ALECT2 amyloidosis was first discovered in 2008 in a 61 year old woman whose kidney was removed because of kidney cancer. Seven years earlier she had been diagnosed with amyloidosis of unknown type. Since then she had suffered from slowly progressive kidney failure. Pathological analysis of the amyloid fibrils from the kidney that had been removed identified a protein called leukocyte chemotactic factor 2 (LECT2). LECT2 is a normal bloodstream protein, mainly produced in the liver. It is believed to play a role in white blood cell migration and stimulation of bone cell growth. It had never previously been known to have amyloid forming potential.
Since then about 200 cases of ALECT2 amyloidosis from around the world have been described in the medical literature.
How common is ALECT2 amyloidosis?
In the US, ALECT2 amyloidosis may be a relatively common cause of amyloidosis that was previously either classified as “unknown type”, or misdiagnosed as a different type of amyloidosis. In US studies it accounted for 2.5-10% of all cases of kidney amyloidosis and 25% of all cases of liver amyloidosis. Recent data from the Mayo clinic suggest that ALECT2 amyloidosis is now as common as AA amyloidosis in the US (in this study the four most common types were AL – 61.7%, ATTR – 24.5%, AA 3.7% and ALECT 3.6%) In the UK it accounts for about 1% of all patients referred with biopsy-proven kidney amyloid.
Who gets ALECT2 amyloidosis?
About 90% of all cases described occurred in people of Hispanic origin, and it was particularly common in the Southwestern US. It also appears to be more common in people of Punjabi, Arab, North African and Native American Indian origin than in those of other ethnic origins.
Is ALECT2 amyloidosis inherited?
Despite the ethnic clustering, ALECT2 amyloidosis is not believed to be a hereditary condition. Apart from one case of 2 brothers with ALECT2 amyloidosis, none of the patients described in the literature had any family history of amyloidosis. All patients with ALECT2 amyloidosis whose LECT2 gene has been examined have a particular, common variant (polymorphism) of the LECT2 gene (called homozygosity for G nucleotide at position 172) but no causative mutations have been described in this disease.
What causes ALECT2 amyloidosis?
The underlying cause of ALECT2 amyloidosis is unknown. It is also unclear whether ALECT2 amyloid deposition is a slow process beginning early in life and remaining undetected for years or whether it is a rapid process beginning later in life.
What are the symptoms and when do they appear?
ALECT2 amyloidosis mainly affects the kidneys and the liver. It generally appears in elderly people (usually after age 60), with only 5 reported cases in people aged under 50.
Patients with ALECT2 amyloidosis affecting the kidneys usually come to medical attention because of progressive chronic kidney failure. Protein in the urine is generally a less prominent disease feature than in other types of amyloidosis affecting the kidneys. Chronic hypertension and diabetes are common in patients diagnosed with ALECT2 amyloidosis and a minority (up to 13% in one study) have kidney cancer.
Many cases of liver ALECT2 amyloidosis were diagnosed incidentally in liver biopsies performed for unrelated conditions. The most common clinical abnormality associated with liver ALECT2 amyloidosis is raised alkaline phosphatase (ALP), an abnormality commonly seen in many liver diseases.
Clinically significant liver ALECT2 amyloidosis is rare in patients diagnosed with kidney ALECT2 amyloid, and clinically significant kidney ALECT2 amyloid is unusual in those diagnosed with liver ALECT2 amyloidosis. ALECT2 amyloid deposits have been described in other organs such as the spleen and prostate, but not in the heart.
How is ALECT2 amyloidosis treated?
There are no specific treatments for ALECT2 amyloidosis.
Patients with ALECT2 amyloidosis affecting the kidneys should receive supportive treatment, as for kidney failure caused by other types of amyloidosis. ALECT2 amyloidosis in the liver may not require treatment.
Correct diagnosis of ALECT2 amyloidosis is crucially important, as misdiagnosis of AL amyloidosis may lead to unnecessary chemotherapy.
Supportive treatment for kidney failure
All patients with ALECT2 amyloidosis affecting their kidney function should be seen regularly by a nephrologist who is expert in amyloidosis. Important principles include:
- carefully monitoring and maintenance of fluid balance
- regular testing of kidney functions with blood and urine tests
- use of diuretics when required
Abnormal kidney function due to ALECT2 amyloidosis may affect the ability of the kidneys to produce urine. This means that the body is unable to cope well with excess fluids. Patients with fluid overload may develop swelling in the legs (oedema) or difficulty breathing due to heart failure.
Fluid excess can be avoided by careful attention to the 3 Ds:
3. Daily weights
Fluid intake should be steady and should usually not exceed 1.5 litres per day.
Salt intake should be limited. This includes attention not just to salt added to the food from the salt shaker, but also to food with high salt content such as crisps, bacon, canned meats, sausages, canned soups and smoked fish. It can be very helpful to meet with a dietician for precise and personalised dietary advice.
Doctors will often prescribe diuretics (water tablets) which help the body to lose excess salt and water. Taking these drugs is not a substitute for avoidance of excessive dietary salt and water.
Removal of excess body fluid reduces ankle swelling and breathlessness.
Furosemide is usually prescribed first, then other diuretics such as spironolactone may be added.
Since diuretics increase the amount of urine produced, they should usually be taken in the morning sometimes with another dose at lunchtime.
3. Daily weights:
Some patients benefit from recording their weight regularly, usually daily or weekly. It is important that weight should be measured consistently- using the same scales, at the same time of day. This is usually best done first thing in the morning after passing urine, just wearing underclothes. Several litres of fluid can accumulate in the body without it being very noticeable. An increase in weight can be an early sign of fluid excess. The doctors or nurse can then recommend appropriate measures such as increased diuretic dose, before the patient even feels unwell because of the fluid overload.
What is the outlook?
ALECT2 amyloidosis is usually diagnosed in the elderly, suggesting that kidney function is usually maintained until late in life. It is unclear whether ALECT2 amyloid deposition in the kidneys is a slow process beginning early in life and remaining undetected for years or whether it is a rapid process beginning later in life.
Kidney survival is variable, with some patients reaching end stage kidney failure and requiring dialysis. Outcomes after kidney transplantation appear to be good, although ALECT2 amyloidosis can slowly recur in the graft. Patients with ALECT2 amyloidosis affecting the kidneys have better overall survival than those with AL or AA amyloidosis affecting the kidneys, presumably because the heart is not affected by ALECT2 amyloidosis.
At present there are no drugs in development specifically targeting ALECT2 amyloidosis. It is hoped that the CPHPC plus anti SAP antibody approach will be beneficial for patients with all types of amyloidosis, including ALECT2 amyloidosis. This treatment approach was developed by Professor Sir Mark Pepys at the Wolfson Drug Discovery Unit in partnership with GSK, and is currently undergoing clinical trials at the NAC.