Regression of Cirrhotic NASH Lesions by Diet and Physical Activity

El kharrazi A, Mutumwinka NM, Nguimtsa Tenefo F, Cherkaoui Tangi H, Diallo Kindy I, Bokana EI, Benhasin FZ, Medmoun M, Zougmore HT and Cadranel JFD

Published on: 2025-07-17

Abstract

We report the case of a 59-year-old female patient with risk factors for MASLD and non-insulin-dependent diabetes with moderate android obesity who presented with cirrhosis related to NASH confirmed by liver biopsy, and thanks to diet treatment combined with regular physical activity, the patient lost 11.5 kilograms. A liver biopsy four years after the first showed complete regression of fibrosis. This was corroborated by several tests, including non-invasive blood markers and elastometry and liver biopsy.

Keywords

NASH; Metabolic risk factors; Fibrosis; Hygienic-dietary measures

Introduction

Metabolic steatosis liver diseases, now known as Metabolic Dysfunction-Associated Steatosis Liver Disease (MASLD) to replace the former Non-Alcoholic Fatty Liver Disease (NAFLD), correspond to the hepatic expression of the metabolic syndrome and are characterized by the accumulation of fat in the liver, irrespective of excessive alcohol consumption [1]. NAFLD is the leading cause of liver disease worldwide, with a prevalence of around 30% [2]. Of these patients, around 25% present hepatic inflammation with hepatocyte damage, henceforth known as NASH for Metabolic Dysfunction-Associated Steatohepatitis, replacing the former term Non-Alcoholic Steatohepatitis (NASH). This inflammation promotes the development of liver fibrosis, which progressively worsens until cirrhosis is reached [3].

MASLD is associated with type 2 diabetes, dyslipidemia, hypertension, and obesity. The worldwide prevalence of MASLD is 55.5% in type 2 diabetic patients [4] and 70% in overweight and obese adults [5].

Type 2 diabetes and obesity (particularly android obesity) are the metabolic pathologies with the greatest impact on the natural history of MASLD, including progression to advanced fibrosis, cirrhosis, and related hepatocellular carcinoma [3]. MASLD is associated with a greater risk of morbidity and mortality. The most frequent causes of death are cardiovascular disease, non-hepatic malignancies, and liver pathologies [6]. The more advanced the fibrosis (F3-F4), the greater the risk of death. Apart from the application of hygienic and dietary rules enabling weight loss, there is currently no specific validated treatment for MASLD in France [3,6,7], apart from morbidly obese patients for whom obesity surgery may be discussed.

Medical Observation

This is the case of a 59-year-old patient, seen in a gastroenterology and hepatology consultation for the first time in June 2012 for a diagnosis of metabolic steatopathy retained on clinical, biological, and radiological criteria.

Her medical history included epilepsy treated with levetiracetam 500 mg daily, non-insulin-dependent type 2 diabetes treated with metformin 1000 mg daily, hypothyroidism treated with levothyroxine 75 mg daily, and fibromyalgia treated with analgesics. She was moderately obese (weight: 71 kg, height: 148 cm with a BMI of 32.4), with no alcohol consumption, no smoking, and no other hepatotoxic drugs.

Clinically, the patient was asymptomatic at the time of consultation, apart from moderate asthenia and fibromyalgia, with predominantly android obesity, with a calculated umbilical circumference of 119 cm.

Table 1: Initial Biological Work-Up.

Liver Function Tests
ASAT	52.7ui/l (<31UI/L)
ALAT	76.8UI/L (<32UI/L)
PAL	87UI/L (<105UI/L)
GGT	26UI/L (<40UI/L)
BT	4.3 mg/l (<17mg/l)
TP	100%
Carbohydrate Balance
Blood glucose	0.93g/l
Glycated hemoglobin	6,9% (4 a 6%)
Lipid Balance
Total cholesterol	2.36g/l (1.40 to 2.35g/l)
Triglycerides	1.71g/l (<1.80g/l)
HDLc	0.43g/l
LDLc	1.59g/l
TSH	6.10 micUI/ml (0.550 to 4.7)
Uric acid	3 mmol/l (2.5 to 7.5mmol/l)
Ferritin	202ng/ml (13 to 150 ng/ml)
Renal Function
Urea	0.33g/l (0.1 to 0.5g/l)
Creatinine	70.8 micromol/l (44 to 79.7 micromol/l)

The initial laboratory work-up revealed a slightly disturbed hepatic work-up with ALT 2.4*N (76.8 ui/l), ASAT 1.7*N (52.7 ui/l), increased ferritinemia (202 ng/ml), normal uric acid, normal lipid work-up, nominal renal function, and glycated hemoglobin slightly increased to 6.9%. The other work-ups were normal in particular (CBC, PT, AFP, viral serologies, and autoimmunity work-up).

