Milky Blood in a Middle‐Aged Man With Diabetes Mellitus: Familial Chylomicronemia Syndrome due to GPIHBP1 Mutation

ABSTRACT

Diabetes mellitus is a common cause of secondary hypertriglyceridemia. However, lipemic plasma with severe hypertriglyceridemia, limited response to strict dietary measures, commonly used pharmacotherapy, and good glycemic control, should raise suspicion of a primary cause. Positive family history and genetic studies can give a diagnosis of familial dyslipidemia syndromes.

Key Clinical Message

While diabetes mellitus is a common cause of hypertriglyceridemia, the presence of strikingly lipemic plasma with severe hypertriglyceridemia with limited response to dietary measures, optimal glycemic control, and commonly used pharmacotherapy should warrant evaluation for primary dyslipidemia. Family history and genetic testing are vital for diagnosing familial dyslipidemia syndromes.

1. Clinical Question

Is severe hypertriglyceridemia in patients with diabetes mellitus always secondary in origin?

2. Case

45 years male, known case of primary hypertension for 2 years presented for routine follow up. On examination his body mass index (BMI) was 23.5 kg/m². His general and systemic examination revealed normal findings. On evaluation he was detected to have type 2 diabetes mellitus with fasting blood glucose 160 mg/dL (Reference: 70–100 mg/dL), post prandial blood glucose 210 mg/dL (Reference: 70–140 mg/dL) and HbA1c of 7.8% (Reference: < 5.7%). He was also found to have severe hypertriglyceridemia where serum triglyceride was 2138 mg/dL (Reference: < 150 mg/dL), total cholesterol 124 mg/dL (Reference: < 200 mg/dL) and HDL cholesterol was 19 mg/dL (Reference: > 40 mg/dL). His blood was grossly lipemic, exhibiting a milky appearance (Figure 1). On further review of history and repeat clinical examination, the patient had no prior episodes of acute pancreatitis or recurrent abdominal pain and there was no eruptive xanthoma, hepatomegaly, splenomegaly or lipemia retinalis. Thyroid function test, liver function tests, urea, creatinine and urine routine examination were within normal limit. He was initiated on insulin followed by addition of oral antidiabetic medications. Fenofibrate in the dose of 200 mg daily was given for hypertriglyceridemia. Omega 3 fatty acid preparation was added. He was advised for diabetic diet with emphasis on low fat diet and limitation of food that increase blood triglyceride level. Blood glucose was well controlled. However, he had persistent hypertriglyceridemia of triglyceride of 976 mg/dL. On revisiting the history, he gave history of hypertriglyceridemia in his mother too. In view of persistent hypertriglyceridemia with positive family history, next generation sequencing was done that revealed a variation in the anti‐glycosylphosphatidylinositol‐anchored high‐density lipoprotein‐binding protein 1 (GPIHBP1) gene (Figure 2). The variant is classified likely pathogenic, inherited in an autosomal recessive pattern, and is associated with Type I hyperlipoproteinemia. These findings established the diagnosis of familial chylomicronemia syndrome due to pathogenic variation in GPIHBP1.

FIGURE 1.

Lipemic blood in a patient with familial chylomicronemia syndrome.

FIGURE 2.

Next generation sequencing of the patient showing a homozygous pathogenic variation in the GPIHBP1 gene consistent with familial chylomicronemia syndrome gene.

3. Answer and Discussion

The patient's milky or lipemic blood is due to marked accumulation of circulating chylomicrons, characteristics of familial chylomicronemia syndrome (FCS). It is a rare genetic disorder characterized by severe hypertriglyceridemia resulting from impaired chylomicron metabolism. A normal BMI is commonly observed in patients with this condition, which was consistent with the findings in our patient. Patient may present with recurrent episodes of pancreatitis, eruptive xanthomas, lipemia retinalis, and hepatosplenomegaly. This rare group of disorders with autosomal recessive inheritance that are usually due to homozygous or compound heterozygous biallelic genetic variants in the five FCS canonical genes (LPA, GPIHBP1, LMF1, APO2 and APOA5). Essential for lipoprotein lipase (LPL) mediated hydrolysis of triglyceride‐rich lipoproteins. GPIHBP1 plays a critical role in transporting lipoprotein lipase from the interstitial space to the capillary lumen, where triglyceride‐rich lipoproteins are hydrolyzed. Loss‐of‐function mutation on GPIHBP1 prevent effective lipolysis, leading to persistent chylomicronemia and severe hypertriglyceridemia, often exceeding 2000 mg/dL [1, 2, 3].

Although our patient had type 2 diabetes mellitus, the degree of hypertriglyceridemia and the striking lipemic appearance of blood were disproportionate to secondary dyslipidemia alone, prompting genetic evaluation. This case highlights the importance of considering monogenic causes of hypertriglyceridemia in adults, even in diabetes mellitus, particularly when triglyceride levels are extreme despite adequate glycemic control and fibrate therapy.

Recognition of FCS is clinically important because affected patients are at risk of developing recurrent pancreatitis and require strict dietary fat restriction and avoidance of triglyceride raising agents in addition to pharmacotherapy. This image underscores how simple visual inspection of blood can provide a clue to the clinician to suspect a rare disorder.

4. Take Home Message

Secondary hypertriglyceridemia is common in diabetes mellitus. However, evaluation for a monogenic cause can be a consideration to identify the etiology if triglyceride levels remain persistently raised despite appropriate dietary restriction, good glycemic control, and lipid‐lowering therapy.

Author Contributions

Mukti Nath Sankhi: data curation, resources, writing – original draft. Naresh Bansal: conceptualization, supervision. Samir Samadarshi: writing – original draft. Santosh Kumar Singh: conceptualization, supervision. Rohit Vashisht: supervision, writing – review and editing.

Funding

The authors have nothing to report.

Ethics Statement

All procedures/investigations in this study were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Consent

Written informed consent was obtained from the patient to publish this report in accordance with the journal's patient consent policy.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data supporting the findings of this study are available within the manuscript. All relevant clinical details, images of diagnostic tests have been included to ensure transparency and reproducibility. Additional data related to this case are available from the corresponding author, Mukti Nath Sankhi, upon reasonable request.