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Severe Hypertriglyceridemia Influenced by Alcohol (SHIBA)

Kirsten Bessembinders, Jos Wielders, Albert van de Wiel
DOI: http://dx.doi.org/10.1093/alcalc/agq088 113-116 First published online: 18 January 2011

Abstract

Aims: This study was conducted to examine the relationship between triglyceride (TG) levels and a history of excessive drinking in patients with severe hypertriglyceridemia (HT). Methods: Alcohol intake as well as other risk factors associated with HT were searched for in case records of 300 patients known to the laboratory to have had a TG level over 11.3 mmol/l. Results: The majority of severe HT could be attributed to obesity, diabetes mellitus, excessive alcohol consumption or combinations of these. Excessive alcohol intake (over 210 g/week for males; over 140 g/week for females) was recorded for 24% of the total, and for 43% in the highest TG quartile. TG levels were significantly higher in the excessive drinkers (P < 0.001) and in patients with acute pancreatitis (P = 0.001). The incidence of pancreatitis in this cohort was 4% and limited to very high TG levels. Conclusion: Excessive alcohol consumption was recorded in a quarter of patients with severe HT. Patients with the combination of obesity, diabetes and alcohol excess are prone to develop extremely high TG values.

INTRODUCTION

Hypertriglyceridemia (HT) is a metabolic disorder due to an elevated synthesis of triglyceride (TG)- rich lipoproteins (chylomicrons, very low-density lipoproteins (VLDL)), a reduced catabolism of these particles or a combination of both mechanisms. Normally, values of TG are below 2.2 mmol/l (200 mg/dl) and in most cases of HT, levels do not rise above 11.3 mmol/l (1000 mg/dl; Ferns et al., 2008). Sometimes, however, HT exceeds this level in which case the presence of chylomicrons may be responsible for the milky creamy aspect of the serum's supernatant. Causes of HT are usually divided into primary (genetic) and secondary causes including excessive alcohol use (Brunzell, 2007; Yuan et al., 2007). Although HT is often asymptomatic, it is almost certainly a risk factor for cardiovascular disease (Yuan et al., 2007), and patients with severe HT are generally considered to be at increased risk for acute pancreatitis (Ewald et al., 2009). Acute pancreatitis, which may also result from a direct toxic effect of alcohol, is a serious condition associated with severe morbidity and high mortality rates.

Ingestion of alcohol causes an increase in the synthesis of (TGs) and TG-rich lipoproteins in the liver (Hannuksela et al., 2003). Furthermore, alcohol stimulates lipolysis in fatty tissue, which results in a larger supply of fatty acids to the liver (Baraona and Lieber, 1979). The role of alcohol in the catabolism of TG-rich particles is less clear. Although alcohol may thus induce HT, little is known about the prevalence of excessive alcohol intake in patients with severe HT and the associated risk of pancreatitis.

The aim of this study was to analyze a large cohort of patients with severe HT (>1000 mg/dl) for secondary causes including excessive alcohol intake and the presence of pancreatitis.

MATERIAL AND METHODS

Study subjects

We searched the laboratory database of the Meander Medical Center (Amersfoort, The Netherlands) for cases of severe HT during a 10-year period from 1999 to 2009. Three hundred patients with TG values ≥ 11.3 mmol/l (1000 mg/dl) were included. In case, more than one laboratory result in time was available for a certain patient, the patient was only included once using the patient's highest TG level. Both ambulatory and admitted patients were included. We searched all patients’ medical records for risk factors of HT, including excessive alcohol use, obesity, diabetes, medication use, hypothyroidism, pregnancy and renal failure (nephrotic syndrome included). We also registered cardiovascular disorders in a patient, a positive family history of cardiovascular diseases, acute pancreatitis or a medical history of pancreatitis. In case of pancreatitis, the presence of gallstones was assessed. Excessive alcohol intake was defined as >21 units per week for men and >14 units per week for women. One unit stands for a glass containing 10 g of alcohol. Overweight was defined as having a body mass index of >25 kg/m2; we also considered the patient to be overweight if obesity was diagnosed by a specialist. Drugs with a potential effect on lipid metabolism were registered and included beta blockers, loop diuretics, thiazide diuretics, estrogens or selective estrogen receptor modulators, glucocorticoids, immunosuppressants, cytostatic drugs, antipsychotics, bile acid sequestrants and anti-retroviral therapy.

