Key Messages from 2 Recent Studies on NAFLD Severity in People with Type 2 Diabetes

Introducing Professor Laurent Castera

PanNash presents Professor Laurent Castera, MD, PhD, leading expert in Hepatology at the University of Paris and Beaujon Hospital in Clichy, France.

Today, he will share insights from two recent studies focusing on the severity of non-alcoholic fatty liver disease (NAFLD) in individuals with type 2 diabetes.

OVERVIEW OF Key Messages from 2 Recent Studies on NAFLD Severity in People with Type 2 Diabetes

The Rise of NAFLD: The Most Prevalent Liver Disease

As healthcare professionals are aware, NAFLD, non-alcoholic fatty liver disease, is steadily emerging as the most prevalent liver disease worldwide. Professor Castera references a comprehensive meta-analysis spearheaded by Dr Zobair M. Younossi and his team.

This analysis, encompassing 92 studies and nearly 10 million subjects, reveals an alarming prevalence of NAFLD, around 30%, peaking at an astounding 44% in Latin America. These findings’ depth and breadth underscore the urgent need for a robust response to this escalating health challenge.

Bridging the Gap: Primary Care, Liver Clinics and Diabetes Clinics

In everyday clinical practice, most patients with NAFLD are initially seen in primary care. They can be identified by risk factors such as age over 40 years, type 2 diabetes, obesity, and metabolic syndrome. The challenge lies in identifying those with advanced fibrosis (stages 3 and 4) who are most at risk of severe liver outcomes and mortality.

Many pathways have been proposed recently using non-invasive tests to facilitate seamless patient transitions from primary care to specialized liver clinics.

Furthermore, efforts should extend to creating links for patients from diabetes clinics to liver clinics, given the significant role T2D plays as the most important risk for NAFLD.

Prevalence of NAFLD is Higher in T2D Patients

Referencing a meta-analysis published four years ago by Dr Younossi, Professor Castera reveals an alarming fact: in a population of approximately 50,000 patients with type 2 diabetes, NAFLD prevalence is twice that of the general population, at a whopping 55%.

NAFLD is More Severe in T2D Patients

Though, intriguingly, NAFLD appears more severe in patients with type 2 diabetes, the current evidence supporting this claim is limited. There are few studies to date – only 10 – and they encompass fewer than 1,000 liver biopsies.

The reported prevalence of NASH is about 70%, while advanced fibrosis is 17%. However, these figures are derived from even fewer studies – just seven – and fewer than 500 liver biopsies.

Moreover, the confidence intervals associated with these findings demonstrate substantial variability, indicating a need for more comprehensive research in this area.

Limitations of Current Studies

Several limitations constrain the current understanding of NAFLD and its prevalence, particularly among patients with type 2 diabetes. One primary constraint is that population-based epidemiological studies often lack liver histopathology data, which is crucial for accurate NAFLD diagnosis and severity assessment.

Additionally, studies that do employ liver histopathology often suffer from their own set of issues. They are generally limited in size, with small participant pools. They may also suffer from spectrum bias, as there is a tendency to biopsy those patients who exhibit more severe symptoms, which may not accurately represent the broader population. Further limitations include varied case definitions and, most importantly, a lack of clear indications for performing a liver biopsy.

Consequently, due to these numerous constraints, the true prevalence of NASH and advanced fibrosis (stages F3-F4) in patients with type 2 diabetes remains largely unknown. Future research needs to address these limitations to provide a more accurate picture of the situation.

Two Studies on NAFLD in Type 2 Diabetes Patients

Recently, two significant studies were published in 2023 addressing the critical issue of NAFLD among patients with type 2 diabetes.

• The first study, hailing from the United States and led by Dr Rohit Loomba’s group in San Diego, focused primarily on the prevalence of NAFLD, advanced fibrosis, cirrhosis, and hepatocellular carcinoma (HCC) among individuals with type 2 diabetes.
• The second study, alternatively, is part of the QUID-NASH project originating from four different centers in Paris, France. This research aimed to determine the prevalence of non-alcoholic steatohepatitis (NASH) and advanced fibrosis in individuals with type 2 diabetes.

These two studies have been instrumental in shedding light on the intersection of NAFLD and type 2 diabetes, further contributing to our understanding of this multifaceted health concern.

Summary: high prevalence of F3F4 in T2D

The key findings of these studies paint a critical picture of the prevalence of NAFLD and its associated conditions in patients with type 2 diabetes.

In the American population:

• The prevalence of NAFLD was 65%
• While advanced fibrosis was seen in 14% of patients
• Cirrhosis in 6%.

