Non-alcoholic fatty liver disease in a patient with maturity onset diabetes in the young

Abstract

We present the case of a 34-year-old man who was first seen in our clinic in 2003. His α-glutamyl transferase (GGT) was raised but the rest of the liver function tests (LFTs) and liver screen were normal. He was diagnosed with maturity onset diabetes of the young (MODY) when he was 21 years old. Abdominal ultrasound showed fatty liver disease. Liver biopsy in 2006 showed non-alcoholic fatty liver disease (NAFLD). This combination has rarely been described in the medical literature. Metformin and gliclizide was started and weight reduction advised. Despite this there is no change in his LFTs, and in 2008, his GGT concentration was even higher. This condition is challenging because of the limited treatment options. Globally, NAFLD is rising and complications such as liver cirrhosis can be seen commonly. NAFLD in a patient with MODY needs thorough attention.

BACKGROUND

• A case like this has not been reported before.

• There is very little information about non-alcoholic fatty liver disease (NAFLD) in maturity onset diabetes of the young (MODY) in the existing medical literature.

• We feel that this case highlights a new perspective on NAFLD and diabetes.

• This case poses a treatment challenge.

• If other colleagues have seen cases like this, we hope this report will give them the motivation to correspond on the condition in order to study NAFLD in MODY in more detail in the future.

• We welcome any suggestions regarding further management of such patients as the one reported here.

CASE PRESENTATION

A 34-year-old man was referred to the diabetic clinic with abnormal liver function tests. He was diagnosed with MODY in 1998 at the age of 21, since when he has been on dietary control. He had no abdominal symptoms and no history to suggest any form of liver disease. He had no risk factors for hepatitis and his weekly alcohol intake was 7 units (<20 g/day). He, his father and his aunt were diabetic and had undergone genetic testing which showed an HNF1α mutation. His body mass index (BMI) was 25.6 kg/m² and abdominal circumference was 96.5 cm. Examination did not show any stigmata of chronic liver disease. He worked in an office with a sedentary lifestyle and originally did not closely follow any particular diet plan or exercise regimen. The first liver function tests (LFTs) conducted by his general practitioner in 2003 showed moderate elevations of γ-glutamyl transferase (GGT) at 296 U/l, aspartate aminotransferase (AST) at 44 U/l, and alanine aminotransferase (ALT) at 46 U/l. Bilirubin was normal, ferritin was 223 μg/l (male, normal range (NR) 20–275 μg/l) and saturation was 30.4%. Hepatitis and autoantibody screenings were negative. Serum copper was 16 μml/l (NR 12.6–26.7 μml/l) and ceruloplasmin was 0.17 g/l (NR 0.21–0.58 g/l), which was slightly low. Repeat liver function tests remained unchanged over time. An ultrasound scan of the liver showed increased echogenicity, in keeping with diffuse fatty infiltration. No focal parenchymal abnormality was identified. The rest of the ultrasound examination was unremarkable.

In 2006 an ultrasound guided liver biopsy was performed and a core sample was obtained from the right lobe using an 18 gauge Somatex needle. It showed maintenance of the overall liver architecture. Diffuse macrovesicular steatosis was seen throughout the core (fig 1). One or two foci of lobular inflammation of cells indicated steatohepatitis. Masson trichrome staining showed no significant fibrosis. Orcein stain for copper was negative (fig 2). These findings were consistent with non-alcoholic fatty liver disease. Metformin 500 mg twice a day was added to gliclazide 80 mg once a day and advice on weight reduction given. The patient’s BMI remained unchanged at 27.7 kg/m². During 2007 his LFTs remained the same, with GGT at 350 U/l, and AST and ALT normal. He stopped drinking alcohol. In 2008, GGT measured 544 U/l with otherwise normal LFTs. His recent BMI was 27.7 kg/m² and glycosylated haemoglobin (HbA1c) was 9.4%. The dosage of metformin was increased to 1 g twice a day, together with gliclazide 160 mg twice a day.

Figure 1.

Macrovesicular steatosis with minimal lobular inflammation showing non-alcoholic fatty liver disease.

Figure 2.

