Simple fatty liver and non-alcoholic steatohepatitis (Part one)
Non-alcoholic steatohepatitis or non-alcoholic (which will be described below as NASH) is a disease not fully known in Europe, but often encountered in outpatient healthcare settings. Patients, although denying it, are accused of excessive alcohol consumption. On the other hand, simple fatty liver is often ignored by doctors as a “cosmetic defect”, which is not entirely accurate.
Based on the latest findings regarding non-alcoholic fatty liver diseases (NAFLD), fatty liver (FL) and non-alcoholic steatohepatitis (NASH), diagnoses, clinics, prognosis, and therapeutic options in non-alcoholic Steatohepatitis will be presented below. We must not forget that non-alcoholic Steatohepatitis (NASH) is a serious disease entity, that has nothing to do with alcohol, but that can lead to liver cirrhosis.
Recent practices differentiate the fatty degenerative changes in alcoholic and non-alcoholic liver. The group of non-alcoholic entities includes simple liver fattiness which in some cases can progress to steatohepatitis and non-alcoholic steatohepatitis (NASH) which end up in cirrhosis in a significant number of patients. Synonyms include: pseudoalcoholic hepatitis, steatonecrosis, alcohol-like hepatitis, and diabetic hepatitis.
Epidemiology of NASH
Non-alcoholic steatohepatitis is more common than thought. Studies from Japan and Italy show that the prevalence of simple fatty liver in the general population ranges from 3% to 58% (average 23%).
The high variability of these findings is probably related to the socioeconomic differentiation of the population studied. The most significant risk factors for simple fatty liver include obesity, alcohol consumption, and insulin resistance. While the prevalence of fatty liver in control groups is 16-20%, it reaches 46% in alcoholics, 76% in overweight individuals, 95% in obese alcoholics. These findings suggest that fatty liver (FL) is more strongly associated with obesity than with alcohol use.
In the USA, the percentage of overweight individuals in the general population increased by 10-25% from 1961-1991, partly explaining why non-alcoholic fatty liver diseases are the most common liver diseases. Type 2 diabetes mellitus is present in 33% of these obese subjects, worsening the prognosis of simple fatty liver and increasing the risk for developing NASH.
In our country, there are no such studies, but we can say that this disease entity is encountered relatively often in outpatient services. The cases we suspected of NASH were obese individuals, with elevated levels of transaminases and cholesterol in the blood, findings that were incidental. It is worth noting that obese females make up the largest number of patients we follow.
Studies show that the degree of obesity correlates positively with the prevalence of liver fattiness, and thus with the emergence of NASH. What is surprising is the fact that patients did not present complaints, but in most cases, the complaints were related to abdominal discomfort and meteoristic symptoms. The patients cataloged in our service present in the early stages of NASH, and no case in the late stage, that is, in the stage of cirrhosis, is recorded.
Non-alcoholic steatohepatitis develops from fatty liver (FL). NASH has been diagnosed in 11% of those patients undergoing liver biopsy to evaluate the increase of transaminases in serum. In obese patients, the prevalence was 19%, but only 2.7% in patients with normal body weight. The comparison between alcoholics is interesting.
Among patients presenting obesity, type 2 diabetes mellitus, or the use of certain drugs, 80% develop fatty liver (FL). Among people who consume alcohol 30-60 gr per day, the corresponding prevalence is only 45%. While alcoholic steatohepatitis (ASH) develops in 85% in the above-mentioned group, NASH appears in the corresponding group (obese, diabetics, medication) only in 20% of patients. (Table 1)
The progression towards liver cirrhosis is seen to be almost the same in both groups: 10% of patients with NASH, (prevalence 0.3%) and 4% of those who consume alcohol (prevalence 0.2-0.3%) develop cirrhosis. Again, these statistics show that, apparently, alcohol leads to liver fattiness less than obesity, diabetes, and some drugs.
Steatohepatitis develops faster in alcoholics. The risk for cirrhosis appears to be the same for both groups: for alcoholic steatohepatitis (ASH) and for non-alcoholic steatohepatitis (NASH) – prevalence 0.3%.
Obese females constitute 75% of patients with NASH. If the diagnosis of NASH is based on strict requirements for fatty degeneration, inflammatory infiltrate, ballooning of hepatocytes, the presence of Mallory bodies, and the development of fibrosis, the larger group of patients consists of lean (not obese) non-diabetic males. It’s worth noting that cirrhosis is almost present in 10-25% of patients with NASH from the time of diagnosis.