Radiological investigations began with a hepatic ultrasound scan, which showed a globally hyperechoic liver suggestive of fat and/or iron overload without any nodular formation.

The workup was subsequently completed by a hepatic MRI, which confirmed hepatic fat overload with steatosis estimated at 58%, with the presence of a dysmorphic liver and irregular contours.

Figure 1: Hepatic Steatosis (Hepatic MRI).

The initial fibro scan was not interpretable given the android obesity, but noninvasive blood tests for fibrosis assessment suggested possible fibrosis (FIB-4 a 2.3, fibrotest a 0.69).

A liver biopsy was performed, which revealed altered hepatic architecture with extensive, septal, sometimes nodular portal fibrosis, with images of patchy necrosis, with vacuoles of steatosis affecting around 35% of the hepatocytes, with no abnormalities of the sinusoids and centro-lobular veins, nor biliary overload. The METAVIR score was A2F4.

Figure 2: Macro Vacuolar Steatosis with Severe Fibrosis F3-F4.

Based on his clinic-biological, radiological, and histological findings, the diagnosis of steatohepatitis with extensive fibrosis and incipient cirrhosis was confirmed.

The patient was put on several non-specific treatments for steatosis (AUDC 750 mg daily for 1 year, TOCO 500 mg daily for 1.5 years) with no biological improvement in the patient's workups.

She was also regularly monitored by a nutritionist, with the implementation of a balanced diet with well-calculated caloric intake, plus daily physical activity, even though she was hampered by fibromyalgia, and of course follow-up by a diabetologist for her diabetes.

After about a year of diet and physical activity, the patient was able to lose around 11.5 kg, including 10 kg of body fat, over a period of 14 months, moving from moderate obesity (weight 71 kg, BMI 32.2) to overweight (weight 59.5 kg, BMI 26).

Table 2: Weight Parameters Before and After MHD Over 14 Months.

	Before MHD	After MHD
Weight in Kg	71	59.5
Size in cm	148	148
BMI	32,4	26.6
Umbilical perimeter in cm	119	105

During her follow-up, the patient underwent regular check-ups, which showed normalization of the liver balance, with a clear decrease in liver overload on liver MRI, with non-invasive tests of normal fibrosis, including normal FIB-4, and fibroscan elasticity at 6 Kpa.

Figure 3: Transaminase Evolution.

Based on the patient's favorable evolution and the satisfactory results of the previous examinations, the patient underwent a 2nd liver biopsy, 4 years after the first, and the results of the new liver biopsy showed an absence of steatosis with total regression of hepatic fibrosis.

Discussion

This exceptional observation shows the regression of steatohepatitis to cirrhosis, as demonstrated by noninvasive tests and confirmed by a liver biopsy with a normalized liver 4 years later. This was achieved by a balanced diet and daily physical activity, with the aim of moving from moderate obesity to normal weight with a BMI of 26.6, combined with drugs that are not validated for the treatment of NASH (AUDC, vitamin E).

Pathophysiology

NASH is a complex pathology that involves environmental, genetic, and metabolic factors [6]. In fact, an unbalanced diet altering microbiota, combined with a sedentary lifestyle and a predisposing genetic background, can lead to an accumulation of stored energy in the liver and adipose tissue, ultimately responsible for insulin resistance and metabolic disorders [8]. When energy intake exceeds metabolic needs and the body's capacity for elimination, carbohydrates lead to the formation and accumulation of intrahepatic fat through de novo lipogenesis. Thus, the development of NASH seems to depend on the type of carbohydrates and fats consumed [9]. Saturated fatty acids and fructose appear to have a greater impact on the liver. Insulin resistance, present in muscle, adipose tissue, and liver, plays a major role in the pathophysiology of NASH. These phenomena induce oxidative cellular stress, particularly in adipose tissue, with increased circulation of free fatty acids, responsible for systemic inflammation and aggravation of insulin resistance. This insulin resistance is linked to an increase in the prevalence and severity of NASH [6,8].

Certain genetic polymorphisms appear to be associated with worsening liver disease and the development of hepatocellular carcinoma (HCC) in NASH [8,10]

A growing number of studies also suggest a role for the intestinal microbiota [11]. Intestinal dysbiosis appears to be associated with modulation of local immune responses and altered intestinal barrier integrity (increased permeability and reduced mucus secretion), which in turn alters secondary bile acid metabolism and promotes translocation of bacterial products such as lipopolysaccharides from gram-negative bacteria or increased production of trimethylamine or endogenous ethanol [12].

Progressive understanding of the pathophysiology of NASH is enabling the development of specific therapies.

