Introduction: Cigarette smoking is associated with musculoskeletal degenerative disorders and increased risk of fracture delayed- and non-union. A lower-than-average concentration of mesenchymal stem cells may be the reason for the reduced regenerative potential. The aim of this study was to compare the concentration of bone marrow MSC of smokers and non-smokers. Methods: As part of a larger IRB approved clinical trial, 20ml bone marrow samples were processed and MSC were isolated. FACS analysis was used both to assess the purity of the separation process and to evaluate the number of MSC recovered from each sample. Differences in continuous outcomes between smoking and non-smoking groups were assessed by two tailed t test and difference between categorical outcomes was measured by chi square test. Results: Twenty six subjects participated in the study. Thirteen were smokers and thirteen were non-smokers. Groups were not significantly different with regard to age and gender. The average concentration of MSC was 352.04x10. 3. /ml for non smokers and 131.23x10. 3. /ml for smokers (SD’s were 245.72 x10. 3. /ml and 161.54 x10. 3. / ml respectively. The difference between the smokers and nonsmokers was significant (t=3.2 p=0.004). Discussion: The present study indicates that cigarette smokers have lower-than-average concentration of MSC in their bone marrow. Since MSC are a key element in every regenerative process of the musculoskeletal system, our findings may contribute to understanding and prevention of delayed and non-union. Further investigation is undertaken to address the issue of bone marrow recovery after smoking cessation

This study evaluated the impact of smoking on the surgical outcome of rotator cuff repair controlling for age, gender, and size of tear.

Two hundred and fifty patients were evaluated by a blind evaluator and by self report (SST and WORC questionnaires) at baseline and one year post-op. Types of cuff repair included arthroscopic, mini-open and open procedures. Smoking status was evaluated as a current smoker, quit, or never smoked. Smoking history was subsequently dichotomised into smoker and non-smoker. Generalised linear modeling was used to determine the impact of smoking on surgical outcome using age, gender, and tear size as covariates.

The mean age of the population used was 56+/−11 years in which 70% were males and 30% females. Tear size was distributed amongst this population as small (0–1 cm {44.9%}), moderate (1–3cm {22.7%}), large (3–5cm {15.2%}) and massive (5+cm {17.2%}). All preliminary analyses indicated gender affected tear size and surgical outcomes, and was also associated with smoking status. Due to this confounding effect, males and females were separated for subsequent analysis. The SST questionnaire found smoking to have a significant negative effect on the 1-year l outcomes of males (8.5 vs. 6.1 p=0.025). A similar trend was seen with the WORC (p=0.07). No significant effects were seen for females, but the sample size was underpowered.

Analysis of this population of rotator cuff repairs showed complex interrelationships may exist between gender, age, physical demands and smoking status. The existence of these confounding interrelationships may explain the mixed results seen in the literature concerning smoking and orthopedic procedures. This relatively large cohort established a negative impact of smoking on outcome, after controlling for covariates and confounders. Future research on mediators of cuff outcome should consider potential confounders. Conclusion: Smoking negatively effected surgical outcomes for males but was inconclusive for females. Sex behaved as a confounding variable that masked the smoking effects.

Aims

To identify the incidence and risk factors for five-year same-site recurrent disc herniation (sRDH) after primary single-level lumbar discectomy. Secondary outcome was the incidence and risk factors for five-year sRDH reoperation.

Aims. Cigarette smoking has a negative impact on the skeletal system, causes a decrease in bone mass in both young and old patients, and is considered a risk factor for the development of osteoporosis. In addition, it disturbs the bone healing process and prolongs the healing time after fractures. The mechanisms by which cigarette smoking impairs fracture healing are not fully understood. There are few studies reporting the effects of cigarette smoking on new blood vessel formation during the early stage of fracture healing. We tested the hypothesis that cigarette smoke inhalation may suppress angiogenesis and delay fracture healing. Methods. We established a custom-made chamber with airflow for rats to inhale cigarette smoke continuously, and tested our hypothesis using a femoral osteotomy model, radiograph and microCT imaging, and various biomechanical and biological tests. Results. In the smoking group, Western blot analysis and immunohistochemical staining revealed less expression of vascular endothelial growth factor (VEGF) and von Willebrand factor (vWF). The smoking group also had a lower microvessel density than the control group. Image and biochemical analysis also demonstrated delayed bone healing. Conclusion. Cigarette smoke inhalation was associated with decreased expression of angiogenic markers in the early bone healing phase and with impaired bone healing. Cite this article:Bone Joint Res. 2020;9(3):99–107

