Thyroid Hormone and Mitochondrial Dysfunction: Therapeutic Implications for Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD).

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly termed nonalcoholic fatty liver disease (NAFLD), is a widespread global health concern that affects around 25% of the global population. Its influence is expanding, and it is anticipated to overtake alcohol as the leading cause of liver failure and liver-related death worldwide. Unfortunately, there are no approved therapies for MASLD; as such, national and international regulatory health agencies undertook strategies and action plans designed to expedite the development of drugs for treatment of MASLD. A sedentary lifestyle and an unhealthy diet intake are important risk factors. Western countries have a greater estimated prevalence of MASLD partly due to lifestyle habits. Mitochondrial dysfunction is strongly linked to the development of MASLD. Further, it has been speculated that mitophagy, a type of mitochondrial quality control, may be impaired in MASLD. Thyroid hormone (TH) coordinates signals from the nuclear and mitochondrial genomes to control mitochondrial biogenesis and function in hepatocytes. Mitochondria are known TH targets, and preclinical and clinical studies suggest that TH, thyroid receptor ß (TR-ß) analogs, and synthetic analogs specific to the liver could be of therapeutic benefit in treating MASLD. In this review, we highlight how mitochondrial dysfunction contributes to development of MASLD, and how understanding the role of TH in improving mitochondrial function paved the way for innovative drug development programs of TH-based therapies targeting MASLD.

Mitochondrial Dysfunction Plays Central Role in Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is a global pandemic that affects one-quarter of the world's population. NAFLD includes a spectrum of progressive liver disease from steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis and can be complicated by hepatocellular carcinoma. It is strongly associated with metabolic syndromes, obesity, and type 2 diabetes, and it has been shown that metabolic dysregulation is central to its pathogenesis. Recently, it has been suggested that metabolic- (dysfunction) associated fatty liver disease (MAFLD) is a more appropriate term to describe the disease than NAFLD, which puts increased emphasis on the important role of metabolic dysfunction in its pathogenesis. There is strong evidence that mitochondrial dysfunction plays a significant role in the development and progression of NAFLD. Impaired mitochondrial fatty acid oxidation and, more recently, a reduction in mitochondrial quality, have been suggested to play a major role in NAFLD development and progression. In this review, we provide an overview of our current understanding of NAFLD and highlight how mitochondrial dysfunction contributes to its pathogenesis in both animal models and human subjects. Further we discuss evidence that the modification of mitochondrial function modulates NAFLD and that targeting mitochondria is a promising new avenue for drug development to treat NAFLD/NASH.

The Utility and Diagnostic Accuracy of Transient Elastography in Adults with Morbid Obesity: A Prospective Study.

Patients with morbid obesity are at high risk for nonalcoholic fatty liver disease (NAFLD) complicated by liver fibrosis. The clinical utility of transient elastography (TE) by Fibroscan in patients with morbid obesity (body mass index (BMI) ≥ 40 kg/m2) is not well-defined. We examined the diagnostic accuracy of Fibroscan in predicting significant liver fibrosis (fibrosis stage ≥2) in morbidly obese patients (BMI ≥ 40 kg/m2). Patients scheduled for bariatric surgery were prospectively enrolled. Intraoperative liver biopsy, liver-stiffness measurement (LSM) by Fibroscan (XL probe), and biochemical evaluation were all performed on the same day. The endpoint was significant liver fibrosis defined as fibrosis stage ≥2 based on the Nonalcoholic Steatohepatitis Clinical Research Network. The optimal LSM cutoff value for detecting significant fibrosis was determined by using the Youden Index method. Routine clinical, laboratory, and elastography data were analyzed by stepwise logistic regression analysis to identify predictors of significant liver fibrosis and build a predictive model. An optimal cutoff point of the new model's regression formula for predicting significant fibrosis was determined by using the Youden index method. One hundred sixty-seven patients (mean age, 46.4 years) were included, of whom 83.2% were female. Histological assessment revealed the prevalence of steatohepatitis and significant fibrosis of 40.7% and 11.4%, respectively. The median LSM was found to be significantly higher in the significant fibrosis group compared to those in the no or non-significant fibrosis group (18.2 vs. 7.7 kPa, respectively; p = 0.0004). The optimal LSM cutoff for predicting significant fibrosis was 12.8 kPa, with an accuracy of 71.3%, sensitivity of 73.7%, specificity of 70.9%, positive predictive value of 24.6%, negative predictive value of 95.5%, and ROC area of 0.723 (95% CI: 0.62-0.83). Logistic regression analysis identified three independent predictors of significant fibrosis: LSM, hemoglobin A1c, and alkaline phosphatase. A risk score was developed by using these three variables. At an optimal cutoff value of the regression formula, the risk score had an accuracy of 79.6% for predicting significant fibrosis, sensitivity of 89.5%, specificity of 78.4%, positive predictive value of 34.7%, negative predictive value of 98.3%, and ROC area of 0.855 (95% CI: 0.76-0.95). Fibroscan utility in predicting significant liver fibrosis in morbidly obese subjects is limited with accuracy of 71.3%. A model incorporating hemoglobin A1c and alkaline phosphatase with LSM improves accuracy in detecting significant fibrosis in this patient population.

