A Multi-Center Study Exploring the Association of Metabolic Syndrome and Non-Alcoholic Fatty Liver Disease in Cuban Patients

Research Article

Austin J Obes & Metab Synd. 2021; 5(1): 1023.

A Multi-Center Study Exploring the Association of Metabolic Syndrome and Non-Alcoholic Fatty Liver Disease in Cuban Patients

Castellanos-Fernández MI1, Stepanova M2, Infante-Velázquez ME1, Henry L2*, Crespo-Ramírez E3, del Valle-Díaz S4, Elias JD5, Santaló-Rodríguez L5, Corrales-Alonso S6, Morales-Martínez I7, Cedeño-Ramirez E8, Pérez-González T9, González-Suero SM1, Ruenes-Domech C1, Suárez EB10, Racila A11, Guridi ZD1 and Soler EA1

1Institute of Gastroenterology, University of Medical Sciences of Havana, Havana, Cuba

2Center for Outcomes Research in Liver Diseases, Washington, District of Columbia, USA

3HospitalGeneral Docente Abel Santamaría Cuadrado, Pinar del Río, Cuba

4HospitalProvincialSaturnino Lora, Santiago de Cuba, Cuba

5HospitalUniversitario General Calixto García, La Habana, Cuba

6HospitalUniversitario Faustino Pérez, Matanzas, Cuba

7HospitalOncológico Celestino Hernández Robau, Villa Clara, Cuba

8Hospital Clínico Quirúrgico Docente Comandante Manuel Fajardo, La Habana, Cuba

9HospitalGeneral DocenteIvan Portuondo, Artemisa, Cuba

10Hospital Universitario Manuel Ascunce Domenech, Camagüey, Cuba

11Guy and Betty Beatty Center for the Study of Obesity and Outcomes, Inova Health Systems, Falls Church, VA, USA

*Corresponding author: Linda Henry, Center for Outcomes Research in Liver Diseases, Washington, District of Columbia, USA

Received: March 03, 2021; Accepted: April 19, 2021; Published: April 26, 2021


Aim: There is a paucity of data on Non-Alcoholic Fatty Liver Disease (NAFLD) and Metabolic Syndrome (MetS) among native Cubans. We aimed to assess the prevalence of MetS in Cubans with NAFLD and the outcomes and predictors for advanced fibrosis.

Methods: A multicenter (outpatient clinics of nine hospitals in seven Cuban provinces) cross-sectional study of adults with NAFLD between September 2018 and May 2019. MetS was defined by the National Cholesterol Education Program Adult Treatment Panel III (NCEP: ATPIII) criteria. Advanced fibrosis was defined using AST to Platelet Ratio Index (APRI) ≥1 and Fibrosis-4 score (FIB-4) ≥2.67.

Results: 819 patients enrolled, 563 (68.7%) had MetS; mean age 54.9 years, 60.3% female, 65.8% white, 95.1% from urban residency, mean BMI 30.7 kg/m². Fibrosis was present in 114 (13.9%); 94 (82.5%) had APRI ≥1; 77 (67.5%) had FIB-4 ≥ 2.67; 57 (50%) both scores were elevated. MetS group had significantly more fibrosis than no MetS, [17% vs. 7% (p=0.0001)]. Patients with fibrosis were older (57.7 vs. 54.5, P=0.0015), of Mestizos ethnicity (36.8% vs. 16.9%, P<0.0001), and from rural residency (17.5% vs. 2.8%, P<0.0001). MetS was independently associated with fibrosis: Odds Ratio (OR) = 2.05 (95% CI 1.10-3.81) (p=0.024), but, rural residency was the strongest fibrosis predictor [OR: 5.30 (95% CI 2.45-11.47, (P<0.0001)]. Other fibrosis predictors were male gender, sedentary life-style, NAFLD family history, and lower estimated glomerular filtration rate (p<0.05). Risk of fibrosis was not associated with age, ethnicity, or smoking (all p>0.05).

Conclusion: Cuban NAFLD patients with MetS have substantial clinical impairment and a higher risk for fibrosis.

