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    Topic review

    Hepatocrinology

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    Definition

    Hepatocrinology is defined as the bidirectional, complex relationship between hepatic and endocrine physiology and dysfunctions. The scope of hepatocrinology includes conditions of varied etiology (metabolic, infectious, autoimmune, and invasive) that we term as hepato-endocrine syndromes.

    1. Introduction

    The subject ‘hepatocrinology’ is the field of medicine that studies the bidirectional relationship between hepatic and endocrine physiology, as well as dysfunction. The hepato-insular axis is a part of hepatocrine physiology [1]. Endocrine manifestations of liver insufficiency (cirrhosis) and malignancy, and hepatic complications of various endocrine disorders are included. The possible hepatotropic effect of endocrine drugs, pleiotropic endocrine consequences of medicines used in the management of liver disease, and potential exaptation of endocrine agents for use in hepatology form part of this science.

    2. The Liver as an Endocrine Organ

    The liver secretes various hormones, which mediate glucose metabolism, blood pressure, growth, and hemorheological homeostasis. These include insulin-like growth factor (IGF)-1, betatrophin, and irisin, all of which mediate insulin sensitivity [2][3]. Angiotensinogen, produced by the liver, is the bedrock of the renin-angiotensin-aldosterone system, which contributes to blood pressure maintenance [4]. Hepcidin and thrombopoietin contribute to the regulation of iron metabolism and platelet production, respectively [5][6]. The hepato-insular axis is a well-researched contributor to glucose metabolism and has been described variously as the entero-insular or adipo-hepato-insular axis [1]. There are several other hormones or their precursors that are synthesized by the liver. Some of the important products are summarized in Table 1 and detailed below.

    Table 1. The liver as an endocrine organ.
    Action Hormones Reference
    Hormone synthesis IGF-1 Bach [2]
    Angiotensinogen Matsuaska [4]
    Thrombopoietin Hitchcock [6]
    Hepcidin Ruchala [5]
    Betatrophin Raghow [3]
    Proprotein convertase subtilsin-kexin type 9 Yadav [7]
    Hormone action modulation IGF binding protein 1 to 6 Allard [8]
    Sex hormone-binding globulin Selby [9]
    Thyroid hormone-binding globulin Schussler [10]
    Transthyretin Palha [11]
    Corticosteroid binding globulin Breuner [12]
    Vitamin D binding protein Bouillon [13]
    IGF—insulin-like growth factor.

    3. Sexual Dimorphism in Liver Disorders

    Many liver diseases show differential gender distribution. NAFLD is more common in men during the reproductive age group, but is more frequent in women after menopause, indicating a possible protective role of estrogen [14]. HCC occurs more commonly in men, while the risk of autoimmune liver diseases such as primary biliary cirrhosis and autoimmune hepatitis is more common in women [15]. Apart from sex hormones, differences in xenobiotics, immune function, genetic alterations, and receptor expression are presumed to drive the dichotomy [16].

    4. Endocrine Manifestations of Hepatic Disease

    The liver modulates the functioning of the endocrine system directly or indirectly in multiple ways. Liver dysfunction is thus predictably associated with various endocrine disorders. The significant anomalies have been detailed below and depicted in Figure 1.

    9. Hepatic Effect of Endocrine Drugs

    The endocrine drugs can have harmful as well as beneficial effects on the liver. Both anabolic steroids and estrogens can cause cholestasis, hepatic adenoma, focal nodular hyperplasia, and other hepatic disorders [39][40]. Acute liver failure has been reported with diverse agents such as propylthiouracil (used for hyperthyroidism) and high doses of methylprednisolone [41][42]. Orlistat, a commonly used therapy for weight loss, has also been described to cause subacute and acute liver failure [43].

    10. Endocrine Effects of Drugs Used in Hepatology

    Spironolactone, commonly used for the management of ascites in patients with cirrhosis, is an anti-androgen which has beneficial effects in PCOS in women, but causes painful gynecomastia in males [44][45]. Interferon-alpha used for management of hepatitis C infection can result in thyroid dysfunction [46]. Beta-blockers have often been associated with erectile dysfunction [47]. Table 5 depicts the common drug interactions in hepatocrinology.

    Table 5. Pharmacological interactions in hepatocrinology.
    Hepatic Effects of Endocrine Drugs
    Drugs Adverse Effects
    Anabolic androgenic steroid [39] Hepatic adenoma, hepatocellular carcinoma, cholestasis, and peliosis hepatis.
    Estrogen/oral contraceptive pills [40] Intrahepatic canalicular cholestasis, hepatic adenomas, focal nodular hyperplasia, hemangioma or hamartoma, peliosis hepatis, and Budd Chiari syndrome
    Tamoxifen [48] NAFLD
    Propylthiouracil, methimazole, carbimazole [41] Hepatitis, cholestasis, and acute liver failure
    Corticosteroids [42] Hepatic enlargement, steatosis, glycogenosis. NAFLD, exacerbate chronic viral hepatitis, and high doses of intravenous methylprednisolone—acute liver failure (sometimes fatal)
    Vasopressin receptor antagonist [49] Transaminitis and acute liver failure
    Orlistat [43] Cholelithiasis, cholestatic hepatitis, and acute and subacute liver failure
    Drugs Beneficial effects
    Pioglitazone [50] Beneficial effect on NAFLD
    GLP-1RA [50] Possible beneficial effect on NAFLD
    SGLT-2 inhibitors [50] Possible beneficial effect on NAFLD
    Saroglitazar [50] Possible beneficial effect on NAFLD
    Corticosteroids [51] Treatment of autoimmune hepatitis and prevention of rejection of liver transplant
    Somatostatin analogs (octreotide and others) [52] Treatment of variceal bleeding (decreases portal blood flow)
    Vasopressin analogs (terlipressin) [52] Treatment of variceal bleeding (decreases portal blood flow)
    Endocrine Effects of Drugs Used in Hepatology
    Drugs Adverse effects
    Spironolactone [45] Gynaecomastia, and hypogonadism in men
    Beta-blockers [47] Erectile dysfunction
    Interferon-alpha [46] Hypothyroidism, autoimmune (Hashimoto’s) thyroiditis, destructive thyroiditis, and Graves’ disease
    Drugs Beneficial effects
    Ursodeoxycholic acid [53] Possible beneficial effect in metabolic syndrome
    Spironolactone [44] Treatment of PCOS
    NAFLD—non-alcoholic fatty liver disease, PCOS—polycystic ovary syndrome, GLP-1RA glucagon-like peptide receptor agonist, SGLT-2—sodium glucose cotransporter-2, GGT—γ-glutamyltransferase, and ALT—alanine aminotransferase.

    The entry is from 10.3390/medsci9020039

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