When we turn to the results from the French study, liver biopsy-based prevalence showed that:

• NASH was present in 58% of patients,
• While 38% had advanced fibrosis
• 10% had cirrhosis

The above results underline a high prevalence of advanced fibrosis (F3-F4) in patients with type 2 diabetes. This overview paves the way for a deeper exploration into the specifics of these studies and their significant findings.

Design, Setting, and Target Population

The two studies conducted in the United States and France differ significantly in their design, settings, and target populations. Here’s a detailed breakdown:

American Study

• Design: This study was a single-center prospective research initiative.
• Duration: The research took place over a significant duration, spanning from 2016 to 2022.
• Setting: The research setting was a liver clinic that worked in conjunction with referrals from primary care and diabetes clinics.
• Target Population: The study focused on a specific group – almost 500 patients with type 2 diabetes, around the age of 50, and all suspected of having Non-alcoholic Fatty Liver Disease (NAFLD).

French Study

• Design: In contrast to the American study, the French research was a multi-center prospective study.
• Duration: The French study had a relatively shorter duration, operating from October 2018 to March 2021.
• Setting: The study was conducted within a tertiary diabetes clinic where hepatologists conducted annual work-ups and interacted with the patients.
• Target Population: Out of 713 patients enrolled in the study, 330 underwent a liver biopsy. This study didn’t impose any age restrictions, and all participants had a confirmed diagnosis of NAFLD.

It’s important to consider these differences when interpreting the results, as they could influence the findings and their applicability to different contexts and populations.

Reference Standard

Both the American and French studies utilized different reference standards in their research:

American Study

• Non-invasive Tests and Liver Biopsy: The reference standard for the American study incorporated both non-invasive tests and a liver biopsy for a subgroup of patients.
• NAFLD Definition: Non-alcoholic Fatty Liver Disease (NAFLD) was characterized by an MRI-PDFF exceeding 5% or a CAP exceeding 288 dB/m.
• Advanced Fibrosis: Advanced fibrosis was identified by a liver stiffness measurement above 3.63 kPa using MRE or above 8.8 kPa using transient elastography.
• Liver Biopsy: A total of 134 patients underwent a liver biopsy, with indications including elevated ALT with steatosis, liver stiffness approximately 7 kPa by transient elastography or MRE 2.65, MRE above 3.63, or MRI-PDFF above 10%.

French Study

• Liver Biopsies: The French study solely relied on liver biopsies performed on 330 patients.
• Standardized Indications: Indications for a liver biopsy were standardized based on pre-set criteria, such as a low ALT threshold (20 IU/L for females, 30 IU/L for males), no consideration of non-invasive tests, and the absence of other causes of liver disease.
• Pathological Analysis: The biopsies were centrally read by a single pathologist, Pierre Bedossa.
• Transjugular Route: In cases of morbid obesity or the presence of anticoagulants, a transjugular route for biopsy was used, applicable to about one set of patients.

These varying reference standards can influence the study results and should be taken into account when comparing the findings.

Demographic and Clinical Profile of NAFLD Population

Delving into the demographic and clinical characteristics of the NAFLD population, we find substantial variations in the patient profiles across the two studies.

• Age and Gender: Patients in the American study were generally older compared to the French study, with a higher proportion of females (63% vs. 37% in the French study).
• Body Mass Index (BMI) and Diabetes Duration: While the BMI and diabetes duration were similar across both studies, it is worth noting that the American study reported lower A1c levels.
• Liver-Related Parameters: Concerning ALT levels, platelet counts, CAP, and liver stiffness measurements, the American study generally reported lower values, albeit not drastically different from those in the French study.

Switching our focus to the subgroup of NAFLD patients, despite initial disparities in age and gender, the characteristics were largely consistent across both studies. They included:

• BMI and Treatment: Both studies reported comparable findings in terms of BMI and treatment received.
• Diabetes Duration and A1c Levels: Interestingly, diabetes duration was shorter and A1c levels were lower in the subgroup of NAFLD patients.

In summary, while there were some differences in the demographic and clinical profiles between the two populations, the core clinical characteristics amongst the NAFLD patients were strikingly similar. This comparison gives us valuable insights into the typical profile of a patient with NAFLD and coexisting type 2 diabetes.

Characteristics of the F3F4 population

Shifting our attention to the subsets of patients with advanced fibrosis (F3F4), we see interesting commonalities in the American and French studies. These groups consisted of 69 patients from the US study and 124 patients from the French study.

• Age and Gender: As with the broader NAFLD population, disparities in age and gender were observed across the two studies.
• BMI and Diabetes Duration: As seen previously, the BMI and diabetes duration were similar in both studies.
• A1c Levels: In line with the previous trend, A1c levels were slightly lower in the US study.
• Liver Stiffness: The two groups saw A clear difference in liver stiffness measurements.

