This document discusses endocrine dysfunction that can occur in patients with chronic liver disease (CLD). It notes that the liver plays an important role in hormone synthesis and metabolism, and CLD can disrupt these processes. Specific endocrine issues addressed include alterations in the GH/IGF-1 axis, thyroid dysfunction including low T3 levels, hypogonadism, adrenal insufficiency, metabolic syndrome/diabetes, and bone disease such as osteoporosis. Low levels of hormones like IGF-1, T3, and testosterone are associated with worse outcomes in CLD patients. Monitoring of thyroid and adrenal function is recommended during treatment of CLD.

1. Endocrine dysfunction
in CLD
Dr. Rohit K Saini
Moderator – Dr. Udit

2. Introduction
• Endocrine system is a complex, sophisticated system.
• Liver is involved in biological actions, synthesis and
metabolism of circulating hormones which maintain
endocrine homeostasis.
• There are numerous, constant relationships and
feedback mechanisms.

3. GH/IGF – 1 axis

4. GH/IGF – 1 axis
• In CLD :
 Basal plasma GH level is increased.
 Serum level of IGF-1 is low :-
1. reduced hepatocyte mass
2. decreased GH receptors in cirrhotic liver
3. decreased IGF binding protein

6. GH/IGF – 1 axis
• Alterations in GH/IGF-1 axis :
 malnutrition,
 insulin resistance,
 decreased immunity,
 osteoporosis/osteopenia,
 hypogonadism,
 short stature.

7. IGF 1 and IGFBP 3
• Low IGF-1 and IGFBP 3 are prevalent in CLD with
negative impact on prognosis

8. IGF - 1
• reduction in IGF-I level preceded the diagnosis of
HCC by 9.3 ± 3.1 months.
Mazziotti G, et al. Cancer. 2002

9. IGFBP - 3
• IGFBP-3 as a better predictor of HCC compared to
IGF-1 in cirrhosis.
• IGFBP 3 levels discriminated between cirrhosis and
HCC at a sensitivity of 87%, a specificity of 80%.

10. IGF - 1
• randomized placebo controlled clinical trial showed
beneficial effect of IGF 1 administartion in increasing
albumin level and improvement of energy
metabolism in patients with cirrhosis.
Conchillo M, et al. J Hepatol. 2005
• However, it should be noted that high serum levels of
IGF-1 has been reported to be associated with cancer
development and may limit the clinical utilization of
IGF-1 therapy in cirrhotic patients.

12. Malespin M, et al. Clin Liver Dis 23 (2019)

13. Thyroid dysfunction in CLD
• alteration in thyroid size, morphology, architectural
pattern & thyroid hormones.
• glandular volume increased up to 17% in patients
with cirrhosis.
Bianchi GP, et al. Liver. 1991.
• Resistant and pulsatility indices of inferior thyroid
artery are increased in cirrhotic patients.
Spadaro L,et al. Ultrasound Med Biol. 2004.
El-Kabbany ZA, et al. ISRN Gastroenterol. 2012.

14. Thyroid dysfunction in CLD
• The prevalence of thyroid hormone abnormalities
ranged from 13 to 61%.
• Sick euthyroid syndrome and hypothyroidism are
most frequently seen.
• Low total T3 and free T3 - most common pattern.
Due to reduced deiodinase 1 activity.
Silveira MG,et al. Liver Int. 2009.
Huang MJ, et al. J Gastroenterol Hepatol. 1995.

15. Thyroid

16. Low T4 variant of sick euthyroid
syndrome in CLD
• correlate significantly with :
1. Mid arm circumference
2. Low short and long term survival rates (at 3, 6 and
12 months)
Caregaro L, et al. J Hepatol.
1998.

17. Low T3
• Multiple studies, indicated that low serum T3 is a
good index of disease severity in cirrhosis.
• Rodríguez-Torres M, et al. Ann Hepatol. 2008.
• Mansour-Ghanaei F, et al. Ann Hepatol. 2012.
• Kayacetin E, et al. Swiss Med Wkly. 2003.
• Güven K, et al. Eur J Med. 1993.

18. ↑rT3 accompanied with HCC
Sorvillo F, et al. Increased serum reverse triiodothyronine levels at diagnosis of
hepatocellular carcinoma in patients with compensated HCV-related liver
cirrhosis. Clin Endocrinol (Oxf). 2003

19. IFN – α induced thyroid dysfunction
• Autoimmune (MC) :
 Hypothyroidism > Hyperthyroidism
• Subacute thyroiditis with transient thyrotoxicosis.

20. Sorafenib
• Hypothyroidism may develop in patients treated with
sorafenib in HCC therapy and in patients treated with
transarterial chemoembolization for HCC.
• Flohr F, et al. Hepatology 2008.
• Tamaskar I, et al. Ann Oncol 2008.
• Henceforth, routine monitoring of thyroid function
should be considered during interferon and sorafenib
treatment.