Keywords: Fatty liver; Metabolic syndrome; Fibrosis; eGFR; Rural residency


MetS: Metabolic Syndrome; NAFLD: Non-Alcoholic Fatty Liver Diseases; NCEP: ATPIII: National Cholesterol Education Program Adult Treatment Panel III; SBP: Systolic Blood Pressure; DBP: Diastolic Blood Pressure; ALT: Alanine Aminotransferase; AST: Aspartate Aminotransferase; NIAAA: National Institute on Alcohol Abuse and Alcoholism; BMI: Body Mass Index; ADA: American Diabetic Association; CKD: Chronic Kidney Disease; MDRD: Modification of Diet in Renal Disease; eGFR: Estimated Glomerular Filtration Rate; APRI: AST to Platelet Ratio Index; FIB-4: Fibrosis 4 Score; Scr: Serum Creatinine

Lay Summary

People with metabolic syndrome have high rates of cardiovascular disease and cardiovascular disease related death. Metabolic syndrome is present when one has three or more of the following criteria: waist circumference >102cm in men, >88cm in women, triglycerides 150mg/dl or greater, HDL-cholesterol <40mg/dl in men and <50mg/ dl in women, blood pressure 130/85mmHg or greater, and fasting glucose 100mg/dl or greater. The components of metabolic syndrome are associated with a liver disease called, Non-Alcoholic Fatty Liver Disease (NAFLD). In this study, we found 68.7% of patients from Cuba who had NAFLD also had metabolic syndrome. The majority of those with NAFLD and MetS were women though men were more likely to develop liver fibrosis.


Non-Alcoholic Fatty Liver Disease (NAFLD) is defined as the presence of ≥5% of hepatic steatosis, in the absence of competing liver disease etiologies, such as chronic viral hepatitis, use of medications that induce steatosis such as amiodarone or tamoxifen, and other chronic liver diseases, such as autoimmune hepatitis, hemochromatosis, Wilson’s disease, or significant alcohol consumption [1]. NAFLD is also considered to be the Metabolic Syndrome (MetS) of the liver due to its close association with features of metabolic syndrome which include hypertension, hyperlipidemia, type 2 diabetes, and obesity. Many consider the relationship to be bidirectional between Mets, components of MetS, and NAFLD in addition to the presence of MetS being associated with advanced liver fibrosis [2-4].

NAFLD is now one of the most prevalent liver diseases worldwide due to parallel increases in the rates of obesity and type 2 diabetes mellitus. The reported overall global prevalence of NAFLD among adults is 24% but with prevalence rates that range from a high of 32% in the Middle East followed by 31% in South America, Asia at 27%, the United States of America at 24% and Europe at 23% while Africa reports only a prevalence rate of 14% [5]. Mortality related to NAFLD is increasing with a reported age-standardized mortality annual percentage change of 11.3% between 2013-2016 [6]. NAFLD is less common in women than men but the more advanced form of NAFLD, Non-Alcoholic Steatohepatitis (NASH), appears to be more common in women [7]. Older age is also associated with NAFLD, but it is also appearing in the younger population.

The demographic characteristics also differ worldwide [5]. Europe and North America appear to follow similar demographic patterns for the prevalence of NAFLD. However, a recent study which investigated the prevalence of suspected NAFLD among 12,133 Hispanic/Latino persons found that persons of Cuban, Puerto Rican, and Dominican backgrounds had lower rates of suspected NAFLD when compared to persons of Mexican heritage while persons of Central American and South American lineage had a similar prevalence of suspected NAFLD compared to persons of Mexican heritage [7].

However, there is a paucity of data regarding the history of NAFLD patients currently living in their native Caribbean countries, particularly Cuba. In fact, the majority of studies investigating the impact of Latino ethnicity (Dominicans, Cubans and Puerto Ricans) on NAFLD were conducted on persons living in the United States where there are very different environmental and socioeconomic conditions that can impact the course of this liver disease [8-10]. Therefore, despite our current understanding of NAFLD and MetS, [11-13] understanding NAFLD by ethnicity from persons living in their respective Caribbean country is important for further understanding of the interplay between one’s environment and genetic make-up in the development of this metabolically based liver disease.

As such, this study will focus on the impact of metabolic syndrome and NAFLD among native Cubans to assist policy makers in developing targeted NAFLD interventions [14-16] that may be applicable to the surrounding areas as Cuba is the largest of the four islands that make up the Greater Antilles and is comprised of 11,338,138 people. Cuba also has a large ethnic admixture even within the country due to the past conquering forces from Europe/Spain, slave trade from West Africa, and the indigenous population (Overall, 64.1% of the population is European Cuban, 26.6% Mulatto or Mixed, and 9.3% are Afro-Cuban) [17-19]. In addition. Cuba is facing several major health issues, which include the growing prevalence of the metabolic diseases of diabetes, obesity and hypertension [20-22].