If we compare the relative frequency of NASH with that of other liver diseases, we find that it corresponds more with chronic hepatitis B. But if we include in the NASH group some patients with alcoholic steatohepatitis (currently many patients with NASH are mistakenly labeled as alcoholics), those with confirmed NASH as well as a portion of patients with cryptogenic cirrhosis (probably NASH in 70% of cases) then the prevalence of NASH would correspond to that of chronic hepatitis C. (Figure 2)
That NASH, despite its high prevalence, remains generally unknown, is explained by the fact that we normally see what we know. In the case of liver disease, we first think about the toxic effects of alcohol and the destruction they cause in the liver. By doing so, we often fail to see another disease entity, which is thought to be difficult to differentiate from the former, and develops regardless of the effects of alcohol.
This explains why in Germany 50% of cases of liver cirrhosis are attributed to alcohol abuse. Perhaps in reality, the extent of alcohol-related damages is low, while the prevalence of non-alcoholic steatohepatitis is high.
Etiology of non-alcoholic steatohepatitis
For the most part, the etiology of NASH remains unclear but appears to be multifactorial.
- Metabolic states: Risk factors for the development of NASH include obesity, type 2 diabetes mellitus, insulin resistance (hypertension, hyperlipidemia, obesity, type 2 diabetes), rapid weight loss and hypertriglyceridemia. In various studies, 20-80% of patients with NASH with hypertriglyceridemia, also suffer from hypercholesterolemia.
- Surgical procedures such as jejunoileal bypass for massive obesity reduction, leading to liver function disorder in 40% of patients. These procedures correlate positively with NASH and ultimately result in liver failure in 6% of cases. Other procedures associated with NASH include extensive small intestine resection and gastropexy for weight reduction.
- Pharmacological agents: Drugs related to the development of NASH include amiodarone, diltiazem, nifedipine, tamoxifen, estrogens, glucocorticoids. Only antiarrhythmic agents like amiodarone are a significant threat leading to NASH in 25% of patients. Due to the long half-life, serum concentrations of the drug remain high for a relatively long time. Accumulation in the liver favors its damage.
An important aspect is also the distribution and uptake of free fatty acids in the liver. Thus, the degree of obesity correlates positively with the prevalence and severity of liver fattiness, and consequently with the appearance of NASH.
Less common causes include Wilson's disease, abetalipoproteinemia, partial lipodystrophy, and jejunal diverticulosis with bacterial overgrowth.
Pathogenesis of non-alcoholic steatohepatitis
The most widespread and accepted explanation for the pathogenesis of NASH is the "two-hit" hypothesis: The first hit is fatty deposition in hepatocytes, which is a substrate of fatty degeneration of the liver or hepatic steatosis. This fatty degeneration increases the organ's sensitivity to the second hit. Hepatic steatosis remains no more than steatosis until the appearance of the second hit. This (the second hit) could be one of the above-mentioned surgical procedures in the intestine, administration of certain drugs, or the development of type 2 diabetes mellitus. The immediate increase in free fatty acids seems to play a key role in this scenario.
Thus, NASH typically appears in patients suffering from diabetes mellitus, obesity, rapid weight loss, alcohol consumption, and all these allow the mobilization of free fatty acids and their uptake by the liver. In the hepatocyte mitochondria, free fatty acids are either oxidized or used for the synthesis of triglycerides, phospholipids, and cholesterol esters. If the distribution of free fatty acids becomes excessive, there is an accumulation of triglycerides.
The second hit makes the steatotic liver more sensitive to oxidative stress from free radicals, intestinal endotoxins, or ischemia. The liver that has not undergone fatty degeneration reacts indifferently to the second hit. In the steatotic liver, which is more sensitive, the increase in fatty content correlates with an intensification of lipid β-oxidation and a decrease in ATP. There is also a reduction in macrophage function, which aggravates the effects of individual toxins.
Oxidative stress, free radicals
Free radicals are the substrate of oxidative stress. They increase during the activation of fat metabolism and are involved in various reactions. Oxidative stress may in some cases have no consequences, whereas in others, cellular proliferation, apoptosis, or often necrosis may appear. Free radicals attack the cell membrane of lipids and initiate their peroxidation.
They also destroy DNA and important cellular proteins. Free radicals originate in the mitochondria, in the cytoplasm from the action of xanthine and aldehyde oxidases, and in the endoplasmic reticulum from the activation of the enzymes CYP2E1 and CYP4A. Dysregulation of CYP2E1 is associated with alcohol consumption, fasting, diabetes mellitus, central obesity, and insulin resistance. The cytochrome P450 system apparently plays a central role in the development of steatohepatitis.