IgG4-related pancreatitis: an uncommon cause of hyperglycaemia

Abstract

Hyperglycaemia is one of the most common metabolic disturbances encountered in clinical practice, with an important differential diagnosis. We report a case of a 72-year-old woman referred to diabetes services with rapidly increasing blood glucose and weight loss despite oral hypoglycaemic therapy. She reported mild upper abdominal discomfort and liver function tests were deranged, prompting further investigation. Abdominal imaging demonstrated a diffusely enlarged pancreas and subsequent investigations noted a markedly raised serum IgG4. She was diagnosed with IgG4-related pancreatitis and swiftly responded to steroid therapy. Secondary causes of diabetes should be considered in people with atypical presentation such as weight loss or rapid progression to insulin use. While IgG4-related disease is rare, its varied clinical presentation as a result of its multiorgan involvement requires a high index of suspicion. This case highlights the importance of a detailed diagnostic work-up and describes an unusual clinical presentation of this increasingly recognised multisystem disease.

Background

Sustained hyperglycaemia (blood glucose >11 mmol/L) is a common clinical finding, typically resulting from greater hepatic glucose production than peripheral glucose utilisation. Classically, hyperglycaemia is associated with symptoms such as polyuria, polydipsia, polyphagia, fatigue and occasionally weight loss. While hyperglycaemia typically occurs as a result of type 1 or type 2 diabetes mellitus, clinicians should always consider other causes of hyperglycaemia. Secondary causes of hyperglycaemia include medications (eg, glucocorticoids, β-blockers and thiazide diuretics), pancreatic disease (eg, chronic pancreatitis, pancreatic cancer and cystic fibrosis), endocrine disturbance (eg, Cushing syndrome, pheochromocytoma and acromegaly) and critical illness and stress (eg, sepsis, acute coronary syndromes and cerebrovascular accident).¹ Clinicians should be aware of atypical features, which may be associated with the clinical presentation of hyperglycaemia meriting further investigation.

In this case report, we describe a patient referred to diabetes services with hyperglycaemia as a result of IgG4-related pancreatitis secondary to IgG4-related disease.

Case presentation

A 72-year-old Sri Lankan woman was referred to the diabetes clinic with rapidly worsening glycaemic control. She had been diagnosed with impaired glucose tolerance in May 2017, and impaired fasting blood glucose in October 2017. In August 2018, her glycaemic control deteriorated, and she was diagnosed with type 2 diabetes mellitus initially treated with metformin, though she was switched to gliclazide due to intolerance. She had no other medical or surgical history of note. Nevertheless, while on holiday in Sri Lanka, her glycaemic control continued to worsen with an associated weight loss of 7 kg, prompting the initiation of insulin in October 2018 before returning to the UK. At this time, she also reported gastrointestinal symptoms including increased frequency of formed stools, which were difficult to flush, abdominal bloating and belching. Despite insulin initiation and marked improvement in glycaemic control, the weight loss continued with mild abdominal discomfort and distension.

Investigations

There was a rapid deterioration in glycaemic control, and the glycated haemoglobin (HbA1c) increased from 45 mmol/mol (6.2%) in October 2017 to 78 mmol/mol (9.3%) in August 2018 and 116 mmol/mol (12.8%) in October 2018, shown in figure 1. The alkaline phosphatase and alanine transaminase increased markedly between March and June 2019, presented in figure 2. Her liver autoantibody screen, serum complement levels and tumour markers proved to be unremarkable. A CT abdomen in June 2019 demonstrated segmental dilatation of the intrahepatic bile ducts with non-specific pancreatic changes. Subsequent MRI exhibited widespread irregular intrahepatic biliary duct dilatation without pancreatic duct dilatation, and diffuse enlargement of the pancreatic parenchyma with restricted diffusion, consistent with autoimmune pancreatitis. No focal lesion was identified. This is shown in figure 3.

Figure 1.

A line graph demonstrating changes in the glycated haemoglobin (HbA1c) over time.

Figure 2.

A line graph showing changes in serum alkaline phosphatase and transaminase over time. ALT, alanine transaminase; ALP, alkaline phosphatase.

Figure 3.

An MRI abdomen in June 2019 demonstrating diffuse enlargement of the pancreatic parenchyma with restricted diffusion, consistent with autoimmune pancreatitis.

Differential diagnosis

Diabetes mellitus was diagnosed based on the high HbA1c level and her symptoms. The likely cause was pancreatitis given her alkaline phosphatase and alanine transaminase levels with the CT and MRI findings described above. Further investigation was undertaken to determine the cause of her pancreatitis.

