Low phospholipid associated cholelithiasis (LPAC) syndrome

Description

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Understanding LPAC Syndrome

LPAC syndrome is a genetic predisposition to the formation of gallstones in and outside the liver. It manifests itself by intense intermittent abdominal pain in the hepatic region, linked to the presence and/or migration of gallstones. Its treatment is based on the daily intake of ursodeoxycholic acid and requires joint medical monitoring by the treating physician and the gastroenterologist.

In order to understand this disease, a few basic notions about the functioning of the liver

The liver continuously produces bile. This greenish liquid has 2 main roles:

1. digest the fats present in our food, mixing with the food bowl in the first centimeters of the small intestine (duodenum),
2. to get rid of toxins from the liver metabolism, by evacuating them in the digestive tract, so that they are eliminated in the stools.

Bile is stored in the gallbladder during periods of youth. Feeding stimulates the gallbladder to contract and empty its contents into the small intestine.

Under certain conditions, bile precipitates in the form of stones, also called gallstones. It is in the gallbladder, where the bile tends to stagnate, that these stones are formed preferentially.

Lithiasis is very common: it is estimated that one French person out of 5 carries at least one vesicular lithiasis, and up to 60% of people over 80 years old.

In 80% of cases, these stones are of the « cholesterol » type, i.e. composed almost exclusively of crystallized cholesterol. Therefore, all situations that lead to an increase in blood cholesterol levels and consequently in biliary cholesterol, favor the appearance of stones: age (maximum around 60-70 years old); women, especially during pregnancy (role of estrogens), overweight and significant weight variations; certain medications (especially the contraceptive pill).

In the vast majority of cases, having one or more gallstones is not alarming, and they will remain asymptomatic throughout life. But 20% of patients with gallstones will have biliary complications.

These complications are of 4 types:

• Hepatic colic: intense but short-lived pain in the region of the liver (under the ribs on the right), occurring when one or more stones migrate into the bile ducts. The pain is often accompanied by transient disturbances of the liver’s biological balance.
• Cholecystitis: inflammation of the gallbladder due to « irritation » of the gallbladder by the presence of calculus or by blockage of the calculus in the cystic duct (between the gallbladder and the common bile duct, which flows into the small intestine). The treatment is usually based on antibiotics and surgery to remove the gallbladder (cholecystectomy) immediately or at a later date.
• Angiocholitis: inflammation, even infection of the entire biliary tree, most often secondary to the migration and blockage of a stone at the end of the bile duct in the intestine. Bile stagnates upstream of the blockage, causing pain, jaundice and fever. Treatment is based on antibiotics and removal of the stone, although in most cases the stone will eventually pass on its own.
• Acute pancreatitis: according to the same mechanism as angiocholitis, the stone becomes lodged at the end of the pancreatic duct, which is common to the bile ducts.
  Any patient who has ever had a stone-related complication is offered cholecystectomy surgery (removal of the gallbladder) to remove the stone reservoir and protect him or her from further complications.

It is possible to live without a gallbladder. The gallbladder only acts as a reservoir. The liver continues its production of bile in an unchanged way.

LPAC (Low-Phospholipid Associated Cholelithiasis) syndrome

LPAC syndrome is the formation of numerous gallstones due to a genetic predisposition. It manifests itself as sudden pain in the liver area and mainly affects young women. The stones are not of the same nature as those that frequently form in the gallbladder, and its removal in LPAC patients is unnecessary. Ursodeoxycholic acid is an effective treatment. It is a rare and recently discovered disease and its diagnosis is often difficult.

What is it?

LPAC syndrome is a genetic predisposition to the formation of intra- and extra-hepatic gallstones, due to an abnormality in the molecular composition of bile.

We have seen previously that in the case of « classical » biliary lithiasis, it is already a problem of bile composition, too rich in cholesterol, which induces stone formation.

In LPAC, the bile has a normal cholesterol composition, but is poor in phospholipids (hence the name low-phospholipid). These molecules have a role of solubilization of cholesterol. In their absence, it crystallizes, forming a stone.

One of the genetic mutations identified to explain the absence or insufficient level of phospholipids in bile is that of the ABCB4 gene. This gene codes for MDR3, a phospholipid transporter at the bile duct wall. This mutation is present in only 30 to 50% of patients.

The crystallization of cholesterol in the whole biliary tree induces the formation of numerous stones, of multiple locations (in the gallbladder, but also IN the liver), and this from a young age. The stones can then become complicated, leading the patient to consult a specialist.

Is it a common disease?

It is a disease of recent discovery (early 2000s, with a major contribution from the hepatology team of the Saint-Antoine Hospital). This recent identification explains why we lack epidemiological data. It is currently thought that 1% of all lithiasis is related to LPAC. But this figure is certainly underestimated, it is possible that with the improvement of the knowledge of this disease, the LPAC syndrome is diagnosed more frequently.

What is the profile of patients with LPAC syndrome?

LPAC syndrome affects mostly young women between 25-35 years old without being overweight, with a family history of gallstones.

The presence of overweight is not incompatible with the diagnosis of LPAC but makes it less likely. Indeed, the risk of common lithiasis is then more important (association of overweight/hypercholesterolemia).

A family history of lithiasis is very common. Unfortunately, they are also present in patients with common lithiasis and do not help in the diagnosis of LPAC syndrome.

What are the symptoms?

LPAC syndrome is manifested by pain in the liver area.

Intra- and extra-hepatic stones can remain asymptomatic for many years. When symptoms do occur, pain is the most prominent.

Most often sudden in onset, it can be triggered by eating a fatty and/or alcoholic meal, it predominates in the region of the liver (under the right ribs), but can radiate into the right shoulder. It usually subsides within a few hours.

The occurrence of other symptoms: jaundice, fever, or persistence of pain beyond 6 hours should suggest a complication related to the stone, and should require urgent medical evaluation.

How is LPAC syndrome diagnosed?

The diagnosis is based on the young age of onset of painful symptoms (<40 years), lack of efficacy of gallbladder removal and/or liver ultrasound in a reference center.

At least 2 of the following 3 criteria are required:

• onset of symptoms (mainly liver colic pain) before the age of 40;
• recurrence of symptoms after cholecystectomy;
• ultrasound of the liver in an expert center, showing intrahepatic stones with a « comet tail » appearance.

The search for the ABCB4 gene mutation can help in the diagnosis, but is inconstant (30 to 50% of cases).

The biological assessment is usually normal. In case of disturbances, no specific abnormality is found.

What is its evolution?

Without treatment, it is the recurrence of painful symptoms that dominates the evolution of this disease.

The presence of stones in the liver and bile ducts exposes the patient to all the lithiasis complications presented above: angiocholitis, acute pancreatitis, cholecystitis.

Cholecystectomy, often performed wrongly, does not lead to clinical improvement. The risk of developing cirrhosis or liver cancer remains to be studied.

Beware of the risk of gravidic cholestasis, a transient disease of the 2nd-3rd trimester of pregnancy, in patients with LPAC syndrome or with a mutation of the ABCB4 gene.

There does not appear to be a difference in prognosis based on the presