Bagus Setyoboedi

Department of Child Health University of Airlangga /

Dr. Soetomo Academic General Hospital, Surabaya, Indonesia
 Introduction

• Cholestatic liver disease  interference of vitamin D

metabolism  osteoporosis
• Osteopenia and pathologic fractures  children with
chronic cholestatic liver disease: Alagille syndrome
(ALGS), progressive familial intrahepatic cholestasis
(PFIC), and biliary atresia
• Bales CB, Kamath BM, Munoz PS, Nguyen A, Piccoli DA, Spinner NB, et al. Pathologic lower extremity fractures in
children with Alagille syndrome. J Pediatr Gastroenterol Nutr. 2010;51:66-70.
• Chen HL, Chang MH. Growth failure and metabolic bone disease in progressive familial intrahepatic cholestasis. J
Pediatr Gastroenterol Nutr. 2004;39:328-330.
• Chongsrisawat V, Ruttanamongkol P, Chaiwatanarat T, Chandrakamol B, Poovorawan Y. Bone density and 25-hydroxy
vitamin D in extrahepatic biliary atresia. Pediatr Surg Int. 2001;17:604-8.
 Cholestasis

• Cholestasis: a pathologic state of bile reduction or

abnormal flow into bile ducts conjugated serum
bilirubin , bile salts concentrations ,
malabsorption of vitamin D
Anwar MM, Arafa AE, Morgan DS, Mohamed KK. Association between vitamin D level and patients with cholestasis. Int J
Community Med Public Health. 2018 May;5(5):1713-17

• Higher serum bilirubin level  vitamin D-deficient 

much higher vitamin D supplement or parenteral
route
Lee WS, Jalaludin MY, Wong SY, Ong SY, Foo HW, Ng RT. Vitamin D non-sufficiency is prevalent in children with chronic liver
disease in a tropical country. Pediatr Neonatol. 2019;60(1):12-8
 Vitamin D

• Mislabeling as “Vitamin”
• Vitamin D is not actually a vitamin at all. "Vitamins”
cannot be produced by the body, but are necessary
for the proper functioning of the tissues and organs
• Vitamin D is produced by our bodies (when our skin
is exposed to ultraviolet rays from the sun)
• It is a Steroid
Vitamin D endogenous synthesis and metabolism
 Potential direct and indirect mechanisms of effect of vitamin D
in liver diseases
Cell Process Potential Roles in Liver Disease
Hepatocyte Antiviral effect through  HCV replication Improved SVR in HCV
(mechanisms unclear)

Hepatic Stellate Cells Hepatic Stellate Cells  fibrosis in viral hepatitis or fibrosis patients
 fibrotic markers through  SMAD3 binding to  HCC proliferation
promoter sites, with associated  proliferation and
HSC activation
Macrophage  Cathelicidin through activation of TLR and HCV and HBV response and clearance
increased
VDR expression [19],  TNF-
, IL-16
Cytokines  TNF  liver inflammation NAFLD
, IL-4, IL-6 andTLR repressed [20]
Adipocytes  oxidative stress;  TNF and inflammatory  inflammation in NAFLD
markers in adipose tissue [21]
T cells Increases Treg cells or Treg differentiation [22,23]  acute cellular rejection liver transplantation
Activates naïve T cells [24] Anti-proliferative effect in HCC
Cholangiocytes Protection of integrity of biliary epithelial cell Improvements in primary biliary cholangitis
junctions;  Cathelicidin (in primary cultured cells) autoimmune hepatitis and primary sclerosing
cholangitis; enhanced effect of ursodeoxycholic acid
(UDCA) treatment
 = decreased,  = increased. Abbreviations: HCC (hepatocellular carcinoma), HCV (hepatitis C virus), HSC (hepatic stellate cell), IL
(interleukin), NAFLD (non-alcoholic fatty liver disease), SMAD (mothers against decapentaplegic homologue), SVR (sustained virological
response), TGF (transforming growth factor), TLR (toll like receptor), TNF (tumor necrosis factor), Treg (regulatory T cells), VDR (vitamin D
receptor).
Handzlik-Orlik G, Holecki M, Wilczyński K, Duława J. Osteoporosis in liver disease: pathogenesis and management. Ther Adv Endocrinol
 Osteoporosis

