DIFFERENCES IN FREE TESTOSTERONE LEVELS BETWEEN MELD DEGREE IN

LIVER CIRRHOSIS PATIENTS

Noviari Liara Justitia, Gontar Siregar

Introduction: The MELD score has been validated as a predictor of survival in patients with
cirrhosis. Serum testosterone is often reduced in men with cirrhosis and decreases progressively
with increasing severity of liver disease, regardless of the etiology. Serum testosterone is reduced
in up to 90% of men with cirrhosis, with levels decreasing as liver disease progresses. This study
aims to determine the difference in free testosterone levels between MELD degrees in patients
with liver cirrhosis

Methods: This study is an observational study with a cross sectional analysis design to measure
the difference in free testosterone levels between MELD degrees in patients with liver cirrhosis
with a total of 50 samples that met the inclusion and exclusion criteria in RSUP H. Adam Malik
Medan.

Results: We found the median age of the patients was 57 years with age range of 24-75 years
with 22 samples (44%) were diagnosed with hepatitis B and 8 samples (16%) were diagnosed
with hepatitis C. 25 samples (50%) of cirrhotic patients in this study had a MELD Score > 20.
Mean free testosterone level was 1.35 ± 0.59 ng/dL. Based on the analysis of the difference in
free testosterone levels between MELD scores degrees showed a significant difference (p =
0.001)

Conclusions: MELD score degree shows a relationship with free testosterone levels in patients
with liver cirrhosis, where the higher MELD score degree indicates lower free testosterone levels
in patients with liver cirrhosis

Keywords: Liver cirrhosis, MELD Score, Free Testosterone

Introduction
 Liver cirrhosis is the most common consequence of the long clinical course of all liver
diseases characterized by liver parenchymal damage. Liver cirrhosis is the final stage of the
diffuse progressive liver fibrosis process characterized by distortion of the liver architecture and
the formation of regenerative nodules. Liver cirrhosis is the third leading cause of death in
patients aged 45-46 years after cardiovascular disease and cancer. Worldwide, liver cirrhosis is
the seventh leading cause of death. Liver cirrhosis sufferers are more men, when compared to
women the ratio is around 1.6: 1. The average age of sufferers is mostly in the age group of 30-
59 years with a peak around the age of 40-49 years. The incidence of liver cirrhosis in America
is estimated at 360 per 100,000 population. The causes of liver cirrhosis are mostly alcoholic
liver disease and non-alcoholic steatohepatitis and hepatitis C. In Southeast Asia, the main
causes of liver cirrhosis are hepatitis B (HBV) and C (HCV). The incidence of liver cirrhosis in
Indonesia due to hepatitis B ranges from 21.2 – 46.9% and hepatitis C ranges from 38.7-73.9%.1

For decades, the Child-Pugh score has been the main prognostic tool for cirrhotic
patients. This score is based on five variables: ascites, encephalopathy, serum bilirubin, serum
albumin and prothrombin time, which were selected empirically, and have been shown to be
reliable prognostic tools in many clinical situations. However, the Child-Pugh score has limited
subjective interpretation of ascites and encephalopathy. Thus, the Model for End-stage Liver
Disease (MELD) score was developed as a liver score that is simpler and more objective than the
Child-Pugh score.2,3

The MELD score has been validated as a predictor of survival in patients with cirrhosis,
alcoholic hepatitis, acute liver failure, and in patients with acute hepatitis. The Model for End-
Stage Liver Disease (MELD) score is a prognostic scoring system, based on laboratory
parameters, used to predict 3-month mortality from liver disease. MELD scores range from 6 to
40; the higher the score, the higher the 3-month mortality associated with liver disease. The
MELD score uses measurements of creatinine, bilirubin, and INR.4

Serum testosterone is often reduced in men with cirrhosis and decreases progressively
with increasing severity of liver disease, regardless of the etiology. Serum testosterone is reduced
in up to 90% of men with cirrhosis, with levels decreasing as liver disease progresses.
Testosterone (T) is an important anabolic hormone, with effects on muscle, bone, and
hematopoiesis. The pathophysiology of low testosterone in cirrhosis is poorly understood, but
there appears to be suppression at all levels of the hypothalamic-pituitary-testis axis. An increase
in inflammatory mediators is one of the postulated mechanisms. Testosterone is an important
anabolic hormone, and its levels are positively related to muscle mass in healthy and
hypogonadal men in a dose-dependent manner. However, the relative contribution of
testosterone deficiency to the symptoms of advanced liver disease is not known with certainty.
Recently, it has been shown that low testosterone in men with cirrhosis is associated with
increased mortality, independent of classically recognized prognostic factors, such as Model
scores for End-Stage Liver Disease.5 However, the relationship between MELD scores and free
testosterone levels is unclear. Therefore, this study aims to determine the difference in free
testosterone levels between MELD degrees in patients with liver cirrhosis

Method

This study is an observational study with a cross sectional analysis design to measure the
difference in free testosterone levels between MELD degrees in patients with liver cirrhosis. The
population of this study was male liver cirrhosis patients who were treated at H. Adam Malik
Hospital in 2017-2020. Liver cirrhosis was established based on the results of ultrasound or
fibroscan examination. Samples were collected by consecutive sampling method which included
all liver cirrhosis patients who met the inclusion and exclusion criteria.

