The Burden and Clinical Care Pathways of Nonalcoholic Steatohepatitis in the Middle East

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Abbreviations

ALP

alkaline phosphatase

ALT

alanine aminotransferase

ANA

antinuclear antibody

ASMA

anti‐smooth muscle antibody

AST

aspartate aminotransferase

BMI

body mass index

BP

blood pressure

CBC

complete blood count

CLD

chronic liver disease

DM

diabetes mellitus

FIB‐4

Fibrosis‐4 score

HCC

hepatocellular carcinoma

HCV

hepatitis C virus

MetS

metabolic syndrome

MRI

magnetic resonance imaging

NAFL

nonalcoholic fatty liver

NAFLD

nonalcoholic fatty liver disease

NASH

nonalcoholic steatohepatitis

T2DM

type 2 diabetes mellitus

UAE

United Arab Emirates

Nonalcoholic fatty liver disease (NAFLD) is defined as cytoplasmic accumulation of fat in more than 5% of hepatocytes with or without inflammation when other causes of steatosis such as excessive alcohol consumption, viral hepatitis, genetic disorders, and drugs are ruled out. NAFLD encompasses a range of histological abnormalities. The mildest form, nonalcoholic fatty liver (NAFL), is characterized by simple steatosis without hepatocyte balloon degeneration, inflammation, or fibrosis. NAFL rarely progresses to cirrhosis. Nonalcoholic steatohepatitis (NASH) is a more severe form of NAFLD where steatosis is accompanied by balloon degeneration and lobular inflammation. NASH can progress to cirrhosis in up to 40% of patients.1

NAFLD is emerging as a leading cause of cirrhosis, liver failure, and hepatocellular carcinoma (HCC) around the globe. The global prevalence rate of NAFLD is around 25%.1 In the United States and Europe, NAFLD is expected to become the main indication for liver transplantation by 2030.2 In addition to liver‐related morbidity and mortality, NAFLD is associated with increased incidence of cardiovascular and chronic kidney disease.

Being the hepatic component of the metabolic syndrome (MetS), the prevalence of NAFLD parallels that of type 2 diabetes mellitus (T2DM) and obesity. Accordingly, overnutrition and a sedentary lifestyle are the major risk factors for NAFLD. However, irrespective of lifestyle, there are important interethnic differences in the susceptibility to NAFLD, which appear to be related to genetic factors.3

Disease Burden in the Middle East

The Middle East is considered a high‐prevalence region for NAFLD. It is estimated that around 30% of adults have NAFLD.1 This estimate is based on three studies (Table 1).4, 5, 6 Two of these studies were carried out on highly selected populations.4, 6 Hence the findings may not be extrapolated to the general population. A fourth report pertaining to the disease burden in Saudi Arabia and the United Arab Emirates (UAE) used a mathematical model that calculated the current and future prevalence of NAFLD, based mainly on the prevalence of diabetes and obesity in both countries.7

Table 1.

Prevalence of NAFLD in the Middle East

Reference	Country	Sample Size	Prevalence Rate (%)
Kasapoglu (2013)4	Turkey	613	55
Zelber‐Sagi (2014)5	Israel	147	31
Eshraghian (2013)6	Iran	832	15
Alswat (2018)7	Saudi Arabia and UAE	—	25 (indirect estimate)

Adapted with permission from Hepatology.1 Copyright 2016, American Association for the Study of Liver Diseases.

Despite these limitations, the notion that NAFLD is common in Middle East populations is supported by the high prevalence of obesity, T2DM, and the MetS (Fig. 1).8 Ten countries in the region are placed in the top 15 countries with the highest levels of obesity in the world.9 In some of these countries, obesity starts at a young age. For instance, in the Gulf Cooperation Council states (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the UAE), the prevalence rates of obesity among schoolchildren and adolescents range between 25% and 30%.10 Overweight and obese children are more likely to stay obese into adulthood and to experience obesity‐related complications. In Kuwait, 22 out of 35 patients (63%) referred for liver transplantation in 2018‐2019 had NASH‐related cirrhosis (with permissions from Moataz Fathi, Ministry of Health, personal communication).

Figure 1.

The prevalence of diabetes (light gray bars), obesity (dark gray bars), and MetS (black bars) in some Middle Eastern countries. Adapted with permission from Gastroenterology Research.8 Creative Commons License Copyright Canada‐China Clinical Medicine Study Association, 2017.

These alarming statistics call for urgent action by government and nongovernment organizations to encourage the population to reduce the consumption of obesogenic diet and increase physical activity through education and legislation. The impact of such interventions should be monitored by conducting population‐based cohort studies and establishing comprehensive national registries.

Diagnostic Workup: A Resource‐Sensitive Approach

NAFLD is usually asymptomatic. The diagnosis is based on: (1) documenting hepatic steatosis on imaging or histology, (2) lack of excessive consumption of alcohol, and (3) ruling out other causes of steatosis and/or chronic liver diseases (CLDs). Because the Middle East encompasses countries with variable resources, a cost‐sensitive approach is recommended.11

The workup of NAFLD is based on history and physical examination, laboratory investigations, imaging, and liver biopsies (Table 2). Clinical assessment requires few resources and has the following goals: (1) identifying high‐risk individuals; (2) excluding competing causes of CLD and hepatic steatosis, especially excessive alcohol intake; and (3) detecting signs of complications such as portal hypertension and hepatic decompensation.

Table 2.

