Fatty Liver (Steatosis Hepatis): Causes

Pathogenesis (development of disease)

Normally, the liver contains less than 5 percent fat. The increased supply of triglycerides (neutral fats) in the serum causes more of them to be stored in the liver (fatty liver disease). If more than half of the hepatocytes (liver cells) contain fat droplets, this is called fatty liver, which leads to mild to moderate hepatomegaly (liver enlargement). A distinction can be made between macrovesicular and microvesicular steatosis. This describes the size of the fat droplets in the hepatocytes. The macrovesicular type of steatosis results from the discrepancy between synthesis and/or transport of lipids from the hepatocytes. The microvesicular type of steatosis is considered a possible precursor of macrovesicular steatosis. It is understood to result from severe hepatocytic damage, as a result of impaired beta-oxidation of fatty acids (oxidative degradation of fatty acids to acetyl-CoA). Furthermore, non-alcoholic fatty liver (NAFL; NAFLE; NAFLD, “nonalcoholic fatty liver disease”) is distinguished from secondary steatosis (see below). Cryptogenic forms of steatosis hepatis have also been described, which cannot be reliably assigned to known causes. An important role in the pathogenesis of fatty liver is played by fat cells, iron, and insulin. Iron may limit the availabilities of the protective hormone ApoE. This hormone plays a role in fat regulation and insulin resistance. Steatosis hepatis may additionally be accompanied by inflammation (fatty liver hepatitis). Among other things, the intestinal microbiome (intestinal micobiome; dysbiosis/disbalance of the intestinal flora) is thought to contribute to this, which can probably also activate inflammatory cells in the intestinal wall. Enzymes from the group of GTPases also play an essential role in the development of steatosis hepatis (see below “Genetic burden”). Their central function is autophagy (process in cells by which they break down and utilize their own components) of fat droplets within liver cells. They bind to a protein (ATGL) that enables fat degradation – only this leads to the formation of the autophagosome. This fuses with the lysosome – enzymatic degradation of fat molecules occurs.

Etiology (causes) of nonalcoholic fatty liver

Biographic causes

• Genetic burden:
  • Families of patients with NAFLD often contain other family members with NAFLD (familial clustering)
  • Twin studies show a clustering of NASH in monozygotic (identical) twins versus dizygotic (fraternal) twins
  • Deficiency of GTPases due to specific gene mutations.
  • Genetic risk dependent on gene polymorphisms:
    • Genes/SNPs (single nucleotide polymorphism; English : single nucleotide polymorphism):
      • Genes: PNPLA3
      • SNP: rs738409 in the gene PNPLA3
        • Allele constellation: CC (3.2-fold; increased risk of alcoholic fatty liver; increased liver fat)
        • Allele constellation: CG (1.79-fold; increased liver fat, risk of alcoholic fatty liver).
        • Allele constellation: GG (low risk of fatty liver).
• Ethnicity – Latin Americans are more likely to be affected than African Americans. Caucasians occupy a middle position in terms of ethnic risk.

Behavioral causes

• Nutrition
  • Excessive caloric intake, especially if the diet is high in carbohydrates (especially glucose, fructose, and sucrose; e.g., also consumption of soft drinks containing sugar and fructose)
    • Increased fructose intake is considered an independent risk factor for nonalcoholic fatty liver disease (NAFLD).Also, excessive fructose intake may promote hepatic inflammation (chronic inflammation in the liver) due to fructose-induced ATP depletion (depletion of energy stores).
  • Too much animal protein – Research shows that, especially in older people who are overweight, a diet high in animal protein is associated with an increased risk of nonalcoholic fatty liver.
  • Rapid weight loss
  • Fatty liver developing during starvation is due to a lack of protein (protein deficiency) on a high-carbohydrate diet (kwashiorkor)
• Consumption of stimulants
  • Alcohol (woman: ≥ 10 g/d, man: ≥ 20 g/d); to distinguish nonalcoholic fatty liver disease (NAFLD) from alcoholic fatty liver (AFL; ALD) or mixed forms, a daily alcohol limit of 10 g in women and 20 g in men can be adopted. At higher daily amounts of alcohol can not be safely excluded alcoholic fatty liver
  • Tobacco (smoking)
• Physical activity
  • Physical inactivity
  • > 10 hours sitting/day and regardless of how much exercise is done (possibly due tohigher caloric intake).
• Overweight (BMI ≥ 25; obesity); prevalence (disease incidence): 30-100%.
• Android body fat distribution, that is, abdominal/visceral, truncal, central body fat (apple type) – high waist circumference or waist-to-hip ratio (THQ; waist-to-hip ratio (WHR)) is present When measuring waist circumference according to the International Diabetes Federation (IDF, 2005) guideline, the following standard values apply:
  • Men < 94 cm
  • Women < 80 cm

  The German Obesity Society published somewhat more moderate figures for waist circumference in 2006: < 102 cm for men and < 88 cm for women.

Disease-related causes (= metabolic risk factors).