Statistical analysis

Statistical analysis was carried out using SPPS Statistics for Windows (SPPS 17.0). Comparisons were performed using the independent samples t-test, and in the case of sample sizes <30, we used the nonparametric Mann–Whitney test. P-values were adjusted for sex and age, using the univariate analysis of variance. Statistical significance was judged at P < 0.05.

RESULTS

The study included 300 patients with TG levels ≥ 11.3 mmol/l (1000 mg/dl), 220 men and 80 women (Table 1). The mean age was 51 years (18–84 years; SD 12.3) and the mean TG level was 24.3 mmol/l (11.3–138.0 mmol/l; SD 20.1) (2162 mg/dl; 1000–12.282 mg/dl). The mean maximal TG level proved to be somewhat higher in younger patients, while no differences were found between men and women and patients with or without cardiovascular disease and with or without a family history of cardiovascular disease. Patients with acute pancreatitis or a history of pancreatitis had significantly higher TG levels than patients without pancreatitis. Tables 1 and 2 show that almost all cases of HT are the result of one of three metabolic disorders: obesity, diabetes mellitus or excessive alcohol intake. In Table 2, all 300 patients were divided in quartiles according to the TG level. In the highest quartile, 96% of cases could be classified by one of the three diagnoses. In 41.3% of the patients in that quartile excessive alcohol use could be noted. Only 20 out of 300 patients did not have any of these three risk factors. One patient with the highest TG level of 138.0 mmol/l was receiving a cytostatic drug, probably responsible for this extreme response. As can be seen in Table 1, mean maximal TG levels do not differ significantly in the presence or absence of diabetes or obesity unless excessive alcohol is also present. The number of patients excessively consuming alcohol and the number of patients suffering from pancreatitis increased as the TG values increased (Figs 1 and 2). Dividing the group of excessive drinkers into quartiles according to TG levels, >40% of them were found in the highest quartile of TG values (Fig. 1). After excluding all pancreatitis patients from the analysis, excessive alcohol intake was still more prevalent in the top quartile of TG values. Overweight patients suffering from diabetes who also excessively consumed alcohol had the highest values of TGs (Table 1, mean maximal TG level 38.1 mmol/l). These are the patients in whom three environmental risk factors of HT were present. Fig. 3 shows the number of risk factors (diabetes, excessive alcohol use, overweight or none of these) and the mean maximal TG level. The number of risk factors does not seem to be of particular importance, although the highest values of TGs were found in the overweight diabetic patients excessively consuming alcohol.

View this table:
Table 1.

Characteristics of patients with hypertriglyceridemia

VariableMean TGP-valueAdjusted P-valuea
Age
 ≤50 years (n = 151)28.2 (22.1)P = 0.001P < 0.001
 >50 years (n = 149)20.4 (17.0)
Sex
 Men (n = 220)25.4 (21.2)P = NSP = NS
 Women (n = 80)21.4 (16.5)
Cardiovascular disease (n = 81)21.6 (16.0)P = NSP = NS
No cardiovascular disease (n = 218)25.3 (21.4)
Familial cardiovascular diseases (n = 111)24.0 (19.8)P = NSP = NS
No familial cardiovascular diseases (n = 111)26.4 (23.8)
Pancreatitis (n = 12)57.8 (37.2)P < 0.001P < 0.001
No pancreatitis (n = 287)22.9 (17.9)
Pancreatitis and/or a medical history of pancreatitis (n = 23)44.8 (31.4)P < 0.001P < 0.001
No–No pancreatitis and/or a medical history of pancreatitis (n = 276)22.6 (17.9)
Hypothyroidism (n = 15)20.0 (14.1)P = NSP = NS
No hypothyroidism (n = 253)24.2 (19.9)
Renal failure (n = 32)18.1 (12.6)P = 0.009P = NS
No renal failure (n = 266)25.1 (20.7)
Medication use
 Beta blockade (n = 76)20.5 (15.2)P = NSP = NS
 Thiazide diuretics (n = 44)20.3 (15.9)P = NSP = NS
 Loop diuretics (n = 18)23.1 (17.1)P = NSP = NS
Excessive alcohol use (n = 72)32.8 (24.8)P = 0.001P < 0.001
No excessive alcohol use (n = 189)21.8 (18.2)
Diabetes (n = 146)25.4 (20.8)P = NSP = NS
No diabetes (n = 152)23.1 (19.4)
Overweight (n = 221)23.9 (19.1)P = NSP = NS
No overweight (n = 55)25.8 (24.1)
  • TG, triglyceride.