Cigarette smoking has a negative impact on the skeletal system by reducing bone mass and increasing the risk of fractures through its direct or indirect effects on bone remodeling. Recent evidence shows that smoking causes an imbalance in bone turnover, making bone vulnerable to osteoporosis and fragility fractures. In addition, cigarette smoking is known to have deleterious effects on fracture healing, as a positive correlation has been shown between the daily number of cigarettes smoked and years of exposure to smoking, although the underlying mechanisms are not fully understood. Smoking is also known to cause several medical and surgical complications responsible for longer hospital stays and a consequent increase in resource consumption. Smoking cessation is, therefore, highly advisable to prevent the onset of metabolic bone disease. However, some of the consequences appear to continue for decades. Based on this evidence, the aim of our work was to assess the impact of smoking on the skeletal system, particularly bone fractures, and to identify the pathophysiological mechanisms responsible for the impairment of fracture healing. Because smoking represents a major public health problem, understanding the association between cigarette smoking and the occurrence of bone disease is necessary in order to identify potential new targets for intervention

Aims. To examine the relationship of sex steroid hormones with osteopenia in a nationally representative sample of men in the USA. Methods. Data on bone mineral density (BMD), serum sex hormones, dairy consumption, smoking status, and body composition were available for 806 adult male participants of the cross-sectional National Health and Nutrition Examination Survey (NHANES, 1999-2004). We estimated associations between quartiles of total and estimated free oestradiol (E2) and testosterone (T) and osteopenia (defined as 1 to 2.5 SD below the mean BMD for healthy 20- to 29-year-old men) by applying sampling weights and using multivariate-adjusted logistic regression. We then estimated the association between serum hormone concentrations and osteopenia by percentage of body fat, frequency of dairy intake, cigarette smoking status, age, and race/ethnicity. Results. Men in the lowest quartile of total E2 concentrations (< 21.52 pg/ml) had greater odds of osteopenia compared with men in the highest quartile (odds ratio (OR) 2.29, 95% confidence interval (CI) 1.11 to 4.73; p-trend = 0.030). Total and free T were not associated with osteopenia. Low total E2 concentrations were associated with greater odds of osteopenia among non-daily dairy consumers (p-trend = 0.046), current or former smokers (p-trend = 0.032), and younger men (p-trend = 0.031). No differences were observed by race/ethnicity and obesity. Conclusion. In this nationally representative study of the USA, men with lower total E2 were more likely to have osteopenia, which was particularly evident among younger men, men with less-than-daily dairy consumption, and current or former smokers. Cite this article:Bone Joint Res. 2020;9(3):139–145

Osteonecrosis of the femoral head is a complex pathologic process with many aetiological factors. Factors most often mentioned in the literature are mechanical disruption (hip trauma or surgery), steroid use, smoking, haemoglobinopathies and hyperlipidaemia. 1. Our case depicts a rare association of crack cocaine related to osteonecrosis of the femoral head which has never been reported in the available literature. Case Report: A 32 year old man was referred to our Orthopaedic clinic with right hip pain. He had a 9 pack-year history of cigarette smoking and had also smoked crack cocaine between ages 20 to 28; shortly after this the hip pain started. He denied antecedent injury. He had undergone a steroid injection into his right ankle abroad for swelling one year before referral, which was after onset of hip pain. MRI of his hip previously performed abroad had been normal. The patient had an indoor job and was otherwise fit and well. On examination he had reduced of movement in his right hip with 5–10 degrees of fixed flexion deformity. Plain radiography demonstrated cyst formation and sclerosis of both femoral heads. Repeat MRI confirmed bilateral osteonecrosis, worse on the right with risk of head collapse. The patient underwent bilateral core decompressions. Subsequent follow-up demonstrated a mobile patient with no need for arthroplasty and he was discharged after two years. Osteonecrosis is caused by the coagulation of the intra-osseous microcirculation leading to thrombosis formation and eventual reduction in osseous blood supply. Steroid use is associated with increased risk of osteonecrosis to the femoral head, however in these cases the patients often undergo either direct local or systemic infiltration of steroid. In this case steroid was administered after symptoms began to a far distant site and therefore cannot be the cause. Cigarette smoking is also known to cause osteonecrosis. Our patient had smoked cigarettes for fourteen years without problems, and it was after he ceased to smoke crack cocaine that his symptoms began. Cocaine blocks voltage-gated sodium-channels causing vasospasm. It is known to cause nasal and facial bone osteonecrosis due to its common intranasal method of delivery. We postulate that in this case crack cocaine was a synergistic factor towards development of femoral head osteonecrosis

