Overview

Definition of abetalipoproteinaemia (ABL)

Abetalipoproteinaemia is a rare condition that results from an inability to absorb fats by the liver and small intestine needed for making protein, thereby, leading to deficiency in protein, lipids and essential vitamins. The symptoms seen in individuals with abetalipoproteinaemia are due to the disruption of fat transportation.¹ 

Importance of understanding gastrointestinal symptoms in ABL

The most common symptom of Abetalipoproteinaemia is gastrointestinal manifestations which are mostly from fat malabsorption disorder. These include diarrhoea, abdominal distension and eventual wasting, which mostly develops in infancy. Fat malabsorption means that fats, cholesterol, and fat-soluble vitamins such as A, D, E, and K are poorly absorbed, leading to dietary deficiency.¹

It is important that the condition is discovered early and treated, to improve nutrition and prevent sequelae. However, if left untreated, a deficiency in vitamin E deficiency may cause irreversible ataxia, peripheral neuropathy, and retinal degeneration.¹

Background of abetalipoproteinaemia

Genetic basis and inheritance pattern

Abetalipoproteinaemia is an inherited but very rare condition with only a few cases found worldwide. The condition is characterised by the inability to absorb dietary fats, cholesterol and fat-soluble vitamins from the liver and small intestine.²

Studies have found that the condition is mainly caused by genetic mutations in the MTTP gene, which is responsible for providing instructions to make a protein called the microsomal triglyceride transfer protein (MTP).²

Role of MTP and its dysfunction in ABL

MTP helps to produce the lipoproteins in the liver and small intestine which then transports cholesterol and vitamins A, D, E and K from the intestine into the bloodstream so that the nutrients can be used by the body tissues. These essential nutrients are necessary for the growth, development and maintenance of body cells and tissues.²

A mutation in MTP proteins could lead to a reduced or absent function which means that these proteins are unable to transfer fats from the lipoproteins causing severe fat malabsorption and dietary deficiency giving rise to nutritional and neurological problems.²

Gastrointestinal symptoms in abetalipoproteinaemia

Abetalipoproteinaemia usually presents in infancy after breastfeeding or in childhood with vomiting, diarrhoea, failure to thrive and fat malabsorption.³

• Malabsorption syndrome

The symptoms mostly include steatorrhea with fat-soluble vitamin (A, D, E, and K) deficiencies. 

• Failure to thrive and growth retardation
• Diarrhoea and its causes
• Abdominal pain and discomfort

Complications associated with gastrointestinal issues

If abetalipoproteinaemia is left untreated it may result in further irreversible complications.

Neurological complications

From neurological sequelae and vitamin E deficiency - Some findings of vitamin E deficiency showed that it could be from degeneration of the spinocerebellar and dorsal column tracts - the part of the body that holds sensory information about the vibration and body position. Some of the effects of Vitamin E deficiency can be irreversible and include ataxia, muscle weakness, and eye degeneration which can typically manifest in the first or second decades of life.⁴

Liver disease and hepatic steatosis

Some haematological manifestations such as anaemia may also occur as fat malabsorption leads to iron and folic acid deficiencies.⁵

Studies also found that vitamin E is involved in protection from free radical damage, therefore, a deficiency could accelerate the formation of cells with lipids lacking oxygen (lipid peroxidation) which can lead to haemolysis exacerbating anaemia.⁵

In addition, vitamin K is involved in blood clotting coagulation - a necessary function to stop excessive bleeding, so, a deficiency could lead to bleeding disorders.⁵

Retinopathy and vision problems 

This may develop from vitamin A and E deficiency due to atypical pigmentation of the retina that may present with progressive loss of night and colour vision in adulthood may appear as the first visual symptoms then a gradual loss of vision till complete blindness in some cases.⁵

Diagnosis of gastrointestinal symptoms in ABL

There are currently no published or official clinical diagnostic criteria for abetalipoproteinaemia, however, there are some suggestive findings that have helped to recognise its diagnosis.

Clinical presentation and physical examination findings

Abetalipoproteinemia presents from infancy with failure to thrive, severe diarrhoea and vomiting, and fat malabsorption. Clinicians have agreed that ABL should be suspected in children with these clinical and physical examination findings. Other clinical manifestations include loss of night and/or colour vision, ataxia, acquired atypical pigmentation of the retina, myopathy and spinocerebellar just to name a few.

