introduction
alcoholic steatohepatitis
non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD)
acute fatty liver of pregnancy (AFLP)

steatohepatitis (fatty liver)

introduction

steatohepatitis is a progression of fatty liver disease and may progress on to cirrhosis and hepatocellular carcinoma
initially it is asymptomatic and may only be discovered as a result of:
- raised liver function tests (LFTs)
- hepatomegaly
- diagnosis on USS or CT abdo
it is classified into:
- alcoholic steatohepatitis
- non-alcoholic steatohepatitis (NASH)
- acute fatty liver of pregnancy (AFLP)

alcoholic steatohepatitis

this is due to excessive alcohol intake
- 6 standard glasses (80g alcohol) over 1-3 days will cause a mild reversible hepatic steatosis with microvesicular lipid droplets accumulating in hepatocytes
- chronic ingestion, esp. more than 80g/d, leads to macrovesicular lipid globules within hepatocytes which compress and displace the nucleus to the periphery and is also associated with increase in inflammatory cells, esp. neutrophils, in the liver, and may result in increase of liver size to 4-6kg
  - this may then cause fibrosis around terminal hepatic veins which extends into adjacent sinusoids and risk development of cirrhosis

non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD)

currently affects 3.5-5% of adults in Western cultures and > 75% of those with morbid obesity
a lean body mass form “lean MALSD/MASH” is common in Asians with normal BMI
- reduced steatosis but significant inflammation and fibrosis
- prevalence of lean MASLD/MASH ranges from 1.94% to 13.11%
- lower prevalence of diabetes while paradoxically having higher risk of all-cause mortality
- this may be partly due to high salt and high fructose intake causing increased urea cycle flux, EIF5AH, and mitochondrial biogenesis ¹⁾
risk factors:
- high fructose diet
  - excessive fructose metabolism in intestinal cells reduces production of proteins that maintain the gut barrier and can cause a chronic endotoxaemia which in the liver is thought to provoke increased production of inflammatory cytokines and stimulate the conversion of fructose and glucose into fatty acid deposits²⁾
- metabolic syndrome
- central obesity
- hyperglycemia
- type 2 diabetes
- arterial hypertension
- hypertriglyceridemia
- chronic PM_2.5 particle exposure including microplastics such as polyethylene ³⁾⁴⁾
- genetic factors⁵⁾:
  - PNPLA3 (I148M, rs738409): the strongest risk allele linked to lipid droplet metabolism dysfunction in hepatocytes and stellate cells, promoting steatosis, fibrosis, and HCC;
  - TM6SF2 (E167K, rs58542926): impairs very-low-density lipoprotein (VLDL) secretion, leading to triglyceride retention;
  - MBOAT7 (rs641738): alters phospholipid remodelling and predisposes to hepatic lipid accumulation;
  - HSD17B13 (rs72613567): confers a protective effect, reducing steatosis and inflammation.
it is a progression from nonalcoholic fatty liver disease (NAFLD) which affects ~20% of the population in Western cultures and is rising rapidly due to obesity
- 90% of obese patients have NAFLD, while up to 70% of type 2 diabetics have NAFLD
two sub groups which are probably stages:
- metabolic dysfunction-associated steatotic liver disease (MASLD)
  - hepatic fat accumulation with little to no inflammation
  - findings from citrin deficiency suggests that in lean people it may be due to the accumulation of glycerol-3-phosphate (G3P) that activates carbohydrate response element-binding protein (ChREBP), a protein that turns on fat synthesis genes and induces fibroblast growth factor 21 (FGF21). FGF21 is normally released into circulation by the liver in response to fasting, ethanol, exercise, ketogenic diet, simple carbohydrates (esp. fructose), refeeding, obesity, type 2 DM, and mitochondrial disease, and has multiple sites of action including specific β-klotho-expressing regions of the brain, where FGF21 functions to restrain the intake of sweets and ethanol, and the periphery, where it increases energy expenditure and body temperature. Fasting, refeeding, ketogenic diet, simple carbohydrates, mitochondrial disease, ethanol and fructose all have direct paths to producing G3P. ⁶⁾