Therefore, we aimed to screen for features of MetS in patients with NAFLD; assess whether the NAFLD clinical profile differed by the presence of MetS; and identify predictors of fibrosis among those with NAFLD with the goal of providing a better understanding of the impact the presence of MetS on the outcomes of patients with NAFLD which may also help further the discussion on which terminology is more appropriate for this fatty liver disease.


Study design and Setting

A multicenter cross-sectional study was performed in adult patients with a well-documented diagnosis of Non-Alcoholic Fatty Liver Diseases (NAFLD). Patients were enrolled from outpatient clinics of nine hospitals in seven provinces of the country, Pinar del Rio, Artemisa, La Habana, Matanzas (Western region), Villa Clara, Camaguey (Central region) and Santiago de Cuba (Eastern region). Patients were continuously enrolled from September 2018 to May 2019. The study was approved by the Institutional Review Board of all the participating hospitals.


The primary inclusion criteria were age ≥18 years with the presence of hepatic steatosis on ultrasonography in the absence of known secondary causes of liver fat accumulation, according to the criteria of the American Association for the Study of Liver Diseases [1]. Patients with secondary causes of hepatic fat accumulation, current or recent alcohol or drug abuse history, use of potentially hepatotoxic drugs, ischemic liver disease, alpha-1 antitrypsin deficiency, hemochromatosis or Wilson’s disease, viral hepatitis B or C, human immunodeficiency virus infection, were excluded from the study. In addition, those who reported excessive alcohol intake which was defined as more than 4 drinks on any day for men or more than 3 drinks for women, following the National Institute on Alcohol Abuse and Alcoholism (NIAAA) guidelines where one “standard” drink was equivalent to 1 regular beer, or 12 oz of liquor or 5 oz of wine or 1 shot of distilled spirit (https://www.niaaa.nih. gov/what-standard-drink) were also excluded [23]. Social drinker or abstinence was assigned to those who either drank alcohol but did not meet the NIAAA guidelines for being a heavy drink or reported that they did not drink alcohol at all [23]. We also excluded those with hypothyroidism, hypopituitarism and polycystic ovarian syndromes as potentially other known causes of NAFLD.

During an office visit, after giving informed consent, demographic, personal habits, medical history, and clinical data were collected from the patients and their clinical charts. In order to standardize data collection, a pre-approved data collection form was used.

Data sources/ measurement

Metabolic Syndrome (MetS) was defined according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP:ATPIII) criteria [24] and updated by the American Diabetes Association (ADA) for impaired fasting glucose tolerance [25,26] as any three or more of the following criteria: waist circumference >102cm in men, >88cm in women, triglycerides 150mg/dl or greater, HDL-cholesterol <40mg/dl in men and <50mg/dl in women, blood pressure 130/85mmHg or greater, and fasting glucose 100mg/dl or greater.

Collected demographics included age, gender, ethnic groups (based on the color of skin: white, black and mestizo), and current residence (urban or rural area). The rural population refers to people living in rural areas as defined by national statistical office [27]. Demographic characteristics, anthropometric measures, and laboratory tests were recorded within 1 month of recruitment.

Personal habits recorded included: current smoking defined as regular or occasional use of tobacco products, physical activity defined as either sedentary which is the engagement in physical activity for <15 minutes less than three times a week during the last quarter or as the practice of any physical activity for ≤90min/week or regular physical activity which is the practice of regular physical activity or exercise for >90min/week. Activity included any activity that occurred in the occupational, educational, home and community settings as well as mode of transportation [28]. Current alcohol use was defined as the amount of alcohol consumed on a daily basis over the past six months. A family history was determined by querying the patients with regards to first-degree relatives with known NAFLD, cirrhosis, diabetes, obesity or cancer. A medical history was also performed which included an inquiry about a history of arterial hypertension defined as a Systolic Blood Pressure (SBP) ≥130mmHg or Diastolic Blood Pressure (DBP) ≥85mmHg or the self-reported use of anti-hypertensive medications [29].