Potential Association of Doxycycline With the Onset of Primary Sclerosing Cholangitis: A Case Series.

BACKGROUND: Primary sclerosing cholangitis (PSC) is linked to inflammatory bowel diseases (IBD). Evidence suggests an association between the gut microbiome and PSC. However, the putative relationship between exposure to antibiotics and onset of PSC has never been reported. We observed 3 cases in which patients without antecedent liver or bowel issues developed symptoms leading to diagnosis of IBD and subsequently PSC after being exposed to doxycycline. We aimed to identify, through the PSC Partners national patient registry, additional cases of PSC in which there is a temporal relationship between exposure to doxycycline and onset of PSC or PSC-IBD. AREAS OF UNCERTAINTY: The etiopathogenesis of PSC remains an enigma. DATA SOURCES: We collected data from patients with PSC and PSC-IBD in which there seemed to be a temporal relationship between exposure to doxycycline and PSC. Time from doxycycline exposure to: (1) onset of PSC or PSC-IBD symptoms and (2) diagnosis of PSC were documented for each patient. Descriptive statistical analyses were performed. RESULTS: We identified 6 additional patients with PSC or PSC-IBD in whom there was a temporal relationship between exposure to doxycycline and onset of PSC or PSC-IBD. The median age of these 9 patients was 20 years, 6 were female, and 7 had ulcerative colitis. The median time from doxycycline exposure to onset of first symptoms was 3 months, and median time from doxycycline exposure to diagnosis of PSC was 15 months. THERAPEUTIC HYPOTHESIS: We describe 9 cases of PSC and PSC-IBD in which there seem to be a temporal relationship between exposure to doxycycline and onset of PSC.

The PSC scientific community resource: an asset for multi-omics interrogation of primary sclerosing cholangitis.

BACKGROUND: Primary sclerosing cholangitis (PSC) is a rare, chronic cholestatic liver disease that often progresses to end-stage liver disease and/or the development of hepatobiliary neoplasia. Lack of prognostic tools and treatment options for PSC is driven in part by our poor understanding of its pathogenesis, which is thought to be complex, the interaction of genetic variants, environmental influences and biological response throughout the course of disease. The PSC Scientific Community Resource (PSC-SCR) seeks to overcome previous shortcomings by facilitating novel research in PSC with the ultimate goals of individualizing patient care and improving patient outcomes. METHODS: PSC patients who receive their health care at Mayo Clinic or a collaborating site are identified by chart review and invited in person or by mail to participate. Non-Mayo patients are offered enrollment if they provide sufficient access to their medical records to evaluate inclusion/exclusion criteria. Controls without liver disease are identified with assistance of the Mayo Clinic Biobank. Participant consent is obtained at the beginning of the recruitment process by mail-in, electronic or face-to-face protocols. Clinical data is extracted from the medical record by qualified physicians and entered in a custom designed database. Participants fill out a custom-designed, comprehensive questionnaire, which collects scientifically relevant demographic and clinical information. Biospecimens are collected using mail-in kits thar are returned via overnight carrier service and processed by the biospecimen accessioning and processing facility at Mayo Clinic, which coordinates sample transfers and provides required sample preparation services. The resource is currently being utilized to perform omics-scale projects investigating the exposome, metabolome, methylome, immunome and microbiome in PSC. Datasets and residual biospecimens will be shared with researchers proposing scientifically sound PSC-focused research with approval of the appropriate review boards. DISCUSSION: Patient-based studies leveraging the latest technologies for targeted and wide-scale interrogation of multiple omics layers offer promise to accelerate PSC research through discovery of unappreciated aspects of disease pathogenesis. However, the rarity of PSC severely limits such studies. Here we describe our effort to overcome this limitation, the PSC-SCR, a repository of patient biospecimens coupled with clinical and omics data for use by the broader PSC research community.

A Model Incorporating Serum Alkaline Phosphatase for Prediction of Liver Fibrosis in Adults with Obesity and Nonalcoholic Fatty Liver Disease.