  • aAdjusted for age and sex.

View this table:
Table 2.

Prevalence of diabetes, overweight, excessive alcohol use and pancreatitis and severity of hypertriglyceridemia (quartiles)

Triglyceride level
VariableTG < 13.0 (n = 74) (%)13.0 ≤ TG ≤ 15.9 (n = 77) (%)15.9 < TG ≤ 26.8 (n = 74) (%)TG > 26.8 (n = 75) (%)
Diabetes (n = 146)32 (21.9)36 (24.7)40 (27.4)38 (26.0)
Overweight (n = 221)56 (25.3)57 (25.8)54 (24.4)54 (24.4)
Excessive alcohol use (n = 72)10 (13.9)13 (18.1)18 (25.0)31 (43.1)
Pancreatitis
 Present (n = 12)01 (8.3)3 (25.0)8 (66.7)
 Present and/or medical history (n = 23)1 (4.3)2 (8.7)6 (26.1)14 (60.9)
  • TG, triglyceride.

Fig. 1.

Amount of excessive alcohol use in relation to severity of hypertriglyceridemia. TG, triglyceride.

Fig. 2.

Patients suffering from pancreatitis in relation to severity of hypertriglyceridemia.

Fig. 3.

Number of risk factors (no risk factor, one of the risk factors ‘excessive alcohol use’, ‘DM’ or ‘overweight’ and two risk factors or all three risk factors) in relation to severity of hypertriglyceridemia. TG, triglyceride; Alc, excessive alcohol use; DM, diabetes mellitus.

Of all patients with recorded pancreatitis either acute or in the past, the majority had TG levels in the two highest quartiles (Fig. 2). In one patient, acute pancreatitis was probably due to gallstones, but all other acute pancreatitis events were attributed to HT and/or excessive alcohol use.

DISCUSSION

The present study demonstrates a strong association between severe HT and excessive alcohol intake. In fact, the likelihood that alcohol is involved increases with the increase in the serum TG level. The highest TG levels are found in patients with a combination of the metabolic syndrome (obesity and diabetes mellitus) and excessive alcohol use.

Most cases of pancreatitis were found in the highest quartiles of TG levels (>15.9 mmol/l (1415 mg/dl)), suggesting that values up to 15.9 mmol/l in the absence of alcohol abuse are not a major risk factor for the development of pancreatitis.

The prevalence of severe HT in the general population is not well known (Capell and Eckel, 2005; Valdivielso et al., 2009). The ICARIA study, a large study regarding prevalence and risk factors of HT in an active Spanish working population, reports a prevalence of 1 in 3000 for severe HT (TG > 11.28 mmol/l; Valdivielso et al., 2009). However, this number is probably an underestimation since the risk factors of diabetes and obesity were less prevalent in the ICARIA study population than in the general Spanish population. Nevertheless, the study shows that diabetes was ten and five times more frequent in severe and moderate grades of HT than in nonhypertriglyceridemic subjects.

Apart from alcohol, obesity and diabetes mellitus were the other major risk factors associated with severe HT. But in contrast to alcohol, there was no relationship between the severity of HT (level of TGs) and the presence of obesity and/or diabetes mellitus. Only when excessive alcohol intake is also present, levels of TG rise dramatically with the highest values in the combination of obesity, diabetes mellitus and alcohol. Alcohol seems to be the most prominent factor in the occurrence of severe HT, since patients with only diabetes and overweight generally had a lower mean maximal TG level (24.5 mmol/l) in comparison with patients who excessively consumed alcohol (32.8 mmol/l). Even in the absence of obesity or diabetes mellitus, excessive alcohol intake may cause severe HT, although obese patients are more at risk of hyperlipidemia using alcohol (Baraona and Lieber, 1979). This suggests that alcohol may induce severe HT either in combination with the metabolic syndrome or another defect, such as a genetic disturbance in lipid metabolism. Because not all patients with the metabolic syndrome, who consume too much alcohol, develop severe HT, such an underlying genetic defect may well be a prerequisite in this group as well. Such a defect becomes more likely in the patient in whom serum lipids do not normalize after cessation of alcohol. According to our experience (Van den Broek et al., 2009) and that of others (Baraona and Lieber, 1998), TG levels drop usually dramatically when alcohol consumption stops. If alcohol consumption continues, the response to lipid-lowering regimens is poor.

