5. Endocrine and metabolic disorders 5.1 Abnormal thyroid function 5.1.1 Overview and mechanisms IFNα treatment can lead to abnormal thyroid function through autoimmune and non-autoimmune mechanisms. In the autoimmune mechanism, IFNα increases the expression of major histocompatibility complex (MHC)1 on the cell surface and induces autoantibody formation, and patients are often positive for anti-thyroid peroxidase antibody (TPoAb) and anti-thyroglobulin antibody (TGAb); the non-autoimmune mechanism may be related to the direct effect of IFNα on the thyroid gland, manifested by destructive thyroiditis and non-auto Non-autoimmune mechanisms may be related to the direct action of IFNα on the thyroid, manifested by destructive thyroiditis and non-autoimmune hypothyroidism, with negative TPoAb and TGAb. Thyroid function abnormalities were most commonly seen in hypothyroidism. About 40% of CHC patients treated with IFNα develop anti-thyroid antibodies and 15% develop clinical thyroid disease. 60% of patients with positive TPoAb or TGAb develop thyroid disease on IFNα treatment, while less than 15% of patients with negative anti-thyroid antibodies develop thyroid disease, and those with positive TPoAb or TGAb before treatment are more likely to develop persistent thyroid disease. 5.1.2 Clinical manifestations The diagnosis of abnormal thyroid function is based on the presence of abnormal thyroid function indicators [total triiodothyronine (TT3), total thyroxine (TT4), free triiodothyronine (FT3), free thyroxine (FT4), thyrotropin (TSH)] and the presence of clinical manifestations of corresponding hyper- or hypothyroidism. Patients may present with the following thyroid disorders: (1) Graves’ disease: systemic hypermetabolic manifestations with diffuse, symmetric, painless goiter, simple or infiltrative proptosis; (2) Hashimoto’s thyroiditis: thyroid autoantibodies and hypothyroidism with or without goiter; (3) some patients may present with positive TPoAb or TGAb and abnormal thyroid function indicators, but do not present with clinical symptoms; (3) some patients may present with positive TPoAb or TGAb and abnormal thyroid function indicators. (4) non-autoimmune thyroid disease, manifesting as destructive thyroiditis and hypothyroidism. It is important to note that patients with destructive thyroiditis may change from hyperthyroidism to hypothyroidism. 5.1.3 Clinical management (1) For all IFNα-treated patients, especially CHC patients, thyroid function TPoAb and TGAb tests should be performed before IFNα treatment, and thyroid disease should be diagnosed in combination with thyroid ultrasound; (2) Those with abnormal thyroid function before IFNα treatment should be treated accordingly before IFNα treatment under the guidance of an endocrinologist, and after (3) thyroid function should be closely monitored during treatment, along with TPoAb and TGAb, and if TPoAb and/or TGAb are found to be positive, continued monitoring of thyroid function and clinical symptoms is recommended; (4) hyperthyroidism can be treated with oral methimazole or propylthiouracil under the guidance of a specialist. (5) Controllable abnormal thyroid function can continue IFNα treatment, but uncontrollable hyperthyroidism, such as Graves’ disease with thyrotoxicosis, especially when thyroid crisis occurs, must immediately terminate IFNα treatment; (6) Hypothyroidism is generally normalized after oral administration of levothyroxine sodium tablets and dose adjustment. Most of the thyroid function can be normalized after oral administration of levothyroxine sodium tablets and dose adjustment, so IFNα therapy is rarely terminated; (7) subclinical hypothyroidism or hyperthyroidism with only TSH abnormalities but not FT3, FT4, TT3, TT4 abnormalities can be left untreated and continue to be observed. (8) Persistent positive TPoAb and TGAb after discontinuation of IFNα therapy is indicative of possible development of thyroid insufficiency. 5.2 Diabetes mellitus 5.2.1 Overview and mechanism IFNα can induce autoimmune damage to pancreatic β-cells and induce diabetes mellitus. PEG-IFNα treatment induces diabetes in 0.1-0.7% of CHC patients. It should be noted that since the liver is an important glucose metabolizing organ, some patients, especially those with CMC, already have diabetes before IFNα treatment. IFNα treatment can aggravate diabetes or help control diabetes due to improvement of liver function during antiviral therapy. 5.2.2 Clinical manifestations The diagnosis of diabetes mellitus during IFNα treatment is based on the diagnostic criteria for the general population, but patients often lack the typical symptoms of diabetes mellitus, and endocrinologists can be consulted to assist in the diagnosis if necessary. 5.2.3 Treatment (1) Patients should have fasting and postprandial glucose tests before IFNα treatment; (2) Regular monitoring during IFNα treatment, and for those with family history of diabetes and obesity, even if fasting glucose is normal, fasting glucose and glycosylated hemoglobin levels should be rechecked every 2 months during IFNα treatment; (3) Patients who developed diabetes before treatment should be treated before IFNα treatment Diabetes mellitus should be effectively controlled before starting IFNα therapy; (4) those who have been diagnosed with diabetes mellitus should choose oral hypoglycemic drugs with less liver damage based on diet control and moderate exercise, and those who cannot be effectively controlled by oral drugs should use insulin, while those with severely elevated blood glucose should prefer insulin injection therapy; (5) those with elevated blood glucose that cannot be controlled by drug therapy or with acute IFNα should be discontinued for complications such as diabetic ketoacidosis or hyperosmolar non-ketotic diabetic coma. 6, other rare adverse reactions 6.1 Interstitial lung disease (1) Overview and mechanism: The pathogenesis of IFNα-induced interstitial lung disease is unclear and may be related to autoimmune and metabolic reactions. IFNα treatment-related pulmonary complications are rare, but they are one of the serious adverse effects