https://www.spg.pt/wp-content/uploads/2015/11/2015-PSC-ACG.pdf

ACG Clinical Guideline: Primary Sclerosing Cholangitis.

An important complication of chronic liver disease is osteodystrophy which includes osteoporosis and the much rarer osteomalacia. Both conditions are associated with significant morbidity through fractures resulting in pain, deformity, and immobility. There is also a further significant increase in the risk of fractures following liver transplantation for end stage chronic liver disease.

Osteoporosis is defined as a “progressive systemic skeletal disease characterised by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture” (World Health Organisation, 1994). Common fractures are vertebral compression fractures, fractures of the distal radius, and proximal femur.

Although guidelines on the prevention and management of osteoporosis, and specifically corticosteroid induced osteoporosis and osteoporosis in men, have recently been published, there is no consensus on how to manage osteoporosis in patients with chronic liver disease.1–3

The scope of these guidelines is to review the assessment and diagnosis of osteoporosis, the therapeutic agents available, and the way in which they can be used in patients with chronic liver disease to prevent osteoporosis with the aim of reducing fracture rate. A number of research priorities have also been identified.

### 2.1 Grading of recommendations and evidence level in patients with chronic liver disease

The guidelines developed are based on systematic review of the published literature. As not all recommendations are based on randomised controlled trials, the recommendations have been scored according to the following criteria.

Grade A: based on meta-analysis or at least one randomised controlled trial.

Grade B: based on at least one well designed but not necessarily controlled study including case control and comparative studies.

Grade C: based on expert reports or opinions.

### 2.2 Process of guideline formation

A systematic review of the literature was undertaken and draft guidelines prepared. The guidelines were then reviewed in a consensus workshop following which a final draft was prepared. The consensus workshop was supported by the …

https://gut.bmj.com/content/gutjnl/50/suppl_1/i1.full.pdf

Guidelines on the management of osteoporosis associated with chronic liver disease

AGA technical review on osteoporosis in hepatic disorders

The purpose of this study was to determine the prevalence of osteoporosis, to estimate the bone turnover and hormonal status, and to identify the factors associated with bone disease in patients with end-stage liver disease who were referred for orthotopic liver transplantation. A prospective study was performed on 58 cirrhotic patients (6 with primary biliary cirrhosis, 14 with alcoholic cirrhosis, and 38 with posthepatitic cirrhosis), who were referred for orthotopic liver transplantation. Patients, excluding those with primary biliary cirrhosis, were classified in Child-Pugh groups according to the severity of liver disease (class B [28 patients], class C [24 patients]). Biochemical parameters of bone mineral metabolism and standard liver function tests were measured in all patients. Additionally, serum osteocalcin, urinary hydroxyproline/creatinine ratio, serum intact parathyroid hormone, serum 25-hydroxyvitamin D, serum 1,25-dihydroxyvitamin D, follicle-stimulating hormone, and luteinizing hormone levels were determined in patients and controls within the same age range. Plasma testosterone, sex hormone-binding globulin levels, and free testosterone index were obtained for all men included in the study. Bone mass of the lumbar spine and femur were measured by dual X-ray absorptiometry (DPX-L), and were expressed as a standard deviation of mean values (Z-score) from a sex and age-matched control group. Spinal X-rays were obtained to assess vertebral fractures. Osteoporosis was considered as a factor in spinal bone mineral density with a Z-score below 2 or at least one vertebral fracture. Twenty-five patients (43%) had osteoporosis, with lower bone mass measurements in the lumbar spine than in the femoral neck (P < 0.005). Alcoholic and Child-Pugh C patients showed the lowest femoral bone mineral density values. Cirrhotic patients showed lower osteocalcin levels than controls (14.3 +/- 5.9 vs. 18.2 +/- 8.1 ng/ml; P < 0.05) and showed increased urinary hydroxyproline (125.1 +/- 51.5 vs. 107.9 +/- 26.6 nM/mg creatinine; P < 0.05). Serum 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and parathyroid hormone levels were significantly lower in cirrhotic patients than in controls (10.3 +/- 9.1 vs. 23.1 +/- 26.6 ng/ml; P = 0.000), (12.9 +/- 9.1 vs. 48.3 +/- 11.5 pg/ml; P = 0.000), (16.6 +/- 9.2 vs. 27.9 +/- 8.2 pg/ml; P = 0.000), with no differences between Child-Pugh groups. Alcoholic Child-Pugh C patients showed the lowest 25-hydroxyvitamin D serum values (4.5 +/- 2.2 ng/ml; P < 0.05). Male patients had lower testosterone levels than controls (302.5 +/- 229.4 vs. 556.7 +/- 146.5 ng/dl; P = 0.000), with increased sex hormone-binding globulin values. Levels of testosterone and gonadotropin were related to Child-Pugh classification. No correlation was found between bone mass and hormonal values. A significant decrease in bone mass, particularly in the lumbar spine, is seen in end-stage cirrhotic patients. Reduced bone formation and significant disorders of bone mineral metabolism, such as vitamin D deficiency, reduced parathyroid hormone levels, and hypogonadism are involved. Moreover, severity and etiology of the liver disease are the main risk factors for developing bone loss and mineral metabolism disorders in patients referred for orthotopic liver transplantation.

Osteoporosis and bone mineral metabolism disorders in cirrhotic patients referred for orthotopic liver transplantation.

Because the osteoporosis occurring in chronic cholestatic liver disease (CCLD) is associated with decreased bone formation and is reversible by liver transplantation, substances retained in plasma during cholestasis may impair osteoblast function. This hypothesis was tested using a new bioassay that measures plasma mitogenic activity (PMA) for normal human osteoblast-like (hOB) cells. In 29 jaundiced patients, mean PMA was 56.4% (P < 0.001) of that in 29 age- and sex-matched normal subjects, and the decrease in PMA was similar in the 14 with CCLD and the 15 with other causes of jaundice. Bile acids and bilirubin are the two major groups of products retained during cholestasis. The common conjugated bile acids and bilirubin were added to normal human plasma in concentrations simulating those found in patients with CCLD. Various bile salts had no effect on PMA whereas unconjugated bilirubin decreased PMA in a dose-dependent fashion (r = -0.98, P < 0.0001) without affecting cell viability. Relatively selective removal of bilirubin from the plasma by photobleaching normalized the decreased PMA in five jaundiced patients but produced no apparent change in five normal subjects. These data support the hypothesis that hyperbilirubinemia or possibly other photolabile substances impair osteoblast proliferative capacity and thus may play a major role in the pathogenesis of the osteoporosis associated with CCLD.

/pdf/role-of-hyperbilirubinemia-in-the-impairment-of-osteoblast-40f8abwaov.pdf

Mariñoso L

Papers

Factors influencing the development of metabolic bone disease in primary biliary cirrhosis.