21. Hepatic osteodystrophy
• The term refers to bone disorders related to CLD.
• most prevalent –
 osteopenia (T score -1 to -2.5) >
 osteoporosis (T score less than -2.5) >
 osteomalacia (rarely)

22. Hepatic osteodystrophy
• several mechanisms are proposed:
 malnutrition,
 hypogonadism,
 IGF 1 deficiency,
 alcohol consumption,
 use of corticosteroid,
 PBC mostly in postmenopausal women.

23. Bone disorder
• Hypogonadism (low testosterone and androgens) -
increase the life span of osteoclasts and decreases
osteoblasts, leading to higher bone resorption.
• Similarly, IGF-1 deficiency - impairs osteoblastic
activity and bone mineralization.
Santos LA, et al. Biomed Res Int 2016.
Chen J, et al. J Bone Miner Res. 2012.
George J, et al. World J Gastroenterol. 2009.

24. Bone disorder
• more prevalent in lumbar spine compared to femoral
neck.

25. Hepatoadrenal syndrome
• Insufficient function of adrenal glands in CLD.
• Probable cause:
 Cholesterol level decreased, which is a substrate for
adrenal gland to produce steroidal hormones.
 proinflammatory markers increase in CLD – reduce
ACTH secretion from pituitary gland
 Spironolactone

26. Hepatoadrenal syndrome

27. Adrenal insufficiency
• AI is seen in both compensated and stable cirrhosis
as well as in cirrhotic patients with septic shock.
• prevalence of AI ranged from 7.2 to 60% in different
studies.
• Nearly all of the studies showed bad prognosis of AI
in cirrhosis.

29. Adrenal insufficiency – poor outcome

30. Adrenal insufficiency – poor outcome
• AI in cirrhosis predict early mortality, as well as
developing HRS, infections, and sepsis independent
of MELD scores.
• Acevedo J, et al. Hepatology 2013.

31. Hypogonadism
• Hypogonadism is frequent in patients with CLD.
• Clinical manifestations:
o gynecomastia,
o decreased libido,
o signs of feminization,
o testicular atrophy,
o infertility,
o reduced spermatogenesis,
o erectile dysfunction.
• more prominent in alcoholic cirrhosis.

32. Hypogonadism
• Female patients with cirrhosis suffer from
o amenorrhea,
o oligomenorrhea,
o infertility,
o metrorrhagia,
o early onset of menopause.

33. Hypogonadism
• Due to :
 Increase estrogens level
 Decrease androgens (DHEA, DHEAS)
 Increase estrogen/androgen ratio
Bannister P, et al. Q J Med. 1987.
 reduction in testosterone level
 Decrease IGF – 1
Tajima Y,et al. Int J Androl. 1995.
 Increase SHBG - Estrogens stimulate production.
Loukovaara M,et al. J Clin Endocrinol Metab. 1995.

34. Hypogonadotropic hypogonadism
• GnRH, LH, FSH levels decreased, despite loss of
inhibitory feedback :
 Hyperprolactinemia present in CLD - inhibitory effect
on gonadotropin.
Simon-Holtorf J, et al. Exp Clin Endocrinol Diabetes. 2006.
 elevate cytokines (IL-1, IL-6, TNF – α) - downregulate
GnRH secretion by hypothalamus
Jones TH,. Cytokines and hypothalamic-pituitary function. Cytokine 1993

35. Hypogonadism

36. Hypogonadism
• In a prospective study, low testosterone levels were
found to be associated with increased mortality,
infections, and the need for transplantation,
independent of the MELD score.
Sinclair M,et al. Liver Transplant 2016

37. Metabolic syndrome and DM
• Metabolic syndrome is a cluster of metabolic
abnormalities including diabetes, hyperlipidemia,
central obesity and hypertension.
• The high incidence of diabetes in CLD has been
known from years.
• On the other hand patients with diabetes and
metabolic syndrome are more susceptible to CLD
(NAFLD and NASH).

38. Insulin resistance
• Insulin resistance has a central role or underlying
cause.
Maheshwari A,et al. Clin Liver Dis 2011.

40. Adipokines
• Cytokines secreted from adipose tissue – Adipokines
Leptin – decreases appetite.
Maheshwari A,et al. Clin Liver Dis 2011.
Resistin – increases LDL cholestrol.
Pagano C, et al. J Clin Endocrinol Metab 2006.
Steppan CM, et al. Nature 2001.
Adiponectin – decreases appetite.
 In fatty liver disease – increase leptin (due to leptin
resistance) and resistin; decrease adiponectin – results in
insulin resistance, metabolic syndrome and CVD.

41. Liver and Endocrine involvement
• Various conditions - involve both liver and endocrine
system :
 infiltrating malignancy (non-Hodgkin’s lymphoma),
 systemic diseases (amyloidosis, hemochromatosis),
 autoimmune diseases.