Introduction: Non-steroidal anti-inflammatory drugs (NSAIDs) are inhibitors of cyclooxygenase activity and are potential therapeutic agents in the prevention of aseptic loosening. Cigarette smoking is a risk factor for decreased proximal femur bone density. We investigated whether the clinical variables of NSAID usage and cigarette smoking are possibly linked to aseptic loosening around total hip arthroplasty (THA). Methods: Retrospective review of records and radiographs of all patients attending for follow-up between August 2002 and 2003 who had undergone THA. Age, gender, primary and revision surgery details, radiographic parameters as detailed above, smoking history and NSAID usage history were recorded. Logistic regression analysis was used to determine the presence of associations. Results: 224 patients were recruited to the study: 143 to the control group with a mean time of THR survival of 14.6 years and 81 to the aseptic group with a mean time to THR failure of 5.1 years. 130 patients had never smoked, 69 were ex-smokers and 25 were smokers (average of 15.5 cigarettes/day). 13.6% of patients in the study group were smokers and 10.5% in the control group. The average duration of NSAID usage pre-operatively was 3.4 years and post-operatively was 4.4 years. Using the logistic regression model, amount of cigarettes smoked, years as a non-smoker and length of usage of NSAID were not found to be associated with aseptic loosening. Discussion and conclusions: We found no such statistically significant relationship with regards to smoking habit or NSAID usage as either protective or risk factors

The purpose of this study was to review the outcomes and complications of all circular external fixators (frames) used for the management of acute lower limb trauma in our institution over a twenty year period. We retrospectively reviewed a prospectively compiled database of all frames applied in our institution and identified all frames which were applied for acute lower limb trauma. We identified 68 fractures in 63 patients. There were 11 femoral fractures and 57 tibial fractures. All fractures were classified using the AO Classification system, and most fractures were Type C fractures. We used an Ilizarov frame in 53 patients and a Taylor Spatial Frame in 15 patients. The mean time in frame was 365 days for a femoral fracture and 230 days for a tibial fracture. There were five tibial non-unions giving an overall union rate of 93%. Factors associated with non-union included high energy trauma and cigarette smoking. The vast majority of lower limb fractures can be treated using ‘conventional’ methods. Complex fractures which are not amenable to open reduction and internal fixation or cast immobilisation can be treated in a frame with excellent results. The paucity of published reports regarding the use of frames for complex trauma reflects the under-utilisation of the technique

The purpose of this study was to review the outcomes and complications of all circular external fixators (frames) used for the management of sterile and infected fracture non-unions in the lower limb in our institution over a twenty year period. We retrospectively reviewed a prospectively compiled database of all frames applied in our institution and identified all frames which were applied for acute lower limb trauma. We identified 76 non-unions in 76 patients. There were 22 femoral non-unions and 54 tibial non-unions. Five femoral non-unions and 12 tibial non-unions were confirmed infected. The mean time in frame was 281 days for a sterile non-union and 457 days for an infected non-union. There was a union rate of 87% for sterile non-unions and 71% of infected non-unions at cessation of treatment. Factors associated with persistent non-union included cigarette smoking, soft tissue complications, and excessive pin-site toilet by the patient. Lower-limb fracture non-unions can be extremely difficult to treat. The patients included in our study had previously undergone more traditional treatments in an attempt to establish union. The results presented demonstrate that circular frames are an excellent treatment modality in non-unions resistant to other forms of treatment. We would recommend this as a first line treatment for patients at higher risk of developing fracture non-union

