Transient infantile hypertriglyceridaemia due to homozygous mutation in GPD1 presenting in childhood with hepatic adenoma

Abstract

Hypertriglyceridaemia in infancy is usually secondary to underlying metabolic disorder which usually has a genetic basis unlike the adult population. One such recently described entity is transient infantile hypertriglyceridaemia (HTGTI). In this disorder, mutation in glycerol-3-phosphate (G3P) dehydrogenase gene leads to deficiency of G3P dehydrogenase resulting in hypertriglyceridaemia and hepatomegaly. Clinical features tend to improve with age but may develop fibrosis. Our patient presented in infancy with hypoglycaemia, hepatomegaly, high transaminases and hypertriglyceridaemia. Limited genetic test for glycogen storage disorder was negative and was kept under follow-up. On follow-up, he developed hepatic lesion and his hepatomegaly with hypertriglyceridaemia persisted. There are only a few cases reported worldwide and none has reported development of adenoma so far. This could be the first report of development of adenoma in transient HTGTI.

Background

Hypertriglyceridaemia with or without hepatomegaly is a common manifestation of various metabolic disorders, especially of glucose metabolism like glycogen storage disorder (GSD), in infancy and has underlying genetic basis. One such disorder is transient infantile hypertriglyceridaemia (HTGTI), a recently described entity with few cases worldwide.¹ It has an autosomal recessive inheritance. Disorder is caused by mutation (homozygous or compound heterozygous) of glycerol-3-phosphate dehydrogenase (GPD1) gene on chromosome 12. Lack of GPD1 impairs lipid metabolism and leads to development of known clinical features which are hypertriglyceridaemia, hepatomegaly, high transaminases, fatty liver and subsequent development of hepatic fibrosis.² Infantile manifestation could be with failure to thrive, vomiting and enlarged abdomen due to hepatomegaly. Hypertriglyceridaemia normalises or improves with age.¹ End-stage liver disease or adenoma has not been described yet as one of the potential features or outcomes. However, the clinical spectrum and the pathophysiology remain largely unclear.

Case presentation

A 7-month-old child was presented to us with complaints of abdominal distension and poor weight gain. The child was born of non-consanguinous marriage with uneventful antenatal and perinatal history. His birth weight was 2.75 kg and he was born at term gestation. His weight was 6 kg (−2.9 SD) at presentation. On examination, he did not have any facial dysmorphism, though pallor was present. His liver was enlarged, 7 cm below costal margin, soft in consistency. The spleen was not palpable.

Laboratory blood tests showed fasting hypoglycaemia, hypertriglyceridaemia and high liver transaminases with high lactate (table 1). Ketone was found on urine examination. After further testing for metabolic disorders, liver biopsy was done. Liver histopathology was suggestive of macrovesicular steatosis of >66% of tissue. Portal triads showed mild chronic inflammation with no features of interface hepatitis, necrosis or ballooning degeneration. Bridging fibrosis from portal to portal and portal to central is identified, forming cirrhotic nodule suggestive of early cirrhotic changes. Stains for iron and copper were negative. Possibility of GSD or similar condition was kept. After sending the GSD gene panel, the child was started on modified high medium-chain triglyceride-based diet on which initially he seemed to be doing well. The child was lost to follow-up for a couple of years and came to us at the age of 7 years. His biochemical profile was similar to infancy and was struggling with weight gain. His weight was 16.5 kg (−2.8 SD), with a similar Z score as in infancy, and dietary compliance was also poor.

Table 1.

Investigations

Investigations	8 months of age	7 years of age
Total bilirubin (mg/dL)	0.3	0.4
ALT (U/L)	126	98
AST (U/L)	326	224
ALP (U/L)	722	919
GGT (U/L)	89	56
TG (mg/dL)	311	298
Cholesterol (mg/dL)	118	111
Lactate (mmol/L)	3.1	2.8
FBS (mg/dL)	55	58
Uric acid (mg/dL)	7	5.8
Phosphorus (mg/dL)	5	4.8
AFP (IU/ml)	NA	68
Ultrasound abdomen	Enlarged liver: 13 cm, coarse echopattern and increased echogenicity Spleen and kidneys normal in size.	Enlarged liver: 13.8 cm, coarse echotexture; focal hypoechoic area 1.29×0.8 cm in segment V with normal vascularity; spleen and kidneys normal in size.
Fibroscan	NA	9.6 kPa

AFP, alfa fetoprotein; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; FBS, fasting blood sugar; GGT, gamma-glutamyltransferase; NA, not applicable; TG, triglyceride.

Investigations

Ultrasound found a single non-vascular nodule in liver with normal alfa fetoprotein (AFP) suggestive of adenoma (figure 1). Whole-exome and mitochondrial gene sequencing was considered to further pursue diagnosis. On whole-exome sequencing, we found a missense variant, NM_005276.4(GPD1):c.500G>A (p.Gly167Asp), in the GPD1 gene, which has not been reported previously. It was a homozygous mutation in Exon 5 of the GPD1 gene.

Figure 1.

(A) Focal hypoechoic area 1.29×0.8 cm in segment V suggestive of adenoma. (B) Normal vascularity of the lesion.

