Osteoporosis in Liver Cirrhosis

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1 Osteoporosis in liver cirrhosis Osteoporosis in Liver Cirrhosis Cristina Cijevschi 1, Cãtãlina Mihai 1, Eusebiu Zbranca 2, Petru Gogãlniceanu 3 1) Institute of Gastroenterology and Hepatology. 2) Endocrinology Clinic, Iaºi, Romania. 3) University College London, UK Abstract Background. Osteoporosis is still an underestimated complication of liver cirrhosis (LC). Aim. To study the prevalence of osteoporosis and osteopenia in patients with LC and to identify the principal risk factors associated. Material and methods. The prevalence of osteoporosis and osteopenia was studied in 150 patients with alcoholic or viral LC who were admitted to the Institute of Gastroenterology and Hepatology, Iasi in Osteoporosis was diagnosed by measuring their bone density using dual energy X-ray absorptiometry (DXA). Patients with liver disease due to multiple aetiologies or with other liver conditions (primary biliary cirrhosis, autoimmune or metabolic causes, etc.) as well post menopausal women were excluded from the study. The variables taken into consideration were: gender, nutritional status (body mass index BMI), etiology of liver disease, presence of cholestasis, severity and duration of disease. Results. Fiftyseven patients with LC (38%) were found to have osteoporosis or osteopenia. There was a statistically significant correlation between the presence of bone changes and a BMI of < 20 kg/m 2, cholestasis, Child class C and long duration of disease (> 10 years). During the study period, despite the relatively high rate of bone metabolism abnormalities, there were no pathological fractures in the patients group. Conclusions. Osteoporosis has a raised prevalence in patients with LC. It is important to be diagnosed and treated early, especially when risk factors such as malnutrition, cholestasis and a severe liver disease are present for a long period of time. Key words Osteopenia - osteoporosis - liver cirhhosis - DXA Romanian Journal of Gastroenterology December 2005 Vol.14 No.4, Address for correspondence: Cristina Cijevschi Prelipcean Institutul Gastroenterol Hepatol Bd. Independenþei, nr.1 Iaºi, Romania cristinacijevschi@yahoo.com Rezumat Premize. Osteoporoza reprezintã o complicaþie încã subevaluatã a cirozei hepatice (CH). Scop: studierea prevalenþei osteoporozei ºi osteopeniei la pacienþii cu CH ºi identificarea celor mai importanþi factori de risc asociaþi. Material ºi metodã. Am studiat prevalenþa osteoporozei ºi osteopeniei la 150 pacienþi cu CH alcoolicã sau viralã, internaþi în Institutul de Gastroenterologie ºi Hepatologie Iaºi în perioada 1 ianuarie 31 decembrie Diagnosticul de osteoporozã a fost stability prin mãsurarea densitãþii osoase folosind DXA (dual energy x-ray absorptiometry). Au fost excluºi din lotul de studiu pacienþii cu etiologie mixtã sau cu alte etiologii ale bolii hepatice (cirozã biliarã primitivã, autoimunã, metabolicã etc.) precum ºi femeile în postmenopauzã. Parametrii luaþi în considerare au fost: sexul, starea nutriþionalã (indicele de masã corporalã - IMC), etiologia bolii hepatice, prezenþa sindromului de colestazã, severitatea ºi vechimea bolii hepatice. Rezultate. 57 pacienþi cirotici (38%) au prezentat osteoporozã sau osteopenie. Prezenþa modificãrilor osoase s-a corelat statistic semnificativ cu IMC < 20 kg/m 2, colestazã, clasa Child C, evoluþia îndelungatã a bolii hepatice (> 10 ani). Pe parcursul perioadei studiate, în ciuda prevalenþei relativ crescute a tulburãrilor metabolismului osos, nu s-a înregistrat nici o fracturã patologicã la pacienþii cirotici. Concluzii. Osteoporoza are o prevalenþã crescutã la pacienþii cirotici; ea trebuie depistatã ºi tratatã precoce, mai ales atunci când existã factori de risc: subnutriþie, colestazã, boalã hepaticã severã cu evoluþie îndelungatã. Introduction Liver cirrhosis (LC) is a debilitating chronic disease associated with severe complications and raised mortality. Hepatic osteodystrophy, and consequent osteoporosis and increased risk of bone fracture, represent some of the more recently investigated complications. Initial studies focused on osteoporosis in patients with primary biliary cirrhosis; more recently, however, it has been shown that LC is a risk