The aim of this study was to identify risk factors for failure of exchange nailing in tibial diaphyseal fracture non-unions. The cohort comprised 99 tibial diaphyseal fracture non-unions treated by exchange nailing. The mean age of the patients at exchange nail surgery was 36 years. The median time from primary fixation to exchange nailing was 6.4 months. The main outcome measures were union, number of secondary fixation procedures required to achieve union and time to union. Univariate analysis and multiple regression were used to identify risk factors for failure to achieve union. Multiple causes for non-union were found in 31.3% cases, with infection present in 32.3%. Further exchange procedures were required in 35.4%, 7.1% required the use of other fixation modalities. Union was ultimately achieved in 97.8%. The median time to union was 8.7 months. Univariate analysis revealed that cigarette smoking, an atrophic pattern of non-union and infection were predictive for failure of exchange nailing (p<0.05). Multi-regression analysis found that only infection was statistically significantly predictive (p<0.05) of exchange nail failure. Exchange nailing is an effective treatment for tibial diaphyseal non-unions even in the presence of infection. Smoking, atrophic pattern of non-union and infection are associated with an increased risk of further fixation surgery

The aim of this study was to identify risk factors for failure of exchange nailing for femoral diaphyseal fracture non-unions. The study cohort comprised 40 patients with femoral diaphyseal non-unions treated by exchange nailing. The main outcome measures were union, number of secondary fixation procedures required to achieve union and time to union. Univariate analysis and multiple regression were used to identify risk factors for failure to achieve union. The mean age of the patients at exchange nail surgery was 37 years. The median time to exchange nailing from primary fixation was 8.4 months. Multiple causes for non-union were found in 14 (35.0%) cases, with infection present in 12 (30.0%) patients. Further exchange procedures were required in nine (22.5%) cases, one patient (2.5%) required the use of another fixation modality, to achieve union. Union was ultimately achieved in 35 (94.5%) patients. The median time to union was 9.4 months after the exchange nail procedure. Univariate analysis confirmed that cigarette smoking and infection were predictive of failure (p<0.05). Multi-regression analysis found that Gustilo-Anderson grade, presence of dead bone or a gap and infection were predictive of exchange nail failure (p <0.05). Exchange nailing is an effective treatment for aseptic femoral diaphyseal fracture non-union. Patients with infection required more than one procedure. Smoking, infection and the presence of dead-bone or a gap at the fracture site were associated with an increased risk of further fixation surgery

Regulations and in force laws impose to obtain an informed consent prior to any care, especially in surgical setting. Such consent must be informed, explicit, personal, specific and aware. Aim of the present study was the drawing of an informed consent form to be used in external fixation. The possible drawbacks of using external fixation have been divided in three main groups: general biological, local biological and external fixation related. Moreover, within this consent, a detailed patient compliance section has been included because of this particular fixation system, with regard on nursing, medications and treatment time. As for the specificity of indications in trauma, the pre-existing of risk factors as cigarette smoking or open fracture has been clearly stressed. Finally, the consent for hardware removal has been predisposed, too

Cigarette smoking prior to and following foot surgery is well recognised as resulting in a higher complication rate. The purpose of this study was to determine the effectiveness of pre-operative counselling prior to elective hallux valgus surgery. A prospective record of smoking histories was taken in all patients prior to surgery. They were counselled as to the increased complication rate and advised to stop prior to surgery and in the immediate peri-operative period. The mechanism of the increased complication rate was explained to improve their understanding to stop smoking. They were advised to see their GP for specific strategies and medications. Further smoking history was taken on admission and in review clinics. A telephone survey was then conducted to ascertain their smoking pattern following discharge from follow-up. Forty-two patients underwent hallux valgus surgery over a 12 month operating period. Ten (23%) were recorded as smokers at the time of initial consultation. Most patients (80%) were unaware of the detrimental effects of smoking following foot surgery. Patient education was effective in providing an impetus to stop or reduce smoking in 6 (60%) patients pre-operatively. One further patient subsequently desisted from smoking following surgery. Only two patients had re-commenced smoking following surgery implying a long term change of behavior. Only one complication of a DVT occurred in a patient who continued to smoke. This small study has shown the effectiveness of educating our patients in the importance of giving up smoking prior to elective foot surgery