Workup of Patients With Suspected NAFLD11, 12

Parameter	Remarks
History
Excessive alcohol consumption	>30 g/day in men, >20 g/day for women Corticosteroids, methotrexate, amiodarone
Medications
T2DM
Hypertension
Dyslipidemias
Physical examination
BMI	Obesity defined as ratio of ≥0.9 in men and ≥0.85 in women Upper limit for BP 130/85 Splenomegaly, caput medusae
Waist‐to‐hip ratio
BP
Signs of portal hypertension
Laboratory tests for DM and MetS
Fasting glucose	Normal 100 mg/dL Normal <5.7%
Lipid profile
Hemoglobin A1c
Serum aminotransferase levels	Can be normal in patients with NAFLD Consider upper limit of normal 35 IU/L in men and 25 IU/L in women Usually levels in NAFLD <300 AST:ALT ratio >1 is suspicious of cirrhosis
Serum bilirubin	Remains normal until decompensation
Platelet count	Thrombocytopenia may indicate cirrhosis
FIB‐4	Calculated on the basis of age, AST, ALT, and platelet count Inaccurate for those <35 years old Reduced sensitivity with increased age Lower cutoff 1.3 (<65 years old), 2 (≥65 years old) Upper cutoff 2.67 28% of patients have indeterminate scores
Tests for other liver diseases
HBsAg and anti‐HCV	Endemic in the Middle East Markers of autoimmune hepatitis, may be positive at low titer in NAFLD but with normal immunoglobulins To rule out Wilson’s disease in patients <45 years old Celiac disease
ANA, ASMA
Ceruloplasmin
Anti‐tissue transglutaminase antibody
Imaging
Ultrasound	Low sensitivity for mild steatosis More quantitative than ultrasound
MRI
Liver biopsy	Gold standard test to assess steatosis, inflammation, and fibrosis Cannot distinguish NAFLD from alcoholic liver disease

Laboratory investigations should include screening for diabetes mellitus (DM) and dyslipidemia. A low platelet count on complete blood count (CBC) can hint to the development of cirrhosis. Serum aminotransferases are inexpensive and readily available but can be “normal” in patients with NAFLD. American Association for the Study of Liver Diseases cutoffs should be used as reference values to enhance the sensitivity of transaminase levels in detecting liver disease. Several noninvasive scoring systems for assessing fibrosis, such as Fibrosis‐4 score (FIB‐4) and NAFLD Fibrosis Score, use transaminase levels. These scoring tools can help primary care providers select high‐risk patients who need referral to specialized centers for further evaluation. When testing for competing causes of CLD, priority is given to ruling out chronic hepatitis B and C infections that are endemic to the region. Once viral hepatitis is excluded, consideration can be given to testing for less frequent causes of liver disease, such as autoimmune hepatitis, Wilson’s disease, and celiac disease, according to the clinical setting and availability of resources. Testing for genetic hemochromatosis is probably unwarranted because the responsible gene mutations are rare in ethnic groups residing in the Middle East.

Imaging tools include ultrasound, computed tomography, and magnetic resonance imaging (MRI). Ultrasonography is the imaging modality of choice due to its low cost. MRI Proton Density Fat Fraction is the most accurate noninvasive imaging tool for the assessment of steatosis, but it is expensive and requires special expertise. Measurement of liver stiffness using transient elastography has been validated as a reliable tool in assessing fibrosis. However, in most Middle Eastern countries, this technology is available only in secondary or tertiary care settings.

Finally, when noninvasive measures are inconclusive or competing liver diseases are suspected, liver biopsy is recommended. It is the gold standard in assessing steatosis, inflammation, and fibrosis, but is invasive and expensive.

The detailed workup presented in Table 2 may not be tenable in all health care systems in the Middle East. Table 3 summarizes diagnostic options taking into consideration available resources.11 An important caveat is that in the Middle East, published data regarding the performance of the noninvasive diagnostic tools of hepatic fibrosis in the setting of NAFLD are still lacking.

Table 3.

Resource‐Sensitive Diagnostic Workup of Suspected NAFLD

Minimal Assessment (Limited Resources)	Optional Tests (Medium Resources)	Additional Tests
History of alcohol consumption Drug history (corticosteroids, methotrexate, amiodarone, tamoxifen, others) BMI Waist‐to‐hip ratio BP CBC Fasting glucose, lipid profile AST, ALT, ALP, albumin Determine FIB‐4 score HBsAg, anti‐HCV Ultrasound	Markers of: Autoimmune hepatitis Wilson’s disease Celiac disease Hemoglobin A1c Transient elastography	MRI Liver biopsy

Modified with permission from Journal of Clinical Gastroenterology.11 Copyright Wolters Kluwer Health, 2014.

Management of NAFLD

Fig. 2 illustrates a roadmap for the management of NAFLD.12 Low‐risk patients with NAFLD can be managed in primary care facilities, whereas high‐risk patients should be referred to specialist care. The mainstay of therapy of NAFLD is directed toward optimizing the treatment of the MetS by weight reduction, exercise, and pharmacological therapy of diabetes, dyslipidemia, and hypertension. Vitamin E and pioglitazone may be used in carefully selected patients.2 Morbidly obese patients (body mass index [BMI] > 40) and those with a BMI of 35 to 40 who have obesity‐related complications may be considered for bariatric surgery. Patients with cirrhosis need monitoring for decompensation, portal hypertension, and HCC.

Figure 2.

Resource‐sensitive pathway for the diagnosis and staging of NAFLD. Adapted with permission from European Medical Journal.12 Copyright 2018, European Medical Group, Ltd. Covered under the Creative Commons License.

Conclusion

NAFLD is a major cause of liver dysfunction in the Middle East. Several diagnostic pathways have been proposed, taking into consideration cost and local expertise. Once validated, these pathways can be used as part of a comprehensive action plan for early identification of individuals at risk, linkage to care, appropriate intervention, and follow‐up.