From liver to hormones: The endocrine consequences of cirrhosis

Table 1 Summary of pharmacological interventions in endocrinopathies associated with liver cirrhosis

Endocrinopathy	Interventions	Comments	Ref.
Diabetes mellitus	Therapeutic goals: Compensated cirrhosis: FPG 4.44-7.22 mmol/L, PP glucose < 9.99 mmol/L; decompensated cirrhosis: FPG 5.00-8.32 mmol/L, PP glucose < 11.10 mmol/L, and pre-meal glucose 5.55-11.10 mmol/L		[28,50]
	Metformin	Maximum 1500 mg/d. Do not use in hypoxemia, dehydration, sepsis, or Child-Pugh B and C	[50,109]
	Sulfonylureas	Can be used in low doses in Child-Pugh A. Contraindicated in Child-Pugh B and C	[28,50,100,109]
	Meglitinides	Do not use repaglinide. Nateglinide can be used in Child-Pugh A and B in lower doses	[28,50]
	Thiazolidinediones	Do not use rosiglitazone. Pioglitazone can be used in Child-Pugh A	[28,50,109]
	DPP-4 inhibitors	Can be used in Child-Pugh A without modifying the dose, except for vildagliptin. Use with caution in Child-Pugh B, but not in Child-Pugh C	[50,109]
	GLP-1 RA	Can be used in Child-Pugh A without modifying the dose. Use with caution in Child-Pugh B, but not in Child-Pugh C, due to limited data Unknown for Tirzepatide and Retatrutide	[50,109]
	SGLT-2i	Can be used in Child-Pugh A, starting with lower doses. Use with caution in Child-Pugh B but avoid in Child-Pugh C due to the risk of dehydration and hypotension	[28,109]
	Alpha-glucosidase inhibitors	Can be used in Child-Pugh A and B but are not recommended in Child-Pugh C	[50,109]
	Insulin	Reserve for those unable to use oral medications, fail to achieve adequate glycemic control, or in cases of sepsis, encephalopathy, bleeding, or acute kidney injury. It is the choice in DM and decompensated LC; start with 0.1-0.2 IU/kg/d (higher if blood glucose is very high). Adjust the dose based on blood glucose, varying by 2 units every 3 d if necessary. Add rapid-acting insulin if goals are not achieved, starting with 4 units or 10% of basal insulin and increasing by 1-2 units every 3-4 d as needed. Prefer analog insulins for a lower risk of hypoglycemia	[28,109]
	Statins	Generally recommended for males, individuals with diabetes, and those with a high Fibrosis-4 index at the beginning of the study	[140]
	Liver transplantation	The worse the beta cell function, the less effective liver transplantation will be in achieving DM remission	[17]
Hypoglycemia	New episodes should be prevented by adjusting the dose or modifying the drugs used
	15-20 g of oral glucose	For conscious patients. Reassess in 15 min and repeat if necessary	[56,142,143]
	Parenteral glucagon	For unconscious patients or those with severe hypoglycemia	[56,142,143]
Sarcopenia	Nutritional support	Caloric intake of 35-40 kcal/kg and protein intake of 1.2-1.5 g/kg. Eat at intervals of 2-3 h and include a bedtime snack with 50 g of carbohydrates and 20 g of protein	[145,146]
	BCAA	Long-term supplementation at a dose of 0.25 g/kg/d	[146]
	Exercise	Recommended moderate-intensity aerobic and resistance exercises	[21]
	Others	Treatments to reduce ammonia, hormonal supplements, and myostatin inhibitors are still under study	[21,22,147]
Male hypogonadism	Testosterone supplementation	Considered adjunctive therapy to improve frailty	[148]
	PDE-5i	Sildenafil, tadalafil, avanafil, and vardenafil are FDA-approved and can be used in Child-Pugh A and B at lower doses	[24]
	Liver transplantation	Restores physiological levels of testosterone, estradiol, SHBG, gonadotropins, and prolactin	[45]
Female hypogonadism	Lifestyle modifications and psychological support should be included		[24]
	Contraception	In compensated cirrhosis, hormonal contraceptives can be used without restriction, but in decompensated cirrhosis, the risks outweigh the benefits	[152]
	Liver transplantation	Restores physiological levels of testosterone, estradiol, SHBG, gonadotropins, and prolactin	[45]
Overt hypothyroidism	Levothyroxine	Immediate treatment per general recommendations, considering higher doses might be necessary due to malabsorption	[67,153]
Subclinical hypothyroidism	Levothyroxine	Treatment per general recommendations. Liver function is not part of the treatment decision	[72]
Euthyroid sick syndrome	Hormonal treatment is not recommended		[72]
Hyperthyroidism	Thiamazole	Recommended starting dose of 20mg in Child-Pugh A with continuous monitoring of liver function. Not recommended in Child-Pugh B and C	[154-156]
	Propylthiouracil	Its use is not recommended	[67]
	Definitive treatments	Radioactive iodine therapy or thyroidectomy based on patient’s need and clinical condition	[67]
	Liver transplantation	Not recommended to restore thyroid function	[45]
Hepatic bone disease	Calcium	1000-1500 mg/d, taken with food	[77,158,160]
	25-OH vitamin D	Supplement only if there is a deficiency of vitamin D	[38]
	PTH	There is not enough evidence in advanced cirrhosis	[158]
	Bisphosphonates	Parenteral use is recommended	[158]
	Raloxifene	There is not enough evidence in cirrhosis	[77,158]
Adrenal insufficiency	Hydrocortisone	Critically ill patients: 200-300 mg/d intravenously, divided into 3 to 4 doses, with progressive titration based on the patient’s clinical evolution; non-critically ill patients without symptoms: 15-20 mg/d orally, divided into 2 doses, only if persistent hypotension and hyponatremia are present	[86,87,91,163,164]
Growth hormone dysfunction	GH	If GH deficiency is demonstrated: 0.4-0.5 mg/d (< 30 years), 0.2-0.3 mg/d (30-60 years), 0.1-0.2 mg/d (> 60 years), with dose titration to maintain IGF-1 within the standard deviation of -2 to 2.	[92,94,95,165-168]
Secondary hyperaldosteronism	Loop diuretics	High doses of furosemide (up to 160 mg/d) in cases without renal insufficiency, although with limited effectiveness	[46]
	Mineralocorticoid receptor antagonists	Spironolactone (up to 400-600 mg/d). Eplerenone is more selective with fewer side effects. Finerenone is a potent and selective non-steroidal antagonist	[46,171]

BCAA: Branched chain amino acid; DM: Diabetes mellitus; FDA: Food and Drug Administration; FPG: Fasting plasma glucose; GH: Growth hormone; GLP-1 RA: Glucagon-like peptid 1 receptor agonist; IGF-1: Insulin-like growth factor 1; LC: Liver cirrhosis; PDE-5i: Phosphodiesterase 5 inhibitor; PP: Posprandial; SGLT-2i: Sodium-glucose cotransporter 2 inhibitor; SHBG: Sex hormone-binding globulin.