• Osteoporosis is a disorder of low bone mass,

microarchitectural malformation and structural
weakness
• Osteomalacia is a disorder of decreased osteoid
mineralization at sites of bone formation
• The etiology of bone loss is multifactorial and not
entirely understood
 Indications for bone mineral density measurement

 Previous fragility fractures*

 Glucocorticoid therapy (>3 months ⩾ 5 mg/day prednisone)
 Cholestatic liver disease (bilirubin >3× upper limit of normal for more than
6 months)
 Liver cirrhosis
 Presence of major risk factors of osteoporosis:
• Postmenopausal women

• Premature menopause (<45 years)

• Secondary amenorrhea (>6 months)

• Male hypogonadism

• Low body mass index (<19 kg/m )

2

 Hemochromatosis
 Alcohol abuse
 Before and after liver transplantation
* Indicates severe osteoporosis; treatment may be initiated prior to bone mineral density assessment.
Handzlik-Orlik G, Holecki M, Wilczyński K, Duława J. Osteoporosis in liver disease: pathogenesis and management. Ther Adv
Endocrinol Metab. 2016 Jun;7(3):128-35
 Pathogenesis

• The pathogenesis of bone loss in liver patients is

poorly understood
• Reduced bone density in children with cholestatic
liver disease is multifactorial and related to growth,
degree of cholestasis, fracture vulnerability, and
contribution of underlying genetic etiology
Loomes KM, et.,al.; Childhood Liver Disease Research Network. Bone density in children with chronic liver disease correlates
with growth and cholestasis. Hepatology. 2019 Jan;69(1):245-57

• Unstable bone remodeling is caused by a number of

mechanisms, some of which remain unknown
 Pathogenesis…

Mechanism of osteoporosis:
Imbalance between rate of resorption and formation

Normal bone Osteoporosis

 Pathogenesis…

• The mechanisms of impaired bone metabolism are

largely caused by the unique characteristics of the
specific liver disease being considered
• There remain a number of common factors related to
chronic liver disease  bone metabolism:
– vitamin D and calcium metabolism alterations
– vitamin K deficiency
– hormonal dysregulation
– release of cytokines
– insulin-like growth factor 1 (IGF-1) deficiency
Handzlik-Orlik G, Holecki M, Wilczyński K, Duława J. Osteoporosis in liver disease: pathogenesis and management. Ther Adv
Endocrinol Metab. 2016 Jun;7(3):128-35
 Factors impairing bone turnover in chronic liver disease

Handzlik-Orlik G, Holecki M, Wilczyński K, Duława J. Osteoporosis in liver disease: pathogenesis and management. Ther Adv
Endocrinol Metab. 2016 Jun;7(3):128-35
 Management

• Addressed to reduce or avoid the risk factors for

osteoporosis and fracture
• Prevention and treatment of osteoporosis  good
nutrition is recommended
• Suppression of the risk factors for
osteoporosis and the administration
of supplements of calcium and
vitamin D
 Management…

• No specific medical treatment for osteoporosis

• Bisphosphonates (weekly alendronate and monthly
ibandronate)  effective in increasing bone mass in
patients with chronic cholestasis
Guañabens N, Parés A. Management of osteoporosis in liver disease. Clin Res Hepatol Gastroenterol. 2011 Jun;35(6-7):438-45

• Children have remarkable improvement in bone

mineral density (BMD) by 1 year after liver
transplantation, often accompanied by significant
catch-up growth
Kryskiewicz E, et., al. Bone metabolism in cholestatic children before and after living-related liver transplantation -- a long-
term prospective study. J Clin Densitom. 2012;15:233-40
23
 Resume

• Cholestasis  reduction or abnormal bile flow 

vitamin D malabsorption
• Vitamin D  produced and metabolized by our
bodies
• The pathogenesis of bone loss in liver patients is
poorly understood
• No specific medical treatment for osteoporosis 
reduce or avoid the risk factors for osteoporosis and
fracture
Factors impairing bone turnover related in chronic
liver disease
Prophylaxis and treatment of osteoporosis in liver diseases according to the
bone mineral density or presence of vertebral fractures
Pathogenesis…