In essence, despite analyzing different patient populations, we observe striking similarities when we compare the same subset of patients (those with advanced fibrosis). These parallels in characteristics suggest that the profile of a patient with NAFLD, type 2 diabetes, and advanced fibrosis (F3F4) could be fairly consistent across different geographical and demographic settings.

Prevalence of NASH and F3F4 on Liver Biopsies

In an intriguing comparison within the subgroups of patients who underwent liver biopsies, similarities in the prevalence of NASH and advanced fibrosis (F3F4) were also observed.

• NASH Prevalence: The presence of NASH was almost equal in both groups, with 61% in the US study versus 58% in the French study.
• Advanced Fibrosis (F3F4) Prevalence: While the prevalence of advanced fibrosis was somewhat lower in the US study at 30% compared to 38% in the French study, the figures are still comparable.
• Cirrhosis Prevalence: The incidences of cirrhosis were remarkably similar, with 9% in the US study compared to 10% in the French study.

These observations further reinforce that despite geographical and study design differences, the prevalence of NASH, advanced fibrosis, and cirrhosis among NAFLD patients with type 2 diabetes is largely similar in different populations.

Role of Comorbidities

What was the role of comorbidity? A vital aspect to consider in these studies is the role of comorbidities, particularly obesity, in exacerbating the risk of advanced fibrosis.

• Obesity: Obesity was found to be a significant comorbidity contributing to the increased risk of advanced fibrosis in both studies. In the American study, the prevalence of advanced fibrosis was two times higher in obese patients than non-obese patients.
• Waist Circumference: In the French study, waist circumference was a crucial factor. A multivariate analysis identified measurements above 102cm in males and 88cm in females as independent predictors of advanced fibrosis.

The association between obesity and advanced fibrosis underscores the importance of weight management strategies in managing and potentially mitigating the progression of NAFLD in type 2 diabetes patients. It also highlights the potential utility of waist circumference as a simple, non-invasive measure to identify individuals at higher risk of advanced fibrosis.

Predicting F3F4: Non-Invasive Models With and Without VCTE

A critical component of managing NAFLD in T2D patients is the use of non-invasive models and tests. The French study provided some insights into the efficacy of different models:

• FIB-4 Alone: FIB-4 is a model that uses age, transaminases, and platelet count to predict the severity of fibrosis. When used alone, it demonstrated mediocre performance, with an AUROC (Area Under the Receiver Operating Characteristic) of 0.71, and the percentage of correctly classified patients (true positives and true negatives) was less than 35%.
• Enhanced FIB-4 Model: A model that incorporated FIB-4, waist circumference, GGT (Gamma-glutamyl Transferase), and HDL cholesterol showed improved performance. This resulted in a higher number of correctly classified patients and a significantly higher AUROC. This model is notable for not using transient elastography (FibroScan), a technology that isn’t widely available in most diabetes clinics.
• Model With Transient Elastography: If transient elastography is available, integrating it into the model can significantly enhance the AUROC and increase the percentage of correctly classified patients.
• Comprehensive Model: A model combining FIB-4, HDL cholesterol, and FibroScan didn’t significantly improve the number of correctly classified patients or the AUROC compared to the model with transient elastography. This suggests that if FibroScan isn’t available, health professionals can still effectively screen their patients using simple, widely available, and inexpensive data.

This analysis underscores the importance of choosing the appropriate predictive model for NAFLD in T2D patients and the potential benefits of using a model that incorporates a variety of parameters, including anthropometric, biochemical, and liver stiffness measurements.

Key Takeaways

• Type 2 Diabetes (T2D) patients with Non-alcoholic Fatty Liver Disease (NAFLD) attending outpatient diabetes clinics have a high prevalence of advanced fibrosis and NASH. This is often the case even when liver-test abnormalities are mild. This emphasizes the need to choose lower thresholds for abnormal ALT levels, specifically 20 IU/L in women and 30 IU/L in men.
• This high prevalence of advanced fibrosis and NASH has often been overlooked due to the lack of available data and the low awareness of NAFLD in diabetes clinics.
• Patients above 50 years old and those who are obese are at the highest risk of developing advanced fibrosis.
• Routinely available parameters can help identify many of these high-risk patients who require further liver assessment. Once identified, they can be linked to appropriate care with a liver specialist.

In conclusion, it’s crucial that patients with type 2 diabetes are systematically screened for liver fibrosis in diabetes clinics. This will help ensure that those with NAFLD and those at risk of developing more serious liver conditions receive the care they need.