and should be given high priority. (2) Clinical manifestations: Respiratory symptoms such as dry cough and shortness of breath are often seen in IFNα therapy, with an incidence of 24% and 26%, respectively. The incidence of interstitial pneumonia induced by IFNα treatment for CHC is common within the first 12 weeks of IFNα treatment, mostly in elderly patients; (3) Clinical management: (1) Double lung imaging before IFNα treatment to exclude potential or existing lung lesions; (2) Persistent cough, fever and respiratory symptoms during IFNα treatment. patients with persistent cough, fever and dyspnea should progress to chest x-ray or CT examination; (3) patients with persistent and progressively aggravated cough, sputum and even dyspnea should be examined by imaging, and once diagnosed as interstitial pneumonia, IFNα therapy must be stopped and a respiratory specialist should be consulted; (4) for those with obvious dry cough without thoracic imaging changes, antihistamines can be used for treatment, and for Those who cannot control the symptoms can use low-dose hormones without contraindication to hormone use. 6.2 Retinopathy (1) Overview and mechanism: IFNα-induced retinopathy is rare. Most retinopathies do not represent a loss of vision. The resulting retinal hemorrhage may be related to vasospasm caused by IFNα, deposition of immune complexes in the retinal vascular system, and is often secondary to systemic diseases such as retinal ischemia, diabetes mellitus, and hypertension; (2) Clinical manifestations may include retinal hemorrhage, absorbent cotton spots, loss of color vision, and occasionally blindness. More rarely, retinal artery or vein obstruction is seen. Typical retinal lesions include massive absorbent cotton spots and flame-like hemorrhages around the posterior pole optic papilla, with superficial linear or discoid hemorrhages that do not significantly affect visual acuity and present a separation of symptoms and signs, but can lead to significant loss of vision if the lesion affects the macula and optic nerve. IFNα can also be directly toxic to the optic nerve, leading to blurred vision similar to optic neuritis. Ocular complications due to IFNα often occur in the posterior pole of the retina, mostly at 1 or 3 months of IFNα treatment.(3) Clinical management: For patients with diabetes and hypertension, a fundus examination should be performed before IFNα treatment, and IFNα should be used with caution in patients with severe fundus lesions. Absorbent cotton spots and retinal hemorrhages often resolve spontaneously during or after IFNα treatment. 6.3 Decrease in body mass (1) Overview and mechanism: 19.7% of patients may experience a decrease in body mass during IFNα treatment (may decrease by 5-10%). It may be associated with a variety of adverse effects such as decreased appetite, nausea, diarrhea, abnormal thyroid function, and diabetes mellitus. (2) Clinical manifestations: Those with a rapid decrease in body mass often experience a decrease in appetite in the first week of IFNα treatment. Most patients showed a gradual decrease in body mass after the 24th week of treatment. (3) clinical management, patients can eat less and more meals diet should be less but fine, should ensure the necessary protein, fat, carbohydrates and vitamin intake. Regular work and rest, to develop good habits of work and rest. Patients with decreased body mass generally do not affect normal study, life and work, so they can continue IFNα treatment (Bl). For those who have too obvious and significant decrease in body mass within a short period of time, hyperthyroidism, malignant tumor and other special diseases should be excluded. 6.4 Diarrhea A small number of patients develop diarrhea during treatment; the exact mechanism has not been clarified, and it is speculated that it may be related to intestinal dysfunction. If diarrhea occurs during IFNα treatment, routine stool, occult blood and even bacteriological examination should be performed first, and colonoscopy should be performed to exclude organic lesions of the colon, inflammatory bowel disease and infectious diarrhea if there is a significant decrease in body mass before continuing IFNα treatment. 6.5 Alopecia IFNα can cause reversible alopecia in about 30% of patients, mostly manifested as thinning hair, irreversible baldness and autoimmune baldness can occur but are less common. Alopecia areata occurs mainly after 3 months of IFNα application and is dose dependent. Alopecia areata is transient and can be accompanied by hair regrowth during the hair loss process. There are no effective measures to prevent alopecia. The frequency of shampooing and friction on the hair can be reduced, and chemical shampoos and perms can be avoided. Hair loss does not affect IFNα treatment, and those with significant hair loss that affects aesthetics can wear a wig. Hair growth can be restored 3-6 months after discontinuation. (Bl) 6.6 Other rare IFNα adverse reactions such as hearing loss and tinnitus can be seen in K-pass IFNα and PEG-IFNα combined with ribavirin therapy, the exact mechanism of which has not been clarified and may be related to direct IFNα ototoxicity, autoimmune or hematologic alterations. Hearing loss does not fully recover if IFNα treatment is interrupted; continued IFNα treatment can worsen symptoms (B1). oral ulcers can also occur during IFNα application and may be associated with autoimmune reactions. if patients cannot tolerate it, discontinuation of IFNα is recommended in CHB patients, and oral prednisone 5 mg once/d after informed consent in CHC patients without contraindications to hormone use. If acute pancreatitis occurs, it is considered to be related to autoimmune reaction and discontinuation of IFNα is recommended.(Bl) Patients with only positive autoantibodies without clinical manifestations are most commonly seen clinically, especially CHC patients who are not contraindicated for IFN therapy, and need to be closely monitored for the occurrence of autoimmune disease during IFNα therapy, and IFNα should be discontinued immediately in case of uncontrollable autoimmune disease.