2 338 factor for osteoporosis and bone fractures independent of its aetiology (1). This study aims to investigate the prevalence of osteopenia and osteoporosis in patients with LC and to identify the key associated risk factors. Material and methods The study cohort consisted of 150 patients with viral or alcoholic LC admitted to the Institute of Gastroenterology and Hepatology Iasi between the 1st of January and 31st of December The diagnosis of LC (established either before or on admission) was re-confirmed using clinical, biological, ultrasound or endoscopic methods, as well as histopathological investigations in some cases. Viral markers were identified (Ag HBs, anti-vhc antibodies) and alcohol consumption was quantified. Alcoholic cirrhosis was diagnosed as an alcohol consumption of over 100g of pure alcohol / day for a period of > 5 years and/or in the presence of clinical or biological stigmata of chronic alcoholism. Patients with liver disease due to multiple aetiologies or with other liver conditions (primary biliary cirrhosis, autoimmune or metabolic causes, etc.) as well post menopausal women were excluded from the study. The following parameters were recorded for each patient: gender, age, body mass index (BMI), cause of liver disease, duration of liver disease (years), past history of pathological fractures, presence of cholestasis (serum level of bilirubin, alkaline phosphatase, gamma glutamyl transpeptidase), severity of liver disease (Child score). The informed patient consent for the study was obtained. The bone density was measured in all patients using biphotonic absorption of X-rays (dual energy X-ray absorptiometry DXA). The results were expressed as a T score (the number of standard deviations STD - from the normal values of a young adult) according to the WHO classification (2): Bone Status T score Normal bone density T score < 1 STD Osteopenia T score between 1 and 2.5 STD Osteoporosis T score < 2.5 STD Severe osteoporosis T score < 2.5 STD and at least one osteoporotic fracture Cijevschi et al Fifty-seven patients (38%) had alcoholic cirrhosis, 41 patients (27.33%) had positive hepatitis B markers and 52 (34.66%) had positive hepatitis C markers. Sixty-one patients had a BMI less than 20 kg/m 2, 70 had a BMI between kg/m 2 and 19 over 25 kg/m 2. Cholestasis was present in 42 patients (28%). We took into consideration a rise in all three biochemical parameters for cholestasis mentioned previously, and not just the isolated rise in gammagt (found in the 35 patients with alcoholic cirrhosis) or ALP (found in 4 patients with viral and 2 patients with alcoholic cirrhosis). In 20 patients (13.33%) the diagnosis of hepatic cirrhosis was established only at admission, while 32 patients (21.33%) had a 10 years history of liver disease. We quantified the severity of liver disease using the Child classification. Thirty-eight patients (25.33%) had LC Child class A, 47 (31.33%) Child class B and 65 (43.33%) Child class C. Patients characteristics are shown in Table I. Table I Patients characteristics Parameters Sex (M/F) Age BMI (kg/m 2 ) Bilirubin (mg%) Alkaline phosphatase (U/l) Gamma glutamyl transpeptidase (U/l) Virus B markers Virus C markers Alcohol consumption Child class A Child class B Child class C Duration of disease Mean ± standard deviations 78/ ± ± ± ± ± /150 (27.3%) 52/150 (34.6%) 57/150 (38.0%) 38/150 (25.3%) 47/150 (31.3%) 65/150 (43.3%) 7.22 ± 6.47 Fifty-seven patients (38%) with LC had osteoporosis (T-score > -2.5) or osteopenia (T-score between and - 2.5). The correlation between osteoporosis and aetiology of LC, Child class, duration of disease, presence of cholestasis, sex and BMI is shown in Table II. Table II Risk factors associated with the presence of osteoporosis / osteopenia in patients with LC The Z score could not be evaluated by the equipment. The data were statistically analysed. Continuous data were expressed using mean ± standard deviations. Categorical data were expressed as number of subjects with a specific characteristic. Chi-square testing was used for comparing categorical data. Results Out of the 150 patients, 78 (52%) were men and 72 were women (48%). The age range was between 18 and 78 years. Risk Factors Virus B Virus C Alcohol Female gender BMI <20 kg/m 2 Cholestasis Child Class C Duration of liver disease > 10 years Patients with normal bone density (n) Patients with osteoporosis/ osteopenia (n) Statistical Significance p=0.007 p=0.024 p=0.50 p=0.0012

3 Osteoporosis in liver cirrhosis 339 The patient history revealed that only three patients had previous bone fractures (two with alcoholic LC and one with viral C LC); one patient had a normal bone mass density and two had osteopenia. In all cases fractures were posttraumatic and could not be correlated to osteoporosis. All patients with osteoporosis were given general lifestyle advice (physical exercise, avoiding the use of alcohol and tobacco, and a diet rich in calcium and vitamin D). Patients with osteopenia received calcium supplements (1 1.5g/day) and vitamin D ( U/day). Patients with osteoporosis were referred to the Endocrinology Clinic and received treatment with bisphosphonates and calcitonin. Discussion Osteopenia is a moderate reduction in bone mass, whilst osteoporosis is defined as a decrease in bone density with alterations in bone micro-architectures and a consequent increased risk of fractures. Osteomalacia is a defect in the mineralization of newly formed bone, most frequently encountered in patients with vitamin D deficiency. Our study showed an increased prevalence of bone metabolic changes in patients with LC. The prevalence in our