Negative orcein stain showing no copper disposition.

TREATMENT

The treatment administered to the patient has included: metformin 1 g twice a day; gliclazide 160 mg twice a day; aspirin 75 mg once a day; atorvastatin 10 mg once a day; ezetimibe 10 mg once a day; and lisinopril 10 mg once a day.

OUTCOME AND FOLLOW-UP

We have been following this case for some time but the problem is still very evident. There is worsening of the patient’s GGT concentrations and we feel that standard treatment is not as helpful as might be expected. We are keeping a watchful eye on the patient and would welcome any useful comments from colleagues reading this case report.

DISCUSSION

Fajans first reported youth onset diabetes in individuals who were not dependent on insulin.¹ Later Tattersall published a report describing non-insulin dependent diabetes presenting in a youth.² A joint report from Tattersall and Fajans followed in which the term “MODY” was used for the first time.³ MODY is due to a genetic mutation. It affects nearly 1–2% of people with diabetes in the UK. MODY results from a change in a single gene that is passed from a parent carrying the affected gene to their child. Children of an affected parent have a 50% chance of inheriting the affected gene and developing MODY themselves. Hyperglycaemia may be so mild as to escape diagnosis.⁴ MODY can result from mutations in at least six different genes; one encodes the glycolytic enzyme glucokinase, which is an important glucose sensor, whereas all the others encode transcription factors that participate in a regulatory network essential for adult β cell function.⁵ So far, six MODY genes have been identified (MODY1–6).⁶

Non-alcoholic fatty liver disease, on the other hand, is a well recognised problem facing the medical community and is challenging health providers all over the world. Fatty liver in diabetes was mentioned in the pre-insulin treatment era of the 18th century. Notable liver enlargement was well known in younger patients.⁷ In the last two decades this has become a major cause of chronic liver disease in the western world. Recent ultrasound studies suggest a 70% prevalence of NAFLD in type 2 diabetic patients.⁸ Recent trends in diet and metabolic syndrome indicate the huge task facing the medical community in the diagnosis, treatment and prevention of NAFLD. Unfortunately, data available for UK patients is scarce but the trend can be elucidated by studies in other parts of the western world. Among children the prevalence of abnormal LFTs in the USA ranges from 6% in the overweight group to 10% in obese children.⁹ Studies from Italy and Japan report that 10–25% of children referred for obesity have elevated aminotransferases. In one US study 50% of children with diabetes had abnormal liver biochemistry.¹⁰ Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in developing countries. Many of the risk factors are well defined, but the underlying pathogenesis is not well understood. The demographics of the condition mirror those of the metabolic syndrome, with obesity and insulin resistance being the most commonly associated conditions.¹¹ NAFLD is predicted to become a major cause of cirrhosis requiring transplantation in the future,¹² but recurrence in the transplanted liver has also been described.¹³ At present, management is aimed at correcting risk factors, but there are no proven therapies at this point. Recent data reviews shows that weight reduction with regular exercise and dietary control is helpful in the treatment plan, with improvement of metabolic parameters.¹⁴

In the medical literature, NAFLD has rarely been described in MODY. It is hard to establish a causative relationship between MODY and NAFLD in the absence of evidence based literature. No treatment is presently licensed for NAFLD. Trials of thiazolidinediones in small numbers of patients showed limited benefits.¹⁵ The lack of effective treatment for the patient reported here is worrying as there is a risk for future development of steatohepatitis and cirrhosis. It is unlikely this case is one of a kind, since the overall problem of liver disease and diabetes is rising, so it is important to highlight this issue. A combination of NAFLD and MODY can lead to morbidity and mortality at a young age; hence, research and new management strategies for intervention in this condition are urgently needed.

LEARNING POINTS

• Non-alcoholic fatty liver disease (NAFLD) and maturity onset diabetes of the young (MODY) have not been described in the medical literature, but they could be associated with metabolic syndrome and type II diabetes.

• There is no evidence based treatment for this condition.

• The long term prognosis for the patient in this report is a cause for concern.

• More research and treatment strategies are needed to prevent complications of chronic liver disease from developing in patients such as this.