Laboratory tests and their significance

Some laboratory test findings that have also supported diagnosis include:

• Lipid profile which shows results of low cholesterol (range of total cholesterol ≤1 mmol/L or ≤40 mg/dL, low or absent low-density lipoprotein (LDL-cholesterol) level, low triglyceride level, and low high-density lipoprotein (HDL-cholesterol) level⁶
• Acanthocytosis
• apolipoprotein B as well as MTTP genetic testing
• Liver function test showing abnormal levels of the liver transaminases such as AST and ALT at 1-1.5 times more than the upper reference limit)
• Prolonged international normalised ratio (INR)
• Low levels of fat-soluble vitamins (A, D, E, and K)⁷

Imaging studies for assessing complications

Some imaging studies that doctors use include ultrasonography which can be used to assess changes in fatty liver, magnetic resonance imaging (MRI) of the spinocerebellar region may show spinal cord degeneration and eye examination/imaging can check for optical degeneration.⁸

Management and treatment

This usually involves a combination of different approaches including preventative measures of primary symptoms, monitoring and assessing of growth at every clinical visit. Some of these interventions require a multidisciplinary approach of healthcare professionals such as dietitians, neurologists, and occupational therapists, etc.⁸

Nutritional interventions

• Mostly by specialised diets that involve low-fat but high-protein diet manipulation⁸
• Vitamin supplementation to correct malnutrition as most complications can be prevented through the supplementation of fat-soluble vitamins (A, D, E, and K) which is lacking in patients with ABL⁸

Medications to alleviate symptoms 

In cases of anaemia, medications such as iron supplements, folic acid, or vitamin B12 may be prescribed to improve symptoms. 

In severe cases, where a high dose of vitamin E is required, administration via injections might be preferred for life-long treatment and to avoid medication error or toxicity compared to oral routes. Care must be taken when a high dose of vitamin E is being given as it might also induce or worsen vitamin K deficiency or cause a miscarriage as a consequence.⁹

Long-term monitoring and follow-up

As ABL is a very rare condition and can be inherited, special testing to detect risk that involves taking sibs of a proband to undergo a full lipid profile and apolipoprotein (apo) B and MTTP gene determination can help to detect ABL early and can be treated immediately. 

This will also include genetic counselling of the family involved, molecular genetic testing during pregnancy can also be done to check the genetic status of at-risk sibs. 

If the test for abetalipoproteinemia is positive, affected sibs will present shortly after birth with the common symptoms of failure to thrive, diarrhoea, vomiting, and malabsorption of fat to indicate diagnosis.¹⁰

Once diagnosed, pregnancy management will involve detecting excess vitamin A that can be harmful to the baby. Therefore, pregnant individuals or those who are planning to become pregnant should be advised to reduce their vitamin A supplement dose along with serum beta-carotene levels. 

Other significant close monitoring includes full blood count (FBC), INR, liver function tests, lipid profile, fat-soluble vitamin levels (vitamin A, D, E and K concentrations), other electrolytes such as calcium, phosphate, uric acid, and TSH levels to be measured every year.¹⁰

An ultrasound to detect any liver damage will be done every 3 years.¹⁰ 

Eye checks and neurology evaluations will also be done every 6 to 12 months.

Prognosis and outlook

Challenges and limitations in managing gastrointestinal symptoms

One of the challenges in managing gastrointestinal symptoms in ABL is the age at diagnosis. As it mostly occurs from infancy, some imaging studies are not appropriate to use to help detect treatment of findings with a low-fat diet and vitamin supplementation as early as it could have been possible. Also, the type of MTP mutation needs to be done appropriately as it can lead to differential diagnosis of patients with abetalipoproteinemia.¹⁰

Recent advancements in treatment options

Due to the rarity of ABL, there is currently a lack of funding for studies on the long-term benefits of current treatment options. However, some small case series and reports from specialists have shown that patients diagnosed early and treated or managed by a specialist medical team have improved outcomes.^3,11

There is also some evidence that prompt vitamin supplementation can improve the prognosis and outcome. However, the long-term outlook for many of these patients is guarded as many go on to develop vision loss and permanent blindness.¹¹

Summary

Abetalipoproteinemia commonly presents at birth with common gastrointestinal symptoms such as diarrhoea, vomiting, and fat malabsorption due to deficiency in fat-soluble vitamins A, D, E, and K.^10,11

Untreated individuals may develop pigmentation of the retina that may indicate progressive loss of night vision and sometimes colour vision later as adults with eventual blindness if not detected early. Therefore, an interprofessional approach is essential for the treatment and management of ABL if one is to improve patient outcomes.¹¹

Although there are ongoing studies in Japan for rare lipid disorders including ABL called the PROLIPID, more studies still need to be done. A study suggested that a nationwide registry for a longer period to evaluate the prognosis would help clarify some of the issues.¹²