In this large cohort study, we found that patients diagnosed with alcohol induced fatty liver disease had a high risk of developing cirrhosis and premature death, for both men and women. In contrast, patients with type 1 NAFLD9
seemed to have the same life expectancy as the average normal population and the risk of progressing to end stage liver disease was small.
The study was based on register, clinical, and histological data. The LPR is a unique source of data for monitoring long term outcome, as in this cohort of patients, and record linkage using the unique personal identification number ensures complete follow up.
The discharge diagnosis in the LPR may vary in validity but is generally high.20–22
We minimised this problem further by a thorough examination of the medical records and a search in the pathology register supplementing the diagnostic information available in the LPR. The index diagnosis, alcoholic versus non-alcoholic, was made from the information on alcohol intake in the medical record at the time of the index biopsy and before we requested data from the LPR and Registry of Causes of Death. However, if the patient had an alcohol related diagnosis at any time during the follow up period, they were characterised as having alcoholic steatosis, regardless of alcohol intake. The ICD diagnoses from the registries were not altered or interpreted.
The majority of patients had not moved from the uptake area of Hvidovre Hospital and medical records from the follow up period were available. It cannot be excluded that some patients with clinical cirrhosis were treated by their general practitioner and thereby not registered in the LPR. However, the structure of the Danish health service makes it likely that patients with clinically significant liver disease are admitted to hospital and the long follow up period makes this even more likely.
Death is recorded without errors in the Registry of Causes of Death while the cause of death may be misclassified. Misclassifications in the death certificates may over or underestimate the risk of death from liver cirrhosis. In the group of patients with known excessive alcohol intake, a tendency towards overestimation of cirrhosis as the cause of death might be expected while patients with non-alcoholic fatty liver are less likely to be suspected of chronic liver diseases. This would underestimate the prevalence of the cirrhosis diagnosis for this group of patients both in the LPR and Registry of Causes of Death. In the four patients who did not die in hospital, it is likely that a general practitioner completed the death certificate. In Denmark, it is the patient’s local general practitioner who writes the death certificate in cases of death outside hospital. This makes the certificate more valid because of their knowledge of the patient. In the inclusion period, a high percentage of patients, who died during hospitalisation, had an autopsy performed. We believe that data on liver disease end points in this study are sufficiently valid even though histological verification could not be obtained in all cases.
Patients were classified as having non-alcoholic or alcoholic fatty liver on the information given to the physician on alcohol intake at the time of the index liver biopsy. As this was not a prospective study, the validity of self reported alcohol intake can be questioned and was most likely underreported; potentially patients with high alcohol consumption may be misclassified as belonging to the non-alcoholic group. Because of the lack of a sensitive and specific marker of alcoholism, it is impossible to prove the non-drinking status of patients with NAFLD. We tried to compensate for this misclassification by examining all discharges registered in the LPR. If the patient was discharged from a hospital during the follow up period with an alcohol related diagnosis, they were classified as having alcoholic fatty liver, regardless of when this hospitalisation took place. Nine patients would have been classified as non-alcoholic, based solely on information on alcohol consumption in the medical report at the time of the index liver biopsy but had an alcohol related diagnosis registered during the follow up period and were subsequently reclassified into the alcoholic group. Two of these developed cirrhosis. Thereby, the prevalence of cirrhosis was lowered in the non-alcoholic group and is likely to have increased the validity of the classification.
Patients may have stopped drinking alcohol after the index liver biopsy and these individuals may not have the same risk of developing chronic liver disease as individuals who continue to drink.14,15
However, the design of the study did not allow us to analyse this aspect further. The same method has been used in other follow up studies7,15
but by using the unique information from the registries, we believe classification into the two groups, non-alcoholic and alcoholic, is even more valid.
Not all patients were examined for hepatitis B, and hepatitis C tests were not available at the time of the index liver biopsy. However, none of these patients had any known risk factors for the development of hepatitis C, and the clinical follow up did not suggest viral hepatitis; furthermore, liver biopsies in all patients were consistent with NAFLD or alcoholic fatty liver and did not show the typical findings of chronic hepatitis C infection.23,24
Also, Denmark is a low prevalence area for infectious hepatitis in the general population (0.08%).25,26
However, we recognise that hepatitis C may be present and that we could not control for this potential confounder in the follow up study.
Bouchier and colleagues27
observed a 75% survival rate after 10 years in patients diagnosed with alcoholic fatty liver. Patients with this histological diagnosis had the best survival rate in the spectrum of alcoholic liver diseases. However, they estimated survival in the various groups of patients from the time of diagnosis, regardless of the age at diagnosis. We performed our statistical analysis with delayed entry, taking into account both the age of the patient and time of entry at diagnosis. Thereby the age distribution was not a bias. We found significantly higher mortality in patients with alcoholic fatty liver in comparison with both type 1 NAFLD patients and the general population, as previous observed by Orholm and colleagues28
in patients with alcohol related liver diseases. Patients in our cohort with NAFLD had a benign course as only one of 109 patients developed cirrhosis after the 16.7 year follow up and the survival rate did not appear to differ from that of the general population when survival curves were compared. We did not compare the survival estimate statistically with the general population but the survival curve of the general population was within the confidence interval of the non-alcoholic fatty liver group for both men and women (fig 2).
Our findings are in contrast with previous reports on the prognosis for NAFLD1,6,9,11,29–33
and the risk of developing chronic liver diseases. This discrepancy may have several explanations. Other studies mainly comprised selected patients with NASH, which accounts for the higher incidence of chronic liver diseases. However, the patient cohort in our study was the same as in other studies, mainly obese women, and we would have expected that the natural history was the same, with development of NASH and a high prevalence of cirrhosis. It seems that factors other than obesity contribute to the development of chronic liver disease in patients with type 1 NAFLD. It may be speculated whether pure non-alcoholic fatty liver predisposes to NASH and the development of chronic liver disease or if NASH develops primarily without the presence of fatty liver, which could explain the apparent different prevalence rates of cirrhosis in the study. Teli and colleagues7
also found a good prognosis for patients with pure non-alcoholic fatty liver. Insulin resistance and hyperlipidaemia are other well known factors that predispose to fatty liver but we have no data to substantiate this hypothesis. The natural history may also be influenced by hitherto unknown genetic or nutritional differences, which could explain the different findings in studies from the USA in particular.
It has previously been shown that obesity in both alcoholic34
and non-alcoholic patients predisposes to the development of fatty liver and chronic liver disease.35,36
Obesity could be a contributing factor in patients in our cohort with alcoholic fatty liver, even though the observed number of cirrhosis among the 106 patients was comparable and not higher than in other reports on non-obese patients with alcoholic fatty liver.15
Non-alcoholic patients in our cohort had an extremely high median BMI of 42 kg/m2
. This makes our population a selected group, but was also a unique opportunity to study the natural history of NAFLD in a large cohort with a long term follow up. Even though they were very obese, only one developed cirrhosis in the 16.7 years of follow up.
In conclusion, in this long term follow up study, we demonstrated a high prevalence of cirrhosis in patients with alcoholic fatty liver, in contrast with a benign clinical course in patients with type 1 NAFLD with no excess mortality. It is important for clinicians to realise that fatty liver is one of the most common causes of liver dysfunction, but few non-alcoholic individuals seem to develop chronic liver disease. However, more information on the natural history of NAFLD in large prospective follow up studies is needed to guide future decisions about diagnostic strategy and identification of subgroups with a risk of developing chronic liver disease and the potential need for future specific treatments.