Outcome and follow-up

Further investigations following this patients abdominal imaging were notable for a significantly raised serum IgG4 level at 7.11 g/L (normal range <1.30 g/L) (Siemens BN II Immunonephelometric assay), and faecal elastase was significantly low at <15 μg/g. Her other serum immunoglobulins, protein electrophoresis, lipid profile and coeliac screen were unremarkable, and her amylase was also observed in the normal range (99 U/L; normal range <130 U/L). She was subsequently diagnosed with IgG4-related pancreatitis with exocrine pancreatic insufficiency in July 2019, and treatment with prednisolone (0.6 mg/kg) and pancreatic enzyme supplementation in the form of Creon (lipase, protease and amylase) was initiated. Unsurprisingly, her glycaemic control worsened with prednisolone, requiring increased insulin doses. With treatment, the abdominal symptoms improved and she reported normal stools and less frequent bloating, with a 5 kg weight gain over the following 2 months and improvement in her serum alkaline phosphatase and transaminases. Likewise, her serum IgG4 levels improved swiftly with prednisolone therapy to 2.78 g/L (normal range <1.30 g/L) after 2 months. Indeed, follow-up MRI after 2 months of steroid therapy demonstrated reduced pancreatic bulk with mild persistent restricted diffusion throughout and minimal intrahepatic duct irregularity with no strictures. This is shown in figure 4. We plan to wean the steroid dose gradually over 6 months, which we anticipate will improve the glycaemic control with regular observation of liver function tests and pancreatic imaging.

Figure 4.

An MRI abdomen in September 2019 demonstrating reduced pancreatic bulk with mild persistent restricted diffusion throughout intellectual property rights assignment or licence statement.

Discussion

IgG4-related disease is a rare inflammatory disorder originally described as a cause of autoimmune pancreatitis but more recently recognised to exhibit several systemic manifestations.² Indeed, the clinical presentation of IgG4-related disease is highly variable. Case reports describe obstructive jaundice,³ liver masses,⁴ submandibular gland swelling,⁵ haemolytic anaemia,⁶ headache,⁷ inferior orbital mass,⁸ pericardial effusion,⁹ mastitis¹⁰ and inflammatory arthritis¹¹ as findings at clinical presentation, rendering this a challenging diagnosis to make. Interestingly, there were no extrapancreatic manifestations of IgG4-related disease observed in this case.

The pathological hallmarks of IgG4-related disease include a dense lymphoplasmacytic infiltrate, obliterative phlebitis and an eosinophilic infiltrate with some fibrosis. While the pathophysiology of IgG4-related disease is poorly understood, likely mechanisms include molecular mimicry and autoimmunity.¹² However, it is unclear whether the IgG4 antibodies act directly to mediate tissue damage, or whether the raised IgG4 antibodies are a response to an underlying inflammatory stimulus.¹² Indeed, certain human leucocyte antigen (HLA) alleles (eg, DRB1*0405−DQB1*0401) are important in the development of autoimmune pancreatitis in some Asian cohorts,¹³ which may be relevant to this case. While the reported prevalence of IgG4-related disease was 0.28–1.08/100 000 in Japan in 2012, this is likely underestimated due to under-recognition as a result of its variable clinical presentation.¹⁴

In this case, fine needle aspiration biopsy of the pancreas was not required given the consistency of imaging findings, serum IgG4 levels and the response to empirical steroid treatment. Indeed, the Mayo clinic histology, imaging, serology, other organ involvement and response to therapy (HISORt) criteria¹⁵ are used to confirm the diagnosis of autoimmune pancreatitis and classify patients into diagnostic groups such as those with diagnostic pancreatic histology, typical serology and imaging and those who respond to steroids. Importantly, one study previously observed that the sensitivity and specificity of an IgG4 level ≥1.4 g/L in making a diagnosis of autoimmune pancreatitis were 76% and 93%, respectively.¹⁶ Given the markedly raised IgG4 level of 7.11 g/L, typical imaging findings and clinical, biochemical and radiological response to steroid therapy our patient did not require biopsy to confirm the diagnosis.

Autoimmune diabetes commonly presents with weight loss and worsening glycaemic control. In this case, we did not test for diabetes-related autoantibodies (eg, anti-glutamic acid decarboxylase antibodies, islet cell antibodies and insulin autoantibodies) as she was already initiated on insulin prior to her return to the UK, and the result would not alter her management. Additionally, she continued to lose weight with persistent gastrointestinal symptoms while using insulin, suggesting an alternative underlying pathology. Indeed, autoimmune diabetes would not fully explain her presentation. This was supported by her rapid response to treatment with steroids and pancreatic enzyme supplementation for her IgG4-related disease.

The weight loss observed in this patient prompted the physician to treat with insulin as this was deemed to be caused by insulin deficiency. However, this was later established to be a result of a pancreatic exocrine insufficiency with associated malabsorption. A considered history is essential to differentiate the causes of weight loss in this setting, and a high index of suspicion is required. Typically, the symptoms and signs of exocrine insufficiency precede those of diabetes mellitus, but this case highlights the importance of further investigation and radiological evaluation in patients with an atypical presentation of hyperglycaemia or rapid progression to insulin use.

Learning points.

• Hyperglycaemia is a common clinical finding with a considerable differential diagnosis.

• People with hyperglycaemia who present with weight loss or rapidly develop insulin-treated diabetes warrant further investigation to explain the underlying disease process.

• Weight loss may be associated with the cause or be a consequence of hyperglycaemia, and further investigation should always be considered.

• IgG4-related disease is an important differential in hyperglycaemia and should be considered in patients with systemic disease features or those with typical radiological findings.

• Biopsy is not required to confirm the diagnosis of IgG4-related autoimmune pancreatitis in the presence of supportive clinical, biochemical and radiological findings.