We assessed the relationship between serum alkaline phosphatase (ALP) and liver fibrosis by histology, in addition to other noninvasive parameters, in obese patients undergoing metabolic surgery. Patients scheduled for elective bariatric surgery were prospectively recruited from a bariatric clinic. An intraoperative liver biopsy was performed, and liver histology was evaluated by a pathologist blinded to the patients' data. The endpoint was significant fibrosis defined as fibrosis stage ≥ 2. Independent predictors of fibrosis were identified by logistic regression. Two hundred ten patients were recruited. Liver histology revealed steatosis in 87.1%, steatohepatitis in 21.9%, and significant fibrosis in 10%. Independent predictors of significant fibrosis were ALP (Odds Ratio (OR) 1.03; 95% Confidence interval (CI), 1.01-1.05), alanine aminotransferase (OR 1.02; 95% CI, 1.01-1.03), HbA1c (OR 1.58; 95% CI, 1.20-2.09), and body mass index (OR 1.06; 95% CI, 1.00-1.13). A tree-based model was developed to predict significant fibrosis, with a receiver operating characteristic (ROC) area of 0.845, sensitivity of 0.857, specificity of 0.836, and accuracy of 0.931. The applicability of serum ALP as an independent biomarker of liver fibrosis should be considered in obesity surgery patients, and in the broader context of obese patients with nonalcoholic fatty liver disease.

Successful response of primary sclerosing cholangitis and associated ulcerative colitis to oral vancomycin may depend on brand and personalized dose: report in an adolescent.

Primary sclerosing cholangitis (PSC) is a rare, progressive liver disease characterized by cholestasis and bile duct fibrosis that has no accepted therapy known to delay or arrest its progression. We report a 23-year-old female patient who at age 14 was diagnosed with moderate pancolonic ulcerative colitis (UC) and at age 15 with small-duct PSC unresponsive to conventional therapy. The patient began single drug therapy with the antibiotic oral vancomycin (OVT) and achieved normalization of liver enzymes and resolution of UC symptoms with colonic mucosal healing. These improvements have persisted over 8 years. There has been no colon dysplasia, liver fibrosis or failure, bile duct stricture, or cancer. Of note, the patient's response was dependent on the brand of oral vancomycin capsule, as well as dose. This raised the questions of possible differences in bioequivalence of different commercial versions of the drug and whether this factor might play into the variability of efficacy seen in published trials. Evidence suggests that oral vancomycin both alters the intestinal microbiome and has immunomodulatory effects. Its striking effectiveness in this and other patients supports further investigation in randomized trials, with careful attention to its bioavailability profile in the gut.

The long-term outcomes of patients with immunoglobulin G4-related sclerosing cholangitis: the Mayo Clinic experience.

BACKGROUND: The long-term outcomes of immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) are not well known. METHODS: The outcomes of patients with IgG4-SC at Mayo Clinic (1999-2018) were compared to an age- and gender-matched (1:1 ratio) group of patients with primary sclerosing cholangitis (PSC). RESULTS: We identified 89 patients with IgG4-SC; median age at diagnosis was 67 years, 81% were males, and the median follow-up was 5.7 years. Seventy-eight patients received prednisone for induction of remission, and 53 received at least one other immunosuppressive agent for maintenance of remission. Of the IgG4-SC group, 10 died (median time from diagnosis until death was 6.5 years): 2 due to cirrhosis, 3 due to cholangiocarcinoma (CCA), and 5 due to non-hepatobiliary causes. Eleven patients in the PSC group underwent liver transplantation, while none did in the IgG4-SC group. The incidence of a hepatobiliary adverse event (cirrhosis or CCA) was 3.4 times greater in the PSC compared to the IgG4-SC group (events per 1000 person-years: 52.6; 95% CI 38-73; vs. 15.6; 95% CI 7-32). The probability of development of a hepatobiliary adverse event within 10 years was 11% in the IgG4-SC compared to 45% in the PSC group (P = 0.0001). The overall survival tended to be higher in the IgG4-SC compared to the PSC group (10-year: 79% vs. 68%, respectively; P = 0.11). CONCLUSIONS: In a cohort of IgG4-SC patients, 88% of whom were treated with immunosuppressive drugs, the risk of cirrhosis and CCA was significantly lower compared to an age- and gender-matched group with PSC.

Open-label prospective therapeutic clinical trials: oral vancomycin in children and adults with primary sclerosing cholangitis.