The effects of alcohol on lipid metabolism are diverse and not totally understood. Alcohol induces both the synthesis of TGs and the formation of VLDL in the liver (Brunzell, 2007; Erkelens and Brunzell, 1980; Hannuksela et al., 2003). Since acute ingestion of alcohol may stimulate catecholamines, which have a lipolytic effect in adipose tissue, there will be an increase in the supply of free fatty acids to the liver (Baraona and Lieber, 1979). In the clearance of TG-rich particles such as VLDL and chylomicrons, the enzyme lipoprotein lipase plays a pivotal role. Alcohol is known to inhibit this enzyme in acute situations, but the effects of chronic use of alcohol on this enzyme are less clear (Schneider et al., 1985). Many of these alcohol-induced changes in lipid metabolism mimic those in insulin resistance (DeFronzo, 2010), explaining the synergistic effect in case of the combination of alcohol abuse and the metabolic syndrome.

Our study showed that 24% of the subjects with severe HT excessively consumed alcohol. This percentage is most likely an underestimation, since it is based on the patient's self-reported estimate of alcoholic intake as recorded in the case notes. Most excessive alcohol users were to be found in the subject group with the highest values of TG. The ICARIA study also found that alcohol consumption was higher among the subjects showing higher TG levels; 10.48% of the subjects in the severe HT group drank more than two alcoholic drinks daily, compared with 8.77 and 2.75% in moderate and nonHT subject groups, respectively (Valdivielso et al., 2009).

Our study showed that pancreatitis occurred in 4% of the patients with HT and mainly in those with very high levels of TGs. This is in accordance with a study by Fortson et al. (1995) who described HT as an etiological factor of pancreatitis in 1.3–3.5% of the cases. The most common presentation of hyperlipidemia in their study was the poorly controlled obese diabetic patient followed by the patient with alcohol abuse. In a study by Lloret Linares et al. (2008), the incidence of pancreatitis in a cohort of 129 patients with severe HT was 20.2%. In this study, however, HT was the primary reason for referral, whereas in our study all patients with severe HT were included regardless of their primary diagnosis. In accordance with our study patients with pancreatitis showed significantly higher TG levels than those without pancreatitis with values far exceeding the arbitrary level of 11.3 mmol/l (1000 mg/dl). The pathogenetic mechanism of pancreatitis induced by HT is not fully elaborated yet. It is suggested that free fatty acids, products of the hydrolysis of TGs by pancreatic lipase, reach toxic concentrations initiating injury followed by an acute inflammatory response (Lloret Linares et al., 2008; Whitcomb, 2010). In daily practice, it is not always easy to differentiate between alcoholic pancreatitis and pancreatitis caused by HT, since alcohol may not only induce HT but is also an independent risk factor for pancreatitis. On the other hand, HT may well be the result of pancreatitis even in cases without excessive alcohol intake (Ewald et al., 2009; Fortson et al., 1995).

Our study has certain limitations. We did not assess data concerning dietary factors, physical activity and smoking habits because this information was rarely reported in the patient's medical record. Furthermore, our study has some amount of missing data because the information was retrospectively attained. Also, some variables are subject to the information provided by the patient: for example, not all patients knew exactly what medication they used and alcohol intake was possibly trivialized.

Nevertheless, we can conclude that a diagnosis of excessive alcohol consumption can be made in many patients with severe HT and that this diagnosis is more likely in the case of very high TG levels. Especially, patients with the metabolic syndrome seem prone to react to alcohol with extremely high serum TG levels, which we propose to call the SHIBA (Severe Hypertriglyceridemia Induced by Alcohol) effect. The risk of developing acute pancreatitis is not very high and mostly limited to the high range of over 15.9 mmol/l.

REFERENCES

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