NASH Treatment

Effect of Weight Loss on Fibrosis Regression

The recommended first-line treatment is based on weight loss, with diet as the main corrective measure, combined with increased physical activity. The recommendations are based on data from the Promrat and Vilar-Gomez studies, which validate a threshold of 7-10% weight loss for the treatment of NASH [13].

A randomized trial suggested that a reduction in body weight of ≥ 5% is required to reduce steatosis, 7-10% to improve inflammation, and 10% to improve liver fibrosis [14].

A specific diet is recommended. Prescriptions based on caloric restrictions of 500-1000 kcal/d and limitation of carbohydrates and animal fats are associated with a greater reduction in markers of insulin resistance and intrahepatic steatosis [13]. Nutritional management is adapted on a case-by-case basis according to the causes of obesity and must be thoroughly investigated.

Which Physical Activity to Prescribe?

Regarding physical activity, the EASL-EASD-EASO, ASSLD, and ESPEN, in agreement with the WHO, recommend regular, adapted physical activity of moderate intensity for at least 150 minutes a week, or vigorous activity for at least 75 minutes a week [3,6,7]. Several studies have demonstrated improvement in the histological lesions of MASLD, proportionally to the intensity of physical exercise. The effect seems even greater when physical activity is combined with dietary advice.

Incentives are not enough. In fact, almost 50% of patients do not consider increasing their physical activity simply on the basis of a medical recommendation [14]. In this context, prescribing physical activity enables patients to commit to a group program.

APA (adapted physical activity) is recommended for patients with diabetes, obesity, and a history of cardiovascular disease.

Is There a Drug Treatment for NASH?

First, optimizing the management and treatment of comorbidities associated with NASH (type 2 diabetes, arterial hypertension, dyslipidemia, etc.) is an essential prerequisite. In the case of dyslipidemia (notably high LDL-cholesterol), prescription of a statin is recommended to prevent cardiovascular complications [15]. This prescription is possible and seems to be relatively well tolerated in the case of MASLD.

Although statins do not have a specific marketing authorization for SAMLD [6], several studies suggest that taking statins is associated with a reduced risk of SAMLD, NASH, and liver fibrosis, as well as a reduced risk of hepatic decompensation, mortality, and liver cancer in people with cirrhosis [3].

Metformin or SGLT2 inhibitors, used for their respective indications, namely type 2 diabetes, heart failure, or chronic kidney disease, can be used safely in NASH [16,17].

As far as NASH-specific therapies are concerned, only RESMETIROM has been granted marketing authorization by the US Food and Drug Administration (FDA) in March 2024. This oral beta-thyroid receptor (β-TRH) analog, targeting only the liver, is specifically designed to treat patients with NASH with moderate to advanced hepatic fibrosis (corresponding to F2 and F3 stages of the disease) associated with regular, adapted physical exercise [18].

Role of Bariatric Surgery?

Bariatric surgery is the most radical and effective treatment for achieving significant and lasting weight loss in morbidly obese patients, particularly diabetics, with an improvement in comorbidities. Its impact on NASH has yet to be demonstrated.

The SOS (Swedish Obese Subjects) study showed an improvement in transaminases that persisted after 10 years of follow-up [19].

The multicenter, open-label, randomized BRAVES study demonstrated histological resolution of MASH without worsening fibrosis in 55% of patients who underwent Roux-en-Y gastric bypass or sleeve gastrectomy after one year of follow-up, versus 15% in the group that modified his way of life in intentional analysis [20].

In France, bariatric surgery is recommended by the Haute Autorite de Sante (HAS) in the event of failure of dietary management and after discussion and collegial validation during a dedicated RCP for patients with a BMI ≥ 40 kg/m² or in patients with a BMI between 35 and 40 kg/m² and metabolic steatohepatitis (MASH) or liver fibrosis (any stage of fibrosis) [21]. Isolated steatosis is not an acceptable comorbidity for indication of bariatric surgery. Bariatric surgery may be proposed in cases of compensated cirrhosis CHILD-PUGH A after discussion within a trained multidisciplinary team including at least one hepatologist, as the risk of complication is very high [3,21]. It is formally contraindicated by all learned societies in cases of decompensated cirrhosis (CHILD-PUGH B and C).

In our clinical case, the patient did not benefit from bariatric surgery, as improvement was achieved through diet and physical activity.

Conclusion

Optimization of drug and non-drug management and co-morbidities (obesity, type 2 diabetes, dyslipidemia) is essential to limit the development and progression of metabolic liver disease. This case study shows significant results of weight loss and diet on the regression of liver fibrosis associated with cirrhosis-stage NASH.

Journal of Clinical Gastroenterology and Hepatology Research