BACKGROUND: Oral vancomycin (OV) in primary sclerosing cholangitis (PSC) has been evaluated as a potential therapeutic agent. We report the long-term biochemical course and outcomes of patients with PSC treated with OV. METHODS: Patients were enrolled in 2 open-label clinical trials (ClinicalTrials.gov Identifier: NCT01802073 and NCT01322386) and offered OV at 50 mg/kg/day in 3 divided doses if weight <30kg, and 500 mg 3 times/day if weight ≥30kg. Patients with biliary strictures requiring stenting or awaiting liver transplant were excluded. Liver biochemistry, MRCP and histology were documented at baseline and while on OV. The primary outcome was a decrease in elevated gamma glutamyl transferase (GGT), alkaline phosphatase (ALP), and/or alanine aminotransferase (ALT) from baseline. RESULTS: 30 subjects were enrolled, and 29 additional subjects who learned of the clinical trial requested OV (total n = 59; median age was 13.5 years [range, 1.5-44 years]; 64.4% were male; and 94.9% had inflammatory bowel disease [IBD]). The median treatment duration was 2.7 years (range, 0.2-14 years). Ninety-six percent (57/59), 81.3% (48/59), and 94.9% (56/59) experienced reduction of GGT, ALP, and ALT, respectively. Furthermore, 39% (23/59), 22% (13/59), and 55.9% (33/59) experienced normalization of GGT, ALP, and ALT, respectively, within the first 6 months of OV treatment. One patient underwent liver transplantation 8 years after beginning OV treatment, and one developed biliary strictures requiring endoscopic intervention. OV was well-tolerated by patients, and no patient developed treatment-related adverse events. CONCLUSION: In PSC, OV was well-tolerated and was associated with improvement in liver chemistry. A randomized placebo-controlled clinical trial is warranted.

The efficacy and safety of endoscopic ultrasound-guided liver biopsy versus percutaneous liver biopsy in patients with chronic liver disease: a retrospective single-center study.

BACKGROUND AND AIMS: There is limited literature on endoscopic ultrasound-guided liver biopsy (EUS-LB), a new method of obtaining liver biopsy (LB). METHODS: We conducted a retrospective study of the efficacy and safety of EUS-LB compared to percutaneous liver biopsy (PC-LB) in patients with chronic liver disease at our center between January 2018 and August 2019. RESULTS: Thirty patients underwent EUS-LB and 60 patients underwent PC-LB were identified (median follow-up post-LB was 8 days; interquartile range (IQR), 3-5 days). The median number of portal tracts was significantly higher in the PC-LB group (13 vs. 5; P < 0.0001). A histologic diagnosis was established in 93% of the EUS-LB group, compared to 100% in the PC-LB group (P = 0.841). Patients in EUS-LB group had significantly shorter hospital stay (median time of hospital stay was 3 vs. 4.2 h in the EUS-LB vs. PC-LB group, respectively; P = 0.004) and reported less pain compared to PC-LB group (median pain score was 0 vs. 3.5; P = 0.0009). EUS-LB were performed using a 19-gauge (n = 27) or 22-gauge (n = 3); there was a tendency towards higher number of portal tracts in the 22- vs. the 19-gauge needle group (6 vs. 5; P = 0.501). No patient in either group had significant adverse events such as bleeding or death. CONCLUSION: EUS-LB is safe and is associated with less pain, shorter hospital stay, and high diagnostic yield (93%) compared to PC-LB. Randomized trials are needed to standardize the utility of EUS-LB.

Surveillance for hepatobiliary cancers in patients with primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a risk factor for cholangiocarcinoma (CCA) and gallbladder carcinoma (GBCa). Surveillance for GBCa is recommended, but the clinical utility of surveillance for other hepatobiliary cancers (HBCa) in PSC, namely CCA and hepatocellular carcinoma (HCC), remains unclear. We aimed to determine whether surveillance is associated with better survival after diagnosis of HBCa in patients with PSC. Medical records of PSC patients seen at the Mayo Clinic Rochester from 1995 to 2015 were reviewed. Patients were included if they had ≥1 year of follow-up and developed HBCa. Patients were categorized according to their surveillance status (abdominal imaging, carbohydrate antigen 19-9, and alpha-fetoprotein). The primary endpoints were HBCa recurrence, HBCa-related death, and all-cause mortality. Overall survival was assessed by the Kaplan-Meier survival method; HBCa-related survival was assessed using competing risk regression. Tests of significance were two-tailed, and a P value <0.05 was considered statistically significant. From 1995 to 2015, a total of 79 of 830 PSC patients were diagnosed with HBCa. Cumulative follow-up was 712 and 283 person-years pre- and post-HBCa diagnosis, respectively. Seventy-eight percent of patients (54/79) developed CCA, 21% (17/79) HCC, 6% (5/79) GBCa, 3% (2/79) both CCA and HCC, and 1% (1/79) both HCC and GBCa. Fifty-one percent (40/79) were under HBCa surveillance, and 49% (39/79) were not. Patients in the surveillance group had significantly higher 5-year overall survival (68% versus 20%, respectively; P < 0.001) and significantly lower 5-year probability of experiencing an HBCa-related adverse event (32% versus 75%, respectively; P < 0.001) compared with the no-surveillance group. CONCLUSION: This study demonstrates that HBCa surveillance significantly improves outcomes, including survival, in patients with PSC. (Hepatology 2018;67:2338-2351).