We investigated the association of Dupuytren’s contracture with smoking and with alcohol by a case-control study in which 222 patients having an operation for this condition were matched for age, operation date and gender with control patients having other orthopaedic operations. Fifty of the cases were also each matched with four community controls. Data were collected by postal questionnaire. Dupuytren’s contracture needing operation was strongly associated with current cigarette smoking (adjusted odds ratio 2.8 (95% confidence interval (CI) 1.5 to 5.2)). The mean lifetime cigarette consumption was 16.7 pack-years for the cases compared with 12.0 pack-years for the controls (p = 0.016). Dupuytren’s contracture was also associated with an Alcohol Use Disorders Test score greater than 7 (adjusted odds ratio 1.9 (95% CI 1.02 to 3.57)). Mean weekly alcohol consumption was 7.3 units for cases and 5.4 units for controls (p = 0.016). The excess risk associated with alcohol did not appear to be due to a confounding effect of smoking, or vice versa. Smoking increases the risk of developing Dupuytren’s contracture and may contribute to its prevalence in alcoholics, who tend to smoke heavily

Introduction: Every ten seconds, somewhere in the world, someone dies of tobacco-related causes. The adverse effects of smoking on the cardiovascular, respiratory, and immune systems have been well documented. Results of foot surgery are also gravely affected by cigarette smoking, with poorer clinical outcomes, lower rates of osteotomy union, bony fusion and higher rates of postoperative infection. However, data on surgeon’s awareness and their practices to overcome the adverse effects of smoking in elective foot surgery is limited. Aim: The purpose of this study was to report the results of a survey of experienced foot and ankle surgeons regarding their awareness about detrimental effects of smoking and the measures they take in their practice to prevent them. Methods: A survey of members of British Foot and Ankle Society was done to document surgeon’s awareness and attitudes towards detrimental effects of smoking in patients undergoing elective foot surgery and the measures they take to prevent these problems. Survey was returned by 104 of the 225 surgeons (47%). Results: One hundred and two (99%) of the surgeons were aware of the damaging effects of smoking in foot and ankle surgery. Eightynine (84%) of these recorded the smoking habits of their patients in their dictated notes. However, only 9% respondent admitted recording the smoking habits of their patients in consent form and warn them about forthcoming risk of complications at the time of consenting. Only twentyfour (23%) had varying protocol’s to prevent smoking related operative complications. Conclusions: Most of the surgeons appreciate the harmful effects of smoking. However they are unaware of the extent to which it causes problems. Majority of the members would like the society to propose a unified policy or evidence based guidelines to deal with smoking related problems in foot surgery

Avascular necrosis (AVN) of the immature femoral head is the final common pathway of the Legg-Calve-Perthes (LCP) disease. Since cigarette smoking has been linked to the development of vascular disease, a study was performed to see if there was any association between parental smoking and LCP disease. The biological parents of 97 children with LCP disease were questioned on their smoking habits, which were compared to a control group of parents with unaffected children. Further comparison was made with respondents from the Perthes’ Association website who completed an on-line questionnaire. Parents were classified as being smokers or non-smokers on the basis of their smoking habit pre-pregnancy, during pregnancy and at the time of diagnosis of LCP being made. There was a higher proportion of children in the LCP group who had parents who smoke (N=67/97, 69%) compared to the control group (N=14/87, 16%). Further analysis showed that the highest rate occurred when both parents smoke before pregnancy (N=37/97, 38%) followed by when only the father smoked (N=23/97, 24 %). Maternal smoking alone appeared to have the least association (N=7/97, 7 %). In the control group the non-smoking rate was 58/87 [67%]. The changes in smoking patterns with respect to the pregnancy concerned were also noted. Fisher’s Exact test was used to determine any difference between the study group and the control group. There was a significant difference between the Perthes’ SE group concerned to the controls in all respects except maternal smoking. Comparison made with data obtained from the Perthes’ association website showed no difference between the two Perthes’ groups. Conclusion: These results support an association between parental smoking and the development of disease LCP disease