patients falls in the range reported by other published studies (10-60%) (1-3). The wide variation seen in the literature is accounted for by the method of patient recruitment (hospitalised or not), method of diagnosis, definition of osteoporosis (T or Z score) and control group. In our study, the prevalence was, as expected, higher because the measurements were performed on a selected patient cohort, comprising patients with a relatively severe hepatic disease, which required hospitalization. The risk factors for osteoporosis are multiple: genetic family history of osteoporosis, female gender, Caucasian ethnicity; hormonal and metabolic menopause, hypogonadism, amenorrhea, diabetes, hyperparathyroidism, hyperthyroidism, renal failure; diet and behavioural deficiency/malabsorption of calcium and vitamin D, malnutrition, sedentary lifestyle, alcohol consumption and smoking; drugs corticosteroids, heparin, anti-epileptics; inflammatory states raised C-reactive protein (CRP), interleukin 6 (Il-6) and tumour necrosis factor α (TNFα) (4,5). In LC, the main risk factors for osteoporosis are: hypogonadism, malnutrition, cholestasis, deficiency of vitamin D, treatment with glucocorticoids, and alcohol consumption. Initially considered as cholestatic complications (primary biliary cirrhosis has an osteoporosis prevalence of 15-50%), the abnormalities of bone metabolism have been reported also in relation with other liver diseases: primary sclerosing cholangitis (50%), viral (20-53%) or alcoholic (%) cirrhosis (6). In our study abnormalities of bone metabolism were detected in 32.25% of patients with viral cirrhosis ( patients) and in 47.3% (27 patients) with alcohol induced cirrhosis. The main risk factors identified were: high body mass index, presence of cholestasis syndrome and longer duration of hepatic disease. The mechanism of bone loss in chronic liver diseases is not completely understood. Two theories exist, one based on a low bone turnover (reduced bone formation with normal resorption of bone), the other on a high bone turnover (increased rate of bone resorption with normal production of bone) (3,7,8). The role of vitamin D in osteoporosis associated with LC is also controversial. Initially, it was believed that the bone loss was caused by vitamin D malabsorption due to cholestasis and the consequent deficient hepatic hydroxylation. It was shown however, that the severity of osteoporosis in LC patients did not correlate with the serum levels of vitamin D, and that, furthermore, vitamin D supplements did not affect the development of osteopenia in LC. In recent years, genetic polymorphisms of the vitamin D receptor have been reported, but the published evidence remains inconclusive. Thus, the bb alleles are associated partly with maintaining bone mass after liver transplantion, and partly with the reduction in bone mass in North American patients with primary biliary cirrhosis (9). The diagnosis of osteoporosis is established using serum and urinary markers of bone turnover (10) and through imaging methods. The serum and urinary markers of bone turnover are established by routine investigations. Although usually normal, a low calcium and phosphorus and a high alkaline phosphatase may be present. Raised urinary levels of N- and C- telopeptide indicate an increased osteoclastic activity. There are decreased serum levels of 25-hydroxy vitamin D (the test is useful when suspecting osteomalacia). These markers have a low use in clinical practice. In our study, the serum levels of alkaline phosphatase were raised compared to the remaining investigations in 6 patients, without correlation with osteoporosis (only one of the 6 patients presented with osteopenia). This confirms the reduced benefit of alkaline phosphatase investigation of bone metabolism. DXA is the gold-standard method of measuring bone density and predicting the risk of fractures occurring. We preferred this method of assessing osteoporosis, as it is quick, precise, reproducible, cheap and minimally invasive. The measurement of bone density using bi-photonic X-ray absorption is performed on the vertebral column (L2-L4) or in the proximal femur. The results are expressed as Z-scores (the number of standard deviations compared to the normal values in an individual of similar age and sex) or T-scores (the number of standard deviations compared to an absolute value typical of a young subject). It is not possible to differentiate osteoporosis from osteomalacia using this method. Bone X-ray investigations are able to identify osteoporosis relatively late in its evolution, when a bone density loss of 50% has taken place (8). Ten patients from our study group were investigated using bone X-rays (hand or foot); 5 of these had osteoporosis (as indicated by DXA) without any radiological evidence of bone changes. These results confirm the fact that X-ray investigations are able to detect bone changes only in the advanced stages of the disease.