• Chronic pancreatitis (inflammation of the pancreas).
• Ulcerative colitis – chronic, episodic inflammation of the colon.
• Diabetes mellitus type II
• Heart failure (cardiac insufficiency)
• Hyperlipidemia (lipid metabolism disorder) (increased triglyceride and decreased HDL cholesterol levels).
• Hypertension (high blood pressure)
• Insulin resistance (reduced effectiveness of endogenous insulin at target organs skeletal muscle, adipose tissue and liver) → insulin and glucose levels ↑ → lack of lipolysis inhibition → release of free fatty acids (FFS) (from adipose tissue and muscle cells) ↑ → de novo lipogenesis (“new fat formation”) in the liver ↑ (= 1st step to steatosis hepatis).
• Metabolic syndrome – clinical name for the symptom combination obesity (overweight), hypertension (high blood pressure), elevated fasting glucose (fasting blood sugar) and fasting insulin serum levels (insulin resistance) and dyslipidemia (elevated VLDL triglycerides, lowered HDL cholesterol). Furthermore, a coagulation disorder (increased tendency to clotting), with an increased risk of thromboembolism is also often detectable
• Cushing’s disease – group of diseases that lead to hypercortisolism (hypercortisolism; excess of cortisol).
• Polycystic ovary syndrome (PCO syndrome) – symptom complex characterized by hormonal dysfunction of the ovaries (ovaries).
• Psoriasis (psoriasis)
• Subclinical inflammation (English “silent inflammation”) – permanent systemic inflammation (inflammation affecting the entire organism), which runs without clinical symptoms.

Microvesicular steatosis

Causes

• Pregnancy

Etiology of secondary hepatic steatosis (modified from)

Biographic causes

• Genetic burden
  • Genetic diseases
    • Wilson disease (copper storage disease) – autosomal recessive inherited disorder in which one or more gene mutations disrupt copper metabolism in the liver.

Behavioral causes

• Nutrition
  • Malnutrition
  • Total parenteral nutrition – infusion program in which the patient is supplied with all necessary macro- and micronutrients via the vascular system (para enteral = next to the intestine); the digestive tract is completely bypassed in the process.

Disease-related causes

• Acute fatty liver of pregnancy
• Intestinal diseases
  • Inflammatory bowel disease (IBD).
  • Celiac disease (gluten-induced enteropathy).
• HELLP syndrome (H = hemolysis / dissolution of erythrocytes (red blood cells) in the blood), EL = elevated liver enzymes (increase in liver enzymes), LP = low platelets (thrombocytopenia / reduction of platelets) – special form of preeclampsia, which is associated with blood count changes and can take life-threatening courses / complication of gestational hypertension.
• Hepatitis C (V. a. genotype 3) [macrovesicular hepatocellular fatty degeneration]
• Jamaican vomiting disease – occurs after eating an unripe type of plum.
• Short bowel syndrome – clinical picture resulting from surgical removal (resection) or congenital absence of large portions of the small intestine
• Metabolic disorders
  • Abetalipoproteinemia (rare, autosomal recessive inherited lipid metabolism disorder).
  • Cholesterol storage disease (CESD).
  • Familial hyperlipidemia
  • Glycogenoses
  • Hereditary fructose intolerance
  • Hypobetalipoproteinemia
  • Lecithin cholesterol acyltransferase deficiency (LCAT deficiency; rare, autosomal recessive enzyme defect of extracellular cholesterol metabolism).
  • LCAT deficiency
  • Lipodystrophy
  • Wilson’s disease (copper storage disease)
  • Weber-Christian syndrome
• Reye syndrome – acute encephalopathy (pathological change of the brain) with concomitant fatty liver hepatitis (inflammation of the fatty liver) after a passed viral infection in young children; occurs on average one week after the previous illness has subsided

Medication (macrovascular fatty liver disease).

• Amiodarone
• Antiretroviral drugs (ART)
• Calcium antagonists
• Hormones
  • Steroids – glucocorticoids
  • Synthetic estrogens
  • Tamoxifen
• Nivolumab (checkpoint inhibitor used as an agent against various tumors).
• Vitamin A (in toxic concentrations* ).
• Cytostatic drugs – methotrexate [chemotherapy-associated steatohepatitis (CASH)]

* Generally, vitamin A toxicity is associated with long-term use of doses of the vitamin that exceed the recommended daily allowance by a factor of 10 – 8,000-10,000 micrograms or 25,000-33,000 IU per day. Medications (microvascular fatty acidosis).

• Acetylsalicylic acid (ASA).
• MDMA (amphetamines)
• Valproic acid
• Tetracycline
• Nucleoside analogues
• Didanosine
• Stavudine
• Valproic acid

Environmental pollution – intoxications (poisonings).

• Antimony
• Barium salts
• Borates
• Chromates
• Copper
• Phosphorus
• Petrochemical products – mineral oils, etc.

Other

• Composition of the gut microbiome?