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1. Introduction

The prevalence of non-alcoholic fatty liver disease (NAFLD) has increased worldwide in the last decades in parallel with the increase in obesity (1-4). NAFLD is a multisystem disease that is associated with many extra-hepatic manifestations or comorbid diseases. Findings of a previous meta-analysis revealed that the prevalence of NAFLD is 25.2% worldwide, the lowest values being recorded in Africa (13.5%) and the highest in South America and the Middle East (30.5 and 31.8%, respectively) (5). Findings have also shown that 10-15% of individuals with normal weight and 70% of obese patients have a fatty liver (6). A higher level of visceral fat increases the risk of hepatic steatosis in both slim and overweight individuals (7). Patients with dyslipidemia and type 2 diabetes mellitus (T2DM) have a higher prevalence of NAFLD than the average population (6,8). The pathogenic mechanism of liver inflammation and fibrosis in patients with NAFLD is incompletely understood. An improved understanding of the pathogenesis, natural history and treatment of NAFLD is necessary (9). One of the triggers is considered to be iron abnormalities. NAFLD is characterized by deposits of triglycerides in hepatocytes without secondary causes of liver disease, and this includes significant alcohol consumption (10). NAFLD includes non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH) which have the potential to progress to advanced fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Histologically, NAFL is present in 80% of patients and NASH is present in 20% of patients (11). The stage of fibrosis is the strongest predictor of disease-specific mortality in NAFLD (12). Patients with elevated liver enzymes or ultrasound-proven steatosis and who have risk factors for NASH without a definitive diagnosis, require a biopsy (13,14). Biopsy is the gold standard technique for detecting liver fibrosis; some of the disadvantages include insufficient sampling, sample site pain, high costs, as well as intra- and inter-observer variability (15,16).

Matteoni et al presented the first diagnostic criteria for the classification of NAFLD into four different subtypes: NAFLD type 1, in which the patient presents only fatty liver; type 2, in which the patient presents fatty liver and lobular inflammation; type 3, in which the patient presents fatty liver plus ballooning degeneration; and type 4, in which the patient presents fat accumulation, ballooning degeneration, and either Mallory-Denk bodies or fibrosis (7). Subtypes 3 and 4 are considered today as NASH (17). Previous studies have assessed the extra-hepatic manifestations of NAFLD and found they were associated with cardiovascular disease (CVD), T2DM, colorectal cancer, chronic kidney disease (CKD), obstructive sleep apnea (OSA), hypothyroidism, polycystic ovarian syndrome (PCOS) as well as hematologic manifestations (18-20). Cardiovascular diseases, followed by extra-hepatic malignancies, and then liver-related mortality is the leading cause of mortality in patients with NAFLD (18-20). It has been (widely) accepted that the standard treatment of patients with NAFLD is loss of weight through diet and exercise.

2. Methods

The aim of the present review was the identification and management of the hematologic manifestations of NAFLD. In this review, a literature search was performed for the term ‘non-alcoholic fatty liver disease (NAFLD)’ combined with ‘hematologic manifestations’ and ‘iron overload’, in the PubMed and Scopus databases from January, 1990 to December, 2020. The inclusion criterion was articles relevant to these searches. The exclusion criteria were studies written in languages other than English, letters to the editor, editorials, comments, conference presentations, opinions, and articles where there was no free access.

3. NAFLD and hematologic disorders

Increased ferritin levels, hepatic iron deposits and iron overload are associated with NAFLD. In NAFLD patients, the iron overload degree and severity are associated with the level of liver fibrosis and with the risk for HCC (21-23).

Even if the evidence that suggests the association between increased ferritin level and liver injury in NAFLD is reasonably strong, in other studies no clear association has been identified (24,25). In one study performed among NAFLD patients, iron indices were significantly reduced by therapeutic phlebotomy; however, there was no effect on insulin resistance or hepatic histology (26). In response to phlebotomy, these patients may develop anemia, in contrast to the experience of phlebotomy in patients with primary hemochromatosis. It is not currently recommended to use serial phlebotomy to decrease the ferritin levels of NAFLD patients, unless it is associated with a well-documented investigation of iron overload. Proinflammatory activity with elevated levels of plasminogen activator inhibitor-I in NAFLD patients leads to low level activation of the coagulation cascade, and the result is an increased risk of vascular thrombosis and thrombophilia (11). NASH etiology of cirrhotic patients is the leading cause for portal vein thrombosis. Furthermore, transplant recipients diagnosed with NASH cirrhosis have a higher risk for poorer post-transplant graft and patient survival, compared to recipients who do not have pretransplant portal vein thrombosis (27).

Approximately one in three NAFLD patients has excess iron deposits. This refers to the dysmetabolic iron overload syndrome (DIOS) and it is characterized by steatosis associated with moderate tissue iron deposition (hemosiderosis) and increased levels of serum ferritin, while the serum transferrin saturation was normal (28,29). The magnitude of hyperferritinemia in patients with NAFLD and/or metabolic syndrome (MetS) overemphasizes the degree of iron overload histologically detected when compared to hemochromatosis (30).

A serum ferritin level that is 1.5-fold higher than the normal upper limit in NAFLD patients is associated with (excessive) deposits of iron in the liver, underlying NASH, and a worse histological activity (31). Elevated levels of serum ferritin are autonomously associated with a higher NAFLD activity score (NAS), even in cases of patients without (excessive) deposition of iron in the liver (31). More severe liver fibrosis is correlated with the serum levels of ferritin. Taken separately, serum ferritin levels have a low level of diagnostic accuracy when it comes to the presence or severity of liver fibrosis in patients with NAFLD (AUROC <0.60) (32).

Specific patterns of hepatic iron deposits are associated with distinct histological features in patients with NAFLD. More advanced histological features, such as NASH and fibrosis, are associated with the presence of iron in the reticuloendothelial system (as opposed to hepatocellular deposits) in cases of patients with NAFLD (33-35). The development of HCC in NASH is associated with sinusoidal iron deposition (22,36).

4. Conclusions

Patients can benefit from the use of appropriate pharmaceutical therapies, such as lipid-lowering agents and insulin sensitizers; these aid in limiting the progression of NAFLD and lower the risk of extrahepatic manifestations. Further studies, with a longer follow-up period, are needed to collect the detailed cardio-metabolic risk profiles of these patients, in order to evaluate the impact of NAFLD as a systemic disease. Additionally, it is recommended that clinical trials be carried out to examine the effect of NAFLD treatment on the risks and outcomes of its extrahepatic manifestations. The treatment for many of the extrahepatic symptoms associated with NAFLD remains a change in the lifestyle, including adequate physical activity, weight loss and diet changes. Further studies are necessary in order to investigate the effect of pharmacological treatment on the extrahepatic manifestations of NAFLD. Consequently, further prospective studies are crucial in determining whether NAFLD has an independent risk factor for hematologic symptoms, besides the known risk factors. Weight loss, diet changes and the stopping of smoking have the potential to prevent the progression of NAFLD and its extrahepatic comorbid complications. Future studies are necessary for a better understanding of the pathophysiology and to potentially alter the natural history of these conditions. Future studies are also needed in order to assess the increasing impact of NAFLD on the micro- and macro-vascular complications of this systemic disease.

Acknowledgements

Not applicable.

Funding

No funding was received.

Availability of data and materials

All information provided in this review is documented by relevant references.

Authors' contributions

VP, DD, AND, RP, AEM, and LN contributed equally to the acquisition, analysis and systematization of the literature data, manuscript writing and critical revision for important intellectual content. All authors read and approved the final version of the manuscript for publication.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References