Differential diagnosis

Disorders of carbohydrate metabolism including GSD were considered as a differential diagnosis, but initial limited testing was negative for known mutations. As he developed hepatic lesion, which favours GSD, whole-exome sequencing was planned, which yielded an entirely different diagnosis.

Treatment

In early infancy, the child was advised a low-fat, high-protein and corn starch diet to prevent hypoglycaemia and to improve his triglyceride profile. As the metabolic derangement persisted, a similar diet was continued to improve his metabolic profile and to facilitate weight gain.

Outcome and follow-up

We are planning a follow-up every 3 months with alfa fetoprotein and ultrasound of the abdomen to monitor the hepatic lesion. Further imaging, including MRI, was not considered as alfa fetoprotein was normal and ultrasound was consistent with adenoma. If the lesion progresses or any other morphological changes occur, we will perform MRI of the liver.

Discussion

Transient HTGTI is a disorder of lipid metabolism caused by the inactivation of GPD1 gene, which encodes cytoplasmic NAD-dependent GPD1. GPD1 participates in the reversible redox reaction of dihydroxyacetone phosphate (DHAP) and nicotine adenine dinucleotide (NADH) to G3P and NAD+. The exact mechanism of hypertriglyceridaemia is unclear. One of the possible reasons for hepatic steatosis is increased G3P available for triglyceride synthesis in the liver due to GPD1 mutations, which limits the conversion of G3P to DHAP.¹ Overall, increased hepatic triglyceride synthesis, decreased output but increased inflow of fatty acids, and impaired hepatic beta-oxidation may lead to liver steatosis.³ High triglyceride is a risk factor for cardiac complications; pancreatitis and fatty liver though long-term effect in such patients may not be clear and they need long-term follow-up.⁴

This disorder has been recently described and few patients have been reported so far. Basel-Vanagaite et al first identified it as the cause of HTGTI in 10 individuals from Israeli Arab families.¹ To our knowledge, this may be the second case report from Indian subcontinent.⁵ Our patient had a homozygous mutation leading to missense variant NM_005276.4(GPD1):c.500G>A (p.Gly167Asp), which has not been described earlier either as pathogenic or likely pathogenic. So far, 52 variants have been described in the GPD1 gene and among them, 10 are pathogenic. The most common mutation is c.361–1G>C.

Our patient presented with hypertriglyceridaemia, marked hepatomegaly, high liver transaminases and hepatic steatosis in infancy, which are classical features described in GPD1 deficiency.^{1 6} Hypoglycaemia was a peculiar finding which has been described as an atypical feature.³ Other atypical findings described in literature are jaundice, short stature, splenomegaly, development retardation, kidney involvement, insulin resistance and obesity.^{3 7–9} So far, literature has not described development of hepatic lesions. Our patient was found to have developed hepatic lesion on follow-up, which was non-vascular in appearance suggestive of possible adenoma. Patient’s alfa fetoprotein was normal and we plan to follow-up the lesion with 3 monthly ultrasound and alfa fetoprotein level. We are also planning to follow-up with an MRI to further delineate the lesion, especially if lesion progresses or any morphological changes occur. GSDs remain one of the differential diagnoses,³ and probably occurrence of adenoma, if reported in more patients, will make it a very close differential diagnosis. Other differential diagnoses described are citrin deficiency, lysosomal acid lipase deficiency and familial partial lipodystrophy.³

Serum triglyceride levels are usually between moderate and severe categories and tend to normalise during childhood or through adolescence. Associated hepatomegaly and high transaminases also tend to improve later in life, though fatty liver may persist and hepatic fibrosis may develop.^{1 2} In our patient, at 7-year follow-up, triglycerides were in the same range and appearance of liver remained similar on ultrasound apart from development of lesion. Poorly controlled metabolic profile may be attributed to lack of follow-up and poor dietary compliance. He had fibrosis with inflammation in the background of steatosis at the onset, which probably has progressed though repeat biopsy was not done. His overall growth was also affected. This child might need longer duration for improvement in the biochemical profile as described in literature.

To summarise, transient HTGTI due to GPD1 deficiency should be a consideration in infants presenting with hypertriglyceridaemia, hepatomegaly, elevated liver enzymes, hepatic steatosis and fibrosis especially in absence of genetic confirmation of GSDs. It should also be considered a differential diagnosis during evaluation of lean non-alcoholic steatohepatitis especially in younger age. Unlike classical description, condition can very well persist in late childhood needing long-term follow-up. Development of hepatic adenoma is a possible manifestation and should be kept under consideration during follow-up warranting periodic ultrasound of liver and serum alfa fetoprotein level

Learning points.

• Transient infantile hypertriglyceridaemia (HTGTI) due to glycerol-3-phosphate dehydrogenase (GPD1) deficiency could be a potential cause of hypertriglyceridaemia with hepatomegaly in infancy.

• It should be considered a differential diagnosis during evaluation of lean non-alcoholic steatohepatitis.

• Metabolic derangements can very well persist in late childhood needing long-term follow-up.

• Development of hepatic adenoma is a possible manifestation of transient HTGTI due to GPD1 deficiency.

Ethics statements

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Consent obtained from parent(s)/guardian(s).