A medical examination was also performed. The medical history included measurements of a patient’s waist circumference, weight, height, Body Mass Index (BMI) [30]. At each examination, three blood pressure measurements were taken at 10min intervals by centrally trained healthcare staff using an appropriately sized cuff and mercury sphygmomanometer (Kindcare medical system, Zhejiang, China), and the average blood pressure was recorded. Type 2 diabetes was defined as a fasting glucose ≥7mmol/l or if the 2-hour plasma glucose value during a 75g oral glucose tolerance test was ≥11mmol/l or the self-reported use of anti-diabetic medications [31]. Cirrhosis, was established using historic liver biopsy or, if unavailable, imaging and existing clinical medical records. Hyperlipidemia was defined as having a total cholesterol ≥5.2mmol/l and/or triglycerides ≥1.7mmol/l or the self-reported use of statins, fibrates or any other anti-lipid drugs [32].

The laboratory tests included platelet counts, Alanine Aminotransferase (ALT) with standardized values for the Upper Limit Normal (ULN) of <46IU/L, Aspartate Aminotransferase (AST) (ULN <49IU/L), alkaline phosphatase (normal range: 60-290 IU/L), gamma-glutamyltransferase (normal <45IU/L), albumin (normal range: 38-64g/L), glucose (normal range: 4.2-6.1mmol/L), total cholesterol (normal range: 2.9-5.2mmol/L), triglyceride (normal range: 0.46-1.71mmol/L), uric acid (normal ranges: male: 208- 428, female: 155-357mmol/l) and creatinine (normal ranges: 47.6 - 113.4mmol/L). All laboratory tests were performed using routine validated methods. The ULN ranges of AST and ALT used were provided according ALT 4+1 test validated available by HELFA diagnostic: https://es.scribd.com/document/383145547/Catalogode- Tecnicas-HELFA. Hematological tests were performed using the BC-3200 Auto Hematology Analyzer (Mindray, Shenzhen, China) and biochemical parameters were measured using the Cobas C311 Clinical Chemistry Analyzer (Roche, Basel, Switzerland).

Serum Creatinine (Scr) measurements were used to estimate Glomerular Filtration Rate (eGFR) using the following equation: Modification of Diet in Renal Disease (MDRD eGFR). (mL/ min/1.73m²) = 175* (Scr/88.4)^(-1.154)*(Age)^(-0.203)*(0.742 if female)*(1.212 if African American) [33] Kidney function was evaluated through eGFR, Chronic Kidney Disease (CKD) stage 1 if eGFR (CKD-MDRD) ≥90, stage 2, eGFR = 60-89, stage 3, eGFR = 30-59, stage 4, 15-29 and stage 5<15 [34].

The presence of fibrosis was established using the AST to Platelet Ratio Index (APRI) and Fibrosis-4 score (FIB-4) calculated for each patient [35]. The cut-off points for advanced fibrosis were APRI ≥1 and/or FIB-4 ≥2.67 [36]. Fibrosis was presumed in patients meeting one of the two cut-offs.

At the time of enrollment, an upper abdominal ultrasound was obtained using one of the following ultrasound machines: Toshiba Aplio 300 (Toshiba Medical Systems Europe, The Netherlands), Aloka SSD-4000 (Hitachi Aloka Medical Ltd) or EPIQ 5 (Philips Ltd). Each ultrasound was reviewed. Hyperechogenicity of liver (increased hepatorenal echogenicity), blurring of vascular margins, and increased acoustic attenuation defined the presence of NAFLD.

Statistical analysis

Patients’ clinico-demographic characteristics were summarized as N (%) or mean +/- standard deviation. Subgroup analyses were performed on the predefined subgroups of: patients with and without MetS and patients with and without fibrosis based on the definitions described above. Comparison of parameters between groups was done using chi-square test or Mann-Whitney non-parametric test for categorical and continuous parameters, respectively. Independent predictors of fibrosis in patients with NASH were assessed using multiple logistic regression. P-values of less than 0.05 were considered statistically significant.

All analyses were run using SAS 9.4 (SAS Institute, Cary, NC, USA).


Of the 6601 patients who visited a clinic during the study period, 1070 met the eligibility criteria and 819 (76.5%) completed all labs and clinical data; the other 251 patients had insufficient medical records for extraction of required data or did not provide informed consent (Figure 1). Patients included were, on average, 54.9 (±10.9) years of age, 60.3% female, 65.8% white, 95.1% from urban residency, with a mean BMI of 30.7±4.6 kg/m² (Table 1).