Cigarette smoking is well recognised as contributing to a higher complication rate following foot surgery. The efficacy of pre-operative counselling to stop smoking has not been evaluated following foot surgery. The purpose of this study was to determine the effectiveness of pre-operative counselling prior to elective forefoot surgery. A record of smoking status was taken in all patients prior to surgery. Counselling as to the increased complication rate was undertaken by the lead surgeon at the initial outpatient visit and repeated at pre-operative assessment, with patients advised to see their GP for specific strategies and medications. Further smoking history was taken on admission and in review clinics. A telephone survey was then conducted to ascertain smoking patterns following surgery. Ninety-eight patients underwent forefoot osteotomy or fusion surgery, over an eighteen-month period, by a single surgeon. Of these, twenty-four were recorded as smokers, with follow-up, at a mean interval of twelve months, achieved in twenty-two. Sixteen stopped smoking pre-operatively, with a further four reducing their daily intake as a direct consequence of the counselling. The majority of patients were unaware of the detrimental effects of smoking following foot surgery. Only four patients re-commenced pre-operative smoking patterns following surgery implying long-term behaviour change in the remainder. One complication of a DVT was recorded in a persistent smoker. This small study has illustrated the benefit of utilizing the pre-operative clinic consultation to educate our patients of the importance of giving up smoking prior to elective surgery. Counselling has been shown to provide an incentive for smoking cessation, which has been maintained after the peri-operative period. Although forefoot fusions and arthrodeses were used to provide the figures in our study, the results are transferable to other branches of foot and ankle surgery. Correspondence should be addressed to Major M Butler RAMC, Princess Elizabeth Orthopaedic Centre, Royal Devon and Exeter Hospital, Exeter, Devon

We present in this work our experience with the sural fasciocutaneous flap to treat coverage defects following a lower limb posttraumatic lesion. This work is a review of the fasciocutaneous sural flaps carried out in different centres between 2000 and 2005. The series consist of 14 patients, 12 men and 2 women with an average age of 38 years (23–54) and with a medium follow-up time of 2 years (12–48 months). In all of the cases, aetiology was a lower limb injury being the most frequent the distal tibial fracture (eight patients), followed by sequelae from Achilles tendon reconstruction (two patients), fracture of the calcaneus (two patients) and osteomyelitis of the distal tibia (two patients) secondary to an open fracture. Associated risk factors in the patients for performing a fasciocutaneous flap were diabetes (1 case) and cigarette smoking (4 cases). The technique is based on the use of a reverse-flow island sural flap with the superficial sural artery dependent on perforators of the peroneal arterial system. The anatomical structures which constitute the pedicle are the superficial and deep fascia, the sural nerve, external saphenous vein, superficial sural artery together with an islet of subcutaneous cellular tissue and skin. The flap was viable in 13 of 14 patients. Only in one case, a diabetic patient, the graft failed. No patient showed signs of infection. Slight venous congestion of the flap occurred in two cases. No further surgical intervention of the donor site was required because of morbidity. In two cases partial necrosis of the skin edges occurred which resolved satisfactorily with conservative treatment. The sural fasciocutaneous flap is useful for the treatment of complex injuries of the lower limbs. Its technical advantages are: easy dissection with preservation of more important vascular structures in the limb, complete coverage of the soft tissue defect in just one operation without the need of microsurgical anastomosis. All of that results in a well vascularised cutaneous islet and thus a reliable flap

Introduction: The purpose of this study was 1) to evaluate the relationship between osteonecrosis of the femoral head (ONFH) and alcohol abuse, 2) to define the patterns of the alcohol intake in the development of ONFH, and 3) to define the risk factors in alcohol induced ONFH. Materials and Methods: Two hundred and fifty patients (333 hips) with ONFH diagnosed on the basis of histopathologic findings after total hip arthroplasty were analyzed. Among these patients, 169 patients who had a history of alcohol and idiopathic ONFH were selected as the case group. Two controls selected by a review of the orthopedic patient records were matched to each case (338 controls). From each patient and control, a detailed history of alcohol drinking, cigarette smoking, and herb medicine, weight, height, sGOT, sGPT and total cholesterol levels were obtained and analyzed. Statistical analysis was performed using the Generalized Linear Model including Chi-Square test, Fisher’s exact test, ANOVA, and T-test. The adjusted relative odds ratio and 95 percent confidence interval (CI) were obtained using a conditional logistic regression model. Results and Discussion: The authors could confirm a direct relationship between alcohol abuse and ONFH. The amount of alcohol intake was more significant than the duration of alcohol intake for the risk of the development of ONFH. The risk factors related with the patterns of alcohol consumption in the development of alcohol induced ONFH are as follows: 1) more than 4 times per week of alcohol intake, 2) more than 90 g of alcohol intake at one time, 3) more than 300 g of weekly alcohol intake, 4) more than 6000 drink-years, 5) no side dishes. The other risk factors are smoking, low body mass index, and abnormal liver function tests