Treatment Resistant Patients with Metabolic Dysfunction-associated Steatohepatitis: Long-term Follow-up Prospective Study.

Abstract

Introduction: Many treatments for patients with metabolic dysfunction-associated steatohepatitis (MASH) have been proposed; however, most studies showed the results for a single medication and a short duration of treatment. The long-term outcomes of the multidrug therapies remain indeterminate. We conducted a study to investigate the usefulness of multidrug combination therapy for every kind of MASH patient and the differences between treatment-sensitive and treatment-resistant patients.

Methods: Fifty-one patients (middle-aged, in their 40s to 60s, metabolic generation) with MASH-determined fibrosis staging were enrolled. Primary treatment (weight control and medication of vitamin E and sodium-glucose cotransporter 2 inhibitor (SGLT2i)) was done and then pemafibrate treatment was added.

Results: Regarding responses to the step-by-step multidrug therapy, patients with MASH were divided into 3 groups, with use of 3 markers-alanine aminotransferase (ALT) (hepatitis), elasticity value (E value, liver stiffness measurement) (hepatitis/fibrosis), and type IV collagen (fibrosis); group 1: sensitive to primary treatment (n = 35), group 2: resistant to primary treatment and sensitive to pemafibrate treatment (n = 11), and group 3: resistant to both treatments (n = 5).To determine the parameters related to treatment resistance, the baseline levels of parameters_-obesity (body mass index), metabolic factor (visceral fat, controlled attenuation parameter), diabetes mellitus (DM) (glycated hemoglobulin (HbA1_c), fasting immunoreactive insulin), lipid metabolism (triglyceride), and hepatitis (ALT)-were compared between treatment-sensitive group 1+group 2 and treatment-resistant group 3. However, none of them had differences statistically. The same analysis showed that type IV collagen, E value, FIB-4 index (age (year) x AST (IU/L)/platelet count (10⁴/L) x ALT (IU/L)^1/2), and MASH fibrosis had differences statistically.

Conclusions: The most effective treatment for patients with MASH could not be determined, according to the baseline levels of characteristics; however, weight control and step-by-step multidrug therapies made it possible to stabilize more than 90% of patient conditions and to solve MASH without worsening fibrosis. Since high levels of liver fibrosis-related markers affected the treatment resistance, MASH treatments should be started in an early stage while the levels of each marker are still low; type IV collagen <5.3 ng/mL, E value <13.7 kPa, FIB-4 index <1.89 and MASH fibrosis stage 2 or less.