Alcoholic and Non-Alcoholic Steatohepatitis

Introduction:

Alcoholic steatosis can arise after excessive alcohol intake. It is a direct result of alcohol and can develop despite a proper diet. Under the electron microscope, early modifications include the buildup of membrane-bound fat droplets, smooth endoplasmic reticulum proliferation, and the slow deformation of mitochondria. In alcoholic liver disease (ALD), lipid buildup is macrovesicular and consists of triglycerides. However, tiny droplets of these triglycerides may resemble microvesicular droplets. Biopsy of the liver is an integral part of the diagnostic process in individuals with suspected ALD because it may grade the severity and rule out other diseases. Furthermore, several histologic abnormalities, such as perivenular fibrosis and the presence of Mallory-Denk bodies (MDB), may be linked with an adverse prognosis in individuals with steatosis but no diabetes. Hans Popper hypothesized that just because alcoholic steatohepatitis (ASH) and non-alcoholic steatohepatitis (NASH) were so similar, comparing them would help us understand both disease processes.

What Are the Clinical Aspects?

• Obesity, type 2 diabetes, hypertension, polycystic ovarian syndrome, and acanthosis nigricans are the disorders that contribute to NASH development. However, ASH develops as a result of addiction to alcohol.

• Symptoms of NASH are lacking or include upper abdominal quadrant discomfort in one-third to one-half of individuals. Fatigue and anorexia are two manifestations of ASH. Hepatomegaly is a sign of NASH that is frequently ignored due to obesity.

• Fever and jaundice may accompany ASH. Atrophy of the muscles, spider angiomata (abnormal collection of the blood vessels close to the skin surface), and encephalopathy (alters brain structure or function) occur when cirrhosis develops.

What Are the Laboratory Findings?

• Various laboratory abnormalities, like increased serum aminotransferases, have been documented in patients with alcoholic liver disease and are used to diagnose ALS. In alcoholic hepatitis, serum aspartate aminotransferase (AST) levels are fewer than 500 IU/L (international units per litre).

• Laboratory findings in NASH comprise alanine aminotransferase (ALT) normal to 300 IU/L, ALT greater than aspartate aminotransferase (AST) (1.5:1 ratio) (Sorbi et al., 1999), and AST greater than ALT in cirrhotic patients. ALP (alkaline phosphatase) levels, total bilirubin, prothrombin time, white blood count (WBC), and mean corpuscular volume (MCV) of erythrocytes are normal.

• Laboratory findings of ASH comprise increased ferritin levels (Kowdley et al., 2012). AST greater than ALT typically by more than a 2:1 ratio, ALP may be raised, total bilirubin may be high, elevated prothrombin time (white blood cells) WBC is elevated up to 50,000/mm2 (millimeter square) and mean corpuscular volume (MCV) is also elevated.

What Are the Histopathological Findings of ASH and NASH?

• Histopathological Findings of ASH: Ballooning the hepatocytes with or without Mallory-Denk structures and parenchymal inflammation of the parenchymal cells that are neutrophil-rich mixed infiltrates of inflammation is seen in ASH.

• Histopathological Findings of NASH: Macrovesicular steatosis, ballooning hepatocyte degeneration, widespread (often lobular) inflammation, apoptotic bodies, and Mallory-Denk bodies (MDBs) are the histologic characteristics of NASH. Interestingly, even though fibrosis is frequently present to some extent to confirm the diagnosis, it is not necessary.

What Are the Pathophysiology of ASH and NASH?

Pathophysiology of ASH:

1. ASH is distinguished by steatosis caused by alcohol-mediated lipid metabolisms disturbances like fatty acid oxidation inhibition and increased lipogenesis, as well as marked necro-inflammation caused by endotoxins transitioned from the gut to the liver due to alcohol-mediated mucosal barrier function disturbance and changes in the gastrointestinal microbiota.

2. Endotoxins are mostly produced by gram-negative bacteria and get attached to activate Kupffer cells, causing them to emit cytokines that cause liver inflammation. TNF-alpha (tumor necrosis factor-alpha) is a critical cytokine in this context, as it is abundantly expressed in ASH patients and associated with mortality.

