Table 1.
The Clinical Features, Etiology, and Distinctive Features of Different Phenotypes of CLD
| Phenotype | Clinical features | Etiology | Epidemiology/prevalence (global and China, wherever applicable) | Distinctive features |
|---|---|---|---|---|
| DILI | It is manifested in the form of elevated liver enzymes, hepatitis, hepatocellular necrosis, cholestasis, fatty liver, and liver cirrhosis.11 DILI is categorized as intrinsic and idiosyncratic. Intrinsic DILI is dose related and occurs in patients with drug exposure within a short period. Idiosyncratic DILI is not dose related, occurs in a smaller population of drug-exposed patients, and variability in onset delays.23 The different categories of DILI are hepatocellular injury, cholestatic injury, hepatocellular-cholestatic mixed injury, and vascular injury based on the site of injury.24 | Pharmacological agents, complementary and alternative medicines including traditional Chinese medicine, and herbal/dietary supplements are the causative agents in DILI.25,26,27 Drug liver toxicity is limited to antibiotics, mainly represented by antitubercular drugs.24,25,28,29 Herbal medicines may also cause liver injury, although the actual composition of the herbal preparation may remain unclear, particularly in multicompound products.24,25,28,29 | DILI has a high incidence rate in China (23.8 per 100,000 inhabitants).25 Large differences in the epidemiology of DILI between Western and Eastern countries have been reported.30 | The development of jaundice or occasionally acute liver failure with coagulopathy and encephalopathy in the presence of jaundice is distinctive in DILI. Fibrosis, granulomatous hepatitis, and nodular regenerative hyperplasia are often present.23 |
| NAFLD/MAFLD | It is primarily asymptomatic comprising several clinical conditions, including steatosis, steatohepatitis, fibrosis, and cirrhosis.31 IR is an important parameter playing a vital role. There are 2 phenotypes of NAFLD, viz. nonalcoholic fatty liver (NAFL or simple fatty liver) and nonalcoholic steatohepatitis (NASH). Nonalcoholic fatty liver indicates the presence of steatosis only, whereas NASH represents steatosis with lobular inflammation and ballooning.32 | NAFLD manifests as excessive liver fat in the absence of secondary causes and significant alcohol consumption.32,33,34 The fat accumulates in the liver in the absence of alcohol consumption (alcohol intake: <20 g/d for female, <30 g/d for male) or any other secondary cause.34 | As of 2017, there were 882 million cases of NAFLD worldwide, with a prevalence rate of 10.9%, majorly seen in the Middle East and North America. The prevalence of NAFLD in China is in the range of 6.3%–27% with a higher occurrence in males than in females and in urban areas vs rural areas. The total number of cases of NASH in China in 2016 was 32.61 million.1,32,35, 36, 37, 38, 39, 40 | The distinct morphological features of NAFLD/MAFLD are large droplet steatosis, ballooning, lobular inflammation. Perisinusoidal fibrosis occurs at the end stages.41 Hepatic steatosis is accompanied by metabolic dysfunctions.42 Delayed diagnosis and intervention may lead to accumulation of diverse exogenous and endogenous hepatotoxic entities that lead to TLD and fibrosis via multiple biochemical pathways.43 |
| For MAFLD, metabolic dysfunctions such as overweight/obesity, type 2 diabetes mellitus additionally take prominence.44 Diverse endogenous or exogenous molecular mediators can result in multiple metabolic syndromes.7 In addition, given the increased risk of cardiovascular events in the NAFLD/MAFLD population, concomitant comorbidities such as viral hepatitis or ALD might worsen the prognosis of such patients.44 | In a meta-analysis by Liu et al, the global prevalence of MAFLD was demonstrated to be 50.7%, 19.7%, and 57.5% in patients with obesity, patients with type II diabetes mellitus, and patients with metabolic syndrome, respectively.36 | |||
| ALD | It is manifested as manifesting as simple steatosis to steatohepatitis and cirrhosis.45,46 Hepatic inflammation, necrosis, apoptosis, and fibrosis occur due to cytokine and oxidative stress cascade involving interactions between Kupffer’s cells, myofibroblasts, and endothelial cells.46,47 | Alcohol is the causative agent. The daily alcohol consumption of 20 g in females and 30 g in males along with clinical or biological alterations might be indicative of liver injury.48 | The prevalence of ALD globally was 26 million as reported by global disease burden, 2018. However, an increase in prevalence was observed in China, from 2.27% in 2000 to 8.74% in 2015, with a higher occurrence noted in males.45 The higher mortality with ALD is due to its detection at a much later stage.19,49 | ALD occurs even in the absence of clinical or biological manifestations and thereby is often diagnosed at later stages.19 The features of ALD include macrovesicular or mixed-type steatosis, hepatocellular injury with ballooning, lobular inflammation.48 |
| Liver fibrosis | Liver fibrosis is manifested in the form of excess collagen due to new fiber formation and leads to the accumulation of extracellular matrix in the liver parenchyma.50 | It is the sequel of other phenotypes of CLD. | - |
ALD, alcoholic liver disease; CLD, chronic liver diseases; DILI, drug-induced liver injury; MAFLD, metabolic associated fatty liver disease; NAFLD, nonalcoholic fatty liver disease.