Our community-based study of 466 patients with newly diagnosed alcoholic cirrhosis supported our hypothesis that patho-etiological factors are causally involved in the development of specific complications. In particular, reduced hepatic metabolic capacity was specifically associated with the risk of developing first-time hepatic encephalopathy. Alcohol consumption increased the risk of all adverse events except the development of first-time hepatic encephalopathy. Hyponatremia, by increasing the risk of all complications as well as mortality, was a non-specific marker of a poor prognosis.
The major strength of our study is that it was designed to evaluate hypotheses about the causal
effects of reduced hepatic metabolic capacity, continued alcohol consumption, and hyponatremia on the development of complications—not merely to examine whether they predict
their development. A clear distinction between causes and predictors is necessary in order to advance our understanding of cirrhosis pathophysiology: A cause is always a predictor, but a predictor can be either a cause or a correlate of a cause, an ‘innocent bystander’
]. A composite score such as the MELD (Model for Endstage Liver Disease) score is a likely predictor of cirrhosis progression, but the causal effect(s) of a high MELD score are unclear because it may represent a loss of kidney function (high creatinine), a loss of hepatic synthetic capacity (high INR), and/or a loss of hepatic conjugative capacity (high bilirubin). Therefore we did not include the MELD score in our analyses. Nor did we include its components or other standard liver biochemistry tests because they correlate with the GEC but are not truly tests of hepatic metabolic capacity
Given this background, our findings are consistent with the definition that loss of hepatic metabolic capacity is a prerequisite for developing hepatic encephalopathy
], but we add that loss of hepatic metabolic capacity does not cause death without hepatic encephalopathy. This novel finding expands upon our previous finding that the GEC is a predictor of the mortality of cirrhosis patients
]: It is now clear that loss of hepatic metabolic capacity causes hepatic encephalopathy and then death
]. Our previous study suggested that a GEC above 1.75 mmol/min was associated with a relatively favorable prognosis, whereas mortality increased linearly with GEC when GEC fell below this limit
]. We speculate that the same limit applies to the risk of hepatic encephalopathy, but our current study did not have sufficient statistical power to clarify this.
Alcohol consumption can cause ascites formation and variceal bleeding, according to our findings. The likely explanation is that alcohol intake induces a prompt increase in portal pressure
]. However, the association might also be partly due to alcohol consumers’ noncompliance with diuretics and beta-blocker treatments, i.e. non-causal. The association between alcohol consumption and mortality was expected because alcoholism is a risk factor for death among infected cirrhosis patients and for several cancers
]. It is even possible that we underestimated the adverse effects of alcohol because we may have missed alcohol relapse in some patients who died at home. The lack of an association between alcohol consumption and hepatic encephalopathy is consistent with findings from a randomized clinical trial comparing porto-systemic shunt placements. In that study, drinking spells during follow-up were more strongly associated with variceal bleeding and mortality than with hepatic encephalopathy
The cirrhosis patients with hyponatremia had higher risk of all
adverse events, so these patients’ clinical course remained as unpredictable as that of patients without hyponatremia. Our findings are consistent with observations that hyponatremia causes hepatic encephalopathy
], but we might have learned more if we had measured urinary sodium excretion which decreases before dilutional hyponatremia develops
]. Unfortunately, it was not measured in a meaningful proportion of our patients, and it remains possible that hyponatremia is an innocent bystander rather than an agent in the causal pathways to the development of cirrhosis complications.
Our data had high validity. We believe that the medical charts from one of Denmark’s two specialized departments of hepatology gave reliable records of all first-time episodes of major cirrhosis complications. The chart data were extracted previously for a different research purpose
], so there was no bias from a conscious or unconscious wish to find certain associations in the data. The absence of data on portal pressure and medication use is a limitation of the study because both factors modify the risk of complications and represent distinct pathophysiological mechanisms.