Mild liver dysfunction in Klinefelter syndrome is associated with abdominal obesity and elevated lipids but not testosterone treatment.

Untreated Klinefelter syndrome males showed higher levels of main liver markers compared to healthy controls, with no significant differences between untreated and testosterone-treated KS males.

• 65 KS males were recruited, of which 32 received testosterone replacement therapy (TRT) and 33 were untreated; 69 healthy controls were also recruited.
• ALAT, alkaline phosphatase, and PP (prothrombin-proconvertin time ratio) were used as the main liver markers.
• Higher levels of main liver markers were observed in untreated KS (U-KS) compared to controls.
• No significant differences in liver markers were found between untreated KS (U-KS) and testosterone-treated KS (T-KS).

KS males demonstrated mild liver dysfunction reflected by a significant increase in main liver markers and a decrease in albumin.

• Both treated and untreated KS males showed elevated liver function markers compared to healthy controls.
• Albumin levels were decreased in KS males relative to controls.
• The authors characterized this as 'mild liver dysfunction' based on the pattern of biomarker changes.

Testosterone-treated KS males had lower abdominal fat, total cholesterol, and LDL cholesterol than untreated KS males.

• T-KS had lower abdominal fat compared to U-KS.
• T-KS had lower total cholesterol than U-KS.
• T-KS had lower LDL cholesterol than U-KS.
• These metabolic differences between treated and untreated groups suggest a beneficial metabolic effect of TRT despite no significant difference in liver markers between the two KS groups.

Multivariable regression identified different predictors of ALAT variation across the three groups, with metabolic factors being predominant in KS males.

• In untreated KS, variation in ALAT was explained by HOMA2%S (a measure of insulin sensitivity).
• In testosterone-treated KS, ALAT variation was explained by BMI and SHBG.
• In healthy controls, ALAT variation was explained by hip circumference and estradiol.
• These findings underscore a primary role of metabolic conditions including obesity and insulin resistance in elevated liver function markers in KS males.

Multivariable regression identified BMI and LDL cholesterol as predictors of PP variation in testosterone-treated KS males, while no multivariable model explained PP variation in untreated KS males.

• No multivariable models explaining variation in PP were found in untreated KS (U-KS).
• In testosterone-treated KS (T-KS), PP was explained by BMI and LDL cholesterol.
• In healthy controls, PP was explained by total cholesterol.
• This highlights the role of unfavourable lipid profile in liver function abnormalities in treated KS males.

Principal component analysis showed that untreated KS was positively associated with an obese metabolic profile that also included ALAT, while controls were negatively associated with this profile.

• Principal component analysis was utilized to demonstrate interconnected patterns among all measured biomarkers.
• U-KS was positively associated with dimension 1 (D1), described as 'an obese profile, which also included ALAT.'
• Controls were negatively associated with D1, representing a 'non-obese profile.'
• This analysis illustrated how the different groups were linked to distinct metabolic and liver function patterns.

The authors concluded that evaluation of liver function should be part of the clinical care in males with Klinefelter syndrome.

• The findings highlight that liver function evaluation should be incorporated into routine clinical care for KS males.
• The data underscore a primary role of metabolic conditions including obesity, insulin resistance, and unfavourable lipid profile in elevated liver function markers in KS.
• Whether TRT can improve liver function in KS was noted to warrant further studies.
• KS is associated with hypergonadotropic hypogonadism contributing to metabolic alterations that may affect liver function.