Inclusion criteria were male > 18 years old, patient diagnosed with liver cirrhosis, and
cooperative and participating. Exclusion criteria for this study were patients with liver disease
other than cirrhosis, patients with hepatocellular carcinoma, patients with a history of previous
liver transplantation, patients receiving testosterone hormone therapy, patients taking warfarin,
and patients who had no data of bilirubin, INR, and creatinine results. The total points were
grouped into four categories at interval of 10 points. MELD 1= ≤ 10 points, MELD 2 = 11-20
points, MELD 3= >21 points. Free testosterone check with MINDRAY microplate ELISA reader
(Model: MR-96A, Mindray, Germany).

The collected data were analyzed and processed using SPSS for Windows 22 software
(IBM SPSS Statistics for Windows, Version 22.0. IBM Corp., Armonk, NY). The statistical test
of the data to determine the association between free testosterone and MELD degree used the
Kruskal-Wallis test. The level of statistical significance was set at P<0.05

Results

Based on the data derived from the medical record at our institution, the study samples
were 50 patients with chirrhosis who fulfilled the inclusion and exclusion criteria as specified in
this study.

Table 1. Characteristics of Research Subjects

Characteristics n (%)
Jenis Kelamin
Man 50 (100)
Woman 0 (0)
Age, median (min-max), years 57 (24-75)
Level of education
Elementary + Middle School 19 (38)
High School + University 31 (62)
Ethnic
Batak 29 (58)
Javanese 16 (32)
Others 5 (10)
Viral marker
HBsAg (+) 22 (44)
Anti HCV (+) 8 (16)
MELD Score
<11 6 (12)
11-20 19 (38)
>20 25 (50)
Free testosterone (ng/dL) 1,35 ± 0,59
 Table 1 shows the median age of the patients was 57 years with an age range of 24-75
years where the highest education level was high school and college education in 31 samples
(62%). The highest ethnicity is Batak ethnic with 29 samples (58%) followed by Javanese ethnic
with 16 samples (32%). 30 cirrhotic patients were diagnosed with hepatitis where 22 samples
(44%) were diagnosed with hepatitis B and 8 samples (16%) were diagnosed with hepatitis C.
25 samples (50%) of cirrhotic patients in this study had a MELD Score > 20, 19 samples (38%) )
patients with MELD score 11-20, and 6 samples (12%) with MELD Score < 11. Mean free
testosterone level was 1.35 ± 0.59 ng/dL

Table 2. Differences In Free Testosterone Levels Between MELD Scores Degree

MELD Score Free testosterone (ng/dL) p

<11 2,39 (0,5-3,1) 0,001*
11-20 1,55 (0,5-3)
>20 0,8 (0,5-2,7)
*p< 0,05

We performed a comparative analysis between MELD scores and free testosterone levels.
In the sample with a MELD score <11, the median free testosterone level was 2.39 (0.5-3.1). In
the sample with a MELD score of 11-20, the median free testosterone level was 1.55 (0.5-3). In
samples with a MELD score >20, the median free testosterone level was 0.8 (0.5-2.7). Based on
the analysis of the difference in free testosterone levels between MELD scores degrees showed a
significant difference (p<0.05)

Figure 1.
Boxplot Diagram of Free Testosterone Levels in Liver Cirrhosis Based on MELD Scores
Discussion

Cirrhosis is characterized by fibrosis and nodule formation of the liver secondary to

chronic injury, leading to alteration of the normal lobular organization of the liver. Various
insults can injure the liver, including viral infections, toxins, hereditary conditions, or
autoimmune processes. With each injury, the liver forms scar tissue (fibrosis), initially without
losing its function. After a chronic injury, most of the liver tissue becomes fibrotic, leading to
loss of function and the development of cirrhosis.6

Chronic liver diseases usually progress to cirrhosis. In the developed world, the most
common causes of cirrhosis are hepatitis C virus (HCV), alcoholic liver disease, and
nonalcoholic steatohepatitis (NASH), while hepatitis B virus (HBV) and HCV are the most
common causes in the developing world. The incidence of liver cirrhosis in Indonesia due to
hepatitis B ranges from 21.2 - 46.9% and hepatitis C ranges from 38.7-73.9%. 1.7
Based on this
study, 30 cirrhotic patients were diagnosed with hepatitis where 22 samples (44%) were
diagnosed with hepatitis B and 8 samples (16%).

