (22-60%), and advanced fibrosis (4-9%) is noted. Possible risk factors for more advanced liver disease include concomitant metabolic syndrome with three or more components, visceral obesity, older age, increased duration of diabetes, and family history of diabetes. Liver biopsy is strongly suggested in these patients. Cardiovascular disease (CVD) and malignancy are the leading causes of death in this population, but a growing body of evidence shows liver-related mortality as an important cause of death, including an increased rate of hepatocellular carcinoma (HCC) in diabetes. The presence of NAFLD in T2DM is also associated with increased overall mortality. We aim with this review to summarize the results from studies investigating NAFLD in T2DM and to outline the factors that predict more advanced liver histology as well as the impact of these hepatic changes on CVD, overall and liver-related mortality.