3. Aside from cytokine activity, oxidative stress and the formation of reactive oxygen species (ROS) and lipid peroxides play a significant role in the progression of ASH.

4. Chronic alcohol intake increases the expression of CYP2E1 to 10 to 20 fold (cytochrome P450 2E1), which converts ethanol to acetaldehyde, a highly toxic and mutagenic chemical, and creates ROS.

5. Most patients' CYP2E1 induction diminishes during cessation, but some individuals have high CYP2E1 activity for several weeks, even after cessation of alcohol. Elevation of CYP2E1 has been linked to fat storage, inflammation and fibrosis, and DNA (deoxyribonucleic acid) damage.

6. Hyperhomocysteinemia is a common characteristic in patients with alcoholic liver disease (ALD), particularly ASH, caused by alcohol-related disturbances in the transfer of methyl group transfer to a variety of mechanisms including folate, vitamin B12, and vitamin B6 deficiency, along with acetaldehyde -mediated inhibition of enzymes involved in methionine and S-adenosylmethionine metabolism.

Proposed Mechanism of ASH

Pathophysiology of NASH:

1. Proposed mechanism of NASH - Free fatty acids ( FFAs) produced from adipose tissue due to insulin resistance and de novo lipogenesis (DNL) caused by dietary sugar enhance the FFA pool in the liver. FFAs can be stored in the liver as triglycerides or converted into lipotoxic lipids. Lipid mediators can cause oxidative stress (an increase in the reactive oxygen species in the cells ) and endoplasmic reticulum stress, leading to cell damage and inflammation. Inflammatory cells are recruited and activated as a result of cell damage. A leaky gut caused by gut dysbiosis can exacerbate liver inflammation. Hepatic stellate cell - activation (HSC - activation) and collagen deposition are triggered by the combination of inflammation and tissue injury.

Proposed Mechanism of NASH

What Is the Treatment of ASH and NASH?

• Treatment of NASH -

  • The cornerstone of management is lifestyle adjustment, intending to lose at least five to ten percent of total body weight. Weight loss, achieved by calorie restriction and exercise, resulted in both biochemical and histological improvement in individuals. It is advantageous to increase omega-3 fats in the diet.

  • Thiazolidinediones tend to improve adipocyte insulin sensitivity while also avoiding incorrect lipolysis. However, their adverse effect profile (weight gain, worsening of congestive heart failure, and osteoporosis) restricts their usage.

  • In nondiabetic individuals, antioxidants such as vitamin E are of minor benefit and presumably safe; a dose of 800 units per day may be provided, and in the case of diabetic patients, 400 units per day are recommended.

  • Bariatric surgery is a successful treatment that should be explored in people with morbid obesity and satisfy the requirements for bariatric surgery.

• Treatment of ASH -

  • General Precautions to Be Taken for the Treatment of Severe Liver Disease - Treatment of ASH is similar to that of individuals with decompensated liver disease of other etiology. Treatment of ascites (fluid collection in the abdomen), bacterial peritonitis, and hepatorenal syndrome (HRS) as per current guidelines includes restriction of salt in the diet, diuretics, paracentesis (a procedure performed to collect ascites fluid for diagnostic and evaluation) with albumin replacement, therapeutic and preventive antibiotics, and vasoconstrictors such as Terlipressin, Midodrine, or norepinephrine.

  • Abstinence - The most significant measure for individuals with ASH is complete cessation of alcohol, which improves liver function histologically and prognosis.

  • Nutritional Therapy - Aggressive enteral nutritional therapy is beneficial to individuals with ASH and should be a part of their treatment plan.

  • Glucocorticosteroids and Tnf-Alpha Antagonists - Glucocorticoids -Corticosteroids inhibit proinflammatory processes in ASH by lowering TNF - alpha expression and inflammatory cell activity.

  • Liver Transplant.

Conclusion:

ASH is a life-threatening disease with a high death rate. There are effective remedies, such as the withdrawal of alcohol, but the patient does not completely accept them. NAFLD is managed as interprofessional teamwork. Any healthcare provider that comes into contact with these patients must support lifestyle modifications to reduce the disorder's death rates and increase the patient's lifespan.