- metabolic dysfunction-associated steatohepatitis (MASH)
  - fat accumulation with active inflammation and cell injury
  - appears to substantially improve with glucagon-like peptide-1 (GLP-1) peptide analogs (eg. Ozempic)
  - substantially increases risk of hepatocellular carcinoma by triggering p53-dependent actions on the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) initially resulting in hepatocyte senescence⁷⁾
histologically, it is characterised by unique zone 3 “chicken wire” fibrosis
accounts for 13% of all cases of hepatocellular carcinoma
appears to decrease 5 year survival rates in metastatic colorectal cancer (bowel cancer) from 73% in those with “encapsulated” liver mets to 44% in those where mets have infiltrated liver fatty tissue⁸⁾
in the Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis (PIVENS) trial, for patients with NASH but without diabetes mellitus, the use of very high dosages of vitamin E (800 IU/day) for four years was associated with a significantly higher rate of improvement than placebo (43% vs. 19%) in the primary outcome
premenopausal women are relatively protected from it due to high oestrogen levels, but risk increases in peri-menopausal women and post-menopausal women
- modulation of oestrogen receptor alpha (ER-α) activity increases the risk of steatohepatitis in vulnerable women - reduced E2 levels in postmenopausal women often lead to insulin resistance (IR) and changes in adiposity, which also trigger the phenotypic expression of the PNPLA3 p.I148M variant. ⁹⁾
- the p.I148M variant of PNPLA3 accounts for the highest proportion of NAFLD heritability and accounts for 27% and 16% of HCC and cirrhosis variance, respectively.¹⁰⁾
role of impaired urea cycle in fatty liver disease
- Arginases mediate arginine hydrolysis to ornithine and urea. ARG1 is the more highly expressed arginase isoform in hepatocytes, whereas Arg2 is minimally expressed in liver under basal, fed conditions but ARG2 deficiency appears to be a driving factor of fatty liver disease.
- Obesity impairs hepatocyte ureagenic and oxidative gene expression. Hepatocyte Arg2 deletion impairs ureagenesis, TCA cycle, and mitochondrial function. Hepatocyte Arg2 deficiency drives obesity, liver steatosis, and insulin resistance with aging. The urea cycle defects lead to secondary impairment in the tricarboxylic acid (TCA) cycle, a key pathway for energy metabolism. This disruption results in inefficient calorie utilization and excessive fat storage in the liver, which can subsequently cause inflammation and fibrosis, contributing to the progression of the disease. ¹¹⁾
role of miR-93 in MASLD
- “miR-93 was significantly upregulated in the livers of patients with MASLD and diet-induced obese mice. miR-93 KO mice exhibited reduced hepatic steatosis. Specifically, miR-93 deficiency upregulated genes involved in fatty acid oxidation and downregulated genes associated with cholesterol biosynthesis. Sirtuin 1 (SIRT1) was identified as a direct target of miR-93, and miR-93 KO enhanced SIRT1 expression and activated the LKB1-AMPK signaling pathway. Niacin treatment downregulated miR-93, ameliorating hepatic steatosis by enhancing SIRT1 activity” ¹²⁾
role of epigentic modifications in NAFLD
- NUPR1, a stress-induced transcriptional regulator, undergoes m1A modification. YTHDF1 directly binds to m1A-modified NUPR1 mRNA, enhancing its stability, thereby leading to elevated NUPR1 protein levels. Functionally, upregulated NUPR1 acts as a core driver of NAFLD pathogenesis by activating lipogenic and suppressing fatty acid β-oxidation genes, thereby exacerbating hepatic lipid accumulation.¹³⁾
role of EFHD1
- it appears that EFHD1 tethers mitochondria to endoplasmic reticulum and helps trigger mitochondrial division as an antiviral stress response, meant to prevent viral replication in infected cells, but in high fat high sugar diets, elevated levels of EFHD1 occur which instead shuts down healthy but strained liver cells, worsening injury.¹⁴⁾