Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease, and is related to fatal and non-fatal liver, metabolic, and cardiovascular complications. Its non-invasive diagnosis and effective treatment remain an unmet clinical need. NAFLD is a heterogeneous disease that is most commonly present in the context of metabolic syndrome and obesity, but not uncommonly, may also be present without metabolic abnormalities and in subjects with normal body mass index. Therefore, a more specific pathophysiology-based subcategorization of fatty liver disease (FLD) is needed to better understand, diagnose, and treat patients with FLD. A precision medicine approach for FLD is expected to improve patient care, decrease long-term disease outcomes, and develop better-targeted, more effective treatments. We present herein a precision medicine approach for FLD based on our recently proposed subcategorization, which includes the metabolic-associated FLD (MAFLD) (i.e., obesity-associated FLD (OAFLD), sarcopenia-associated FLD (SAFLD, and lipodystrophy-associated FLD (LAFLD)), genetics-associated FLD (GAFLD), FLD of multiple/unknown causes (XAFLD), and combined causes of FLD (CAFLD) as well as advanced stage fibrotic FLD (FAFLD) and end-stage FLD (ESFLD) subcategories. These and other related advances, as a whole, are expected to enable not only improved patient care, quality of life, and long-term disease outcomes, but also a considerable reduction in healthcare system costs associated with FLD, along with more options for better-targeted, more effective treatments in the near future.

Background and Aims: Thyroid axis is currently under investigation as a therapeutic target in metabolic dysfunction‐associated steatotic liver disease (MASLD). Thyroid function was examined herein in the full spectrum of disease. Methods: Subjects were recruited and had liver biopsies in two Gastroenterology‐Hepatology Clinics (Greece and Australia) and one Bariatric‐Metabolic Surgery Clinic (Italy). The main working sample was n = 677 subjects with MASLD after excluding subjects with abnormal free thyroxine levels. Participants were classified according to thyroid‐stimulating hormone (TSH) standard criteria: Subclinical hyperthyroidism (<0.4 uIU/mL); Euthyroidism with relatively low (0.4 to 4 uIU/mL). Results: TSH as a continuous variable was positively associated with significant fibrosis ( F ≥ 2), metabolic dysfunction‐associated steatohepatitis (MASH) and at‐risk MASH. Subclinical hypothyroidism was associated with fibrosis F ≥ 2 (odds ratio [OR] = 3.47, 95% confident interval [CI] [1.50, 8.05], p = .02), MASH (OR = 3.44, 95% CI [1.48, 7.98] p = .001) and at‐risk MASH (OR = 3.88, 95% CI [1.76, 8.55], p = .001), before and after controlling for adiposity, central obesity, and insulin resistance. When leptin, adiponectin, or growth differentiation factor‐15 were examined as moderators, significance was lost. Sex‐specific analysis revealed a strong association between TSH and the presence of significant fibrosis among women, eliminated only when adipokines/mitokines were adjusted for. Restricted cubic spline analysis revealed associations between TSH and liver outcomes ( p ‐values < .01) with inflection points for fibrosis F ≥ 2 being 2.49, for MASH being 2.67 and for at‐risk MASH being 6.96. Conclusions: These observations provide support for studies on the administration of thyroid hormone in MASLD therapeutics for subclinical hypothyroidism and liver‐specific thyroid receptor agonists for subjects across the TSH continuum.

Primary hyperparathyroidism is a disease with multisystemic and heterogeneous manifestations, characterized by underlying high parathormone concentrations. Despite neuropsychiatric involvement being one of the manifestations, psychosis is rare. This is the case of a 68-year-old female with a 10-day clinical course of anorexia, mutism, dysphagia, constipation, and weight loss. The patient had disorganized speech associated with paranoid delusions. Prior to this visit, the patient was recently diagnosed with a mixed anxiety-depressive disorder. For this reason, treatment with antidepressants in combination with atypical antipsychotics was administered without a satisfactory response. Neuroimaging, infectious panel, and toxicology screening showed no abnormal findings. Hypercalcemia secondary to a retropharyngeal ectopic parathyroid adenoma was the causative etiology of her primary hyperparathyroidism, and hypercalcemia treatment resolved the psychotic episode. We highlight the importance of recognizing psychosis as a possible initial presentation of hyperparathyroidism and hypercalcemia. Ruling out organic etiologies prior to diagnosing a primary cause of psychosis is crucial, as their treatment can reverse the psychotic symptoms.