4 340 Quantitative ultrasound is a cheap and non-invasive method of identifying osteoporosis, which can provide information regarding bone density and structure (11). It is used in case of superficial bone structures (phalanges, calcaneus, tibia). There are no data to suggest that this method should be used routinely, on a large scale. Quantitative Computed Tompography (CT) is able to achieve a volumetric, three-dimensional measurement of bone density. It is however, an expensive method that does not provide any additional information compared to DXA, with exception of cases where skeletal or artefactual changes can cause erroneous DXA measurements (vertebral osteophytes, calcified aorta) (12). Bone biopsy is the only method that is able to identify osteomalacia. However, this is an invasive procedure, not used in clinical practice. No patients in our study underwent ultrasound investigations, CT scanning or bone biopsy. Overall, the treatment of osteoporosis in LC does not differ from the management of osteoporosis secondary to other conditions. Beside general measures, calcium (1-1.5 g/day) and vitamin D ( UI/day) are recommended for moderate osteopenia, prophylactically for those taking corticosteroids or where other risk factors are present (1). It has been shown that oestrogen replacement therapy lowers the risk fractures in post-menopausal women. Longterm oestrogen therapy is limited by the risk of thromboembolic events and breast cancer. Raloxifene, 60 mg/day, an oestrogen receptor modulator, lowers the risk of vertebral fractures (but not the risk of extra-vertebral ones) and prevents the breast cancer (13). In LC the use of oestrogens is limited by their secondary effects on cholestasis. Their preferred method of administration is transdermal, in order to avoid first pass liver metabolism (3). Testosterone may be given to men over the age of 55 that are suffering from osteoporosis (14). The use of testosterone is however limited by the increased risk of hepatocarcinoma. Calcitonin 500 mg/day, given as an intranasal spray, intramuscularly or subcutaneously, can inhibit bone resorption, prevent fractures and reduce osteoporotic bone pain without major side effects. However, the high cost of the therapy has led to its replacement with bisphosphonates in clinical practice. (15). Bisphosphonates are synthetic analogues of inorganic pyrophosphate, which inhibit bone resorption. Etidronate (400 mg/day), alendronate (10 mg/day) and risedronate (5 mg/day) are given orally, whilst ibandronate, minodronate, pamidronate and zoledronic acid are given intravenously every 3-12 months (16). Their side-effects are limited (diarrhoea, constipation, nausea) but they can cause oesophageal and gastric ulcers, theoretically being able to induce uppergastrointestinal haemorrhage in patients with cirrhosis. Etidronate and alendronate have been shown to be efficient in the treatment of osteoporosis in patients with primary biliary cirrhosis. There are few studies regarding the use of bisphosphonates in LC and their results are contradictory (17). Cijevschi et al Parathyroid hormone (s.c. 20mg/day, for 18 months) inhibits bone resorption, increases bone mass and reduces the risk o fractures (16). The effects of sodium fluoride, vitamin K, IGF-1, statins, TNFα inhibitors (infliximab) and osteoprotegerine agents are presently investigated (18). Further studies are needed in order to establish the safety and efficacy of the various therapeutical measures for treating osteoporosis in patients with LC. The following approach was adopted for our patients: in case of normal BMI or osteopenia - general measures, calcium and vitamin D supplements followed by repeated measurement of bone density after 2 years. To treat osteoporosis, bisphosphonates or calcitonin were recom-mended, as well as bone density measurement after 2 years. Conclusions Osteoporosis is neither the commonest nor the most severe complication of LC. However, its prevalence in LC patients is increased. Therefore, it has to be diagnosed and treated early in order to increase the quality of life of LC patients. In our patients, osteopenia and osteoporosis correlated well with duration of hepatic disease, presence of cholestasis and the BMI. There were no correlations with gender, severity or etiology of liver disease, although patients in Child class C and those with alcoholic cirrhosis had a greater prevalence of bone metabolic changes. References 1. Bikle D. Osteoporosis in gastrointestinal, pancreatic, and hepatic diseases. In: Osteoporosis, Robert M (ed). Acad Press, Washington 2001: Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group. 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