The Model for End-Stage Liver Disease (MELD) is a scoring system for evaluating the
severity of end-stage liver disease (ESLD). MELD was originally developed to predict mortality
in patients who had undergone transjugular intrahepatic portosystemic shunt procedures, but it
has also been shown to be a useful assessment of patients with ESLD. The MELD score has been
shown to be a reliable means of predicting prognoses of patients with ESLD as well as a means
for prioritizing recipients of liver transplants.8 Patients with more serious conditions of ESLD
often have higher MELD scores. In this study, 50% of cirrhotic patients had a MELD score > 20.

Low serum testosteron has been reported in up to 90% of men with cirrhosis. The extent
of androgen deficiency increases in parallel with worsening severity of liver failure, as classified
by the Child Pugh score. Low T is thought to contribute to many of the clinical features of
advanced liver disease in men, including altered body hair distribution, gynecomastia, testicular
atrophy, muscle wasting, impaired sexual function, anemia, and fatigue.5,9

In our study, higher MELD scores correlated with lower free testosterone levels. This is
in accordance with the research of Nguyen et al. added that severe liver disease was associated
with lower free testosterone and higher sex hormone-binding globulin levels. 10 Nguyen et al.
found that men with low fibrosis scores (0-2) on the modified Knodell histological activity index
were more likely to have lower sex hormone-binding globulin (SHBG) levels (38.2 +/- 13.2 vs
66.6 +/- 43.3 nmol/L, P < 0.001) and higher free testosterone levels (380.4 +/- 102.0 vs 255.9 +/-
83.0 pmol/L, P = 0.01) than those with higher fibrosis scores (3-6). SHBG directly correlated
with fibrosis scores (r = 0.37, P = 0.032). Free testosterone levels inversely correlated with liver
fibrosis scores (r = -0.43, P = 0.011).11

Hypogonadism is also a common clinical condition in patients with ESLD. Males with
hypogonadism may present with muscle wasting and the absence of secondary sex
characteristics, ambition and energy. Many of the clinical features of advanced liver disease are
similar to those exhibited by men with hypogonadism, including low libido, general weakness,
high fatigue level, depression, testicular atrophy and impotence. The total testosterone level is
lower than normal in most men with liver disease, and the level tends to decrease markedly as
the disease progresses. An observational study conducted by Grossmann et al. revealed that low
total testosterone was an independent predictor of mortality in patients with chronic liver disease.
8,9
A recent observational study of 171 male patients referred for liver transplant found a
significant association between reduced T levels and mortality. 9 Reductions in both free and total
T were significant predictors of death, independent of both the Model for End-stage Liver
Disease (MELD) score and serum sodium. Because this study was observational, no inferences
regarding causality can be made, but it remains possible that low T contributes to increased
mortality.5
 The pathogenesis of hypogonadism in cirrhotic patients is complex and not well
elucidated. It involves both a gonadal and a hypothalamic-pituitary dysfunction which is shown
in laboratory tests by a decrease in gonadotropins (FSH and LH), total testosterone and Free
Testosterone serum levels. Southren et al. demonstrated a decreased plasma level and production
rate of testosterone in cirrhosis of the liver and that the mechanism of the hypogonadism is
probably secondary to hypothalamic-pituitary suppression rather than to primary testicular
dysfunction.10

This study is the first study to assess the relationship between MELD scores and free
testosterone levels in male patients with liver cirrhosis. In addition, this study uses free
testosterone as an indicator of hormone assessment where free testosterone is a more accurate
measure of androgen status than total T in conditions of altered SHBG. However, this study has
limitations in the form of a small sample size and the timing of testing for free testosterone,
which are not all carried out in the morning. For clinical purposes, the measurement of total T by
immunoassay on a morning blood sample is the mainstay for biochemical diagnosis of androgen
deficiency. Since testosterone levels exhibit a circadian variation with peak levels in the
morning, evidence-based guidelines recommend measuring morning total testosterone (TT)
levels as the initial diagnostic test for androgen deficiency. 12
Therefore, the results of this study
still require further research on a large scale and further research is needed regarding the clinical
implications of testosterone hormone replacement in patients with liver cirrhosis.

Conclusion

MELD score degree shows a relationship with free testosterone levels in patients with liver
cirrhosis, where the higher MELD score degree indicates lower free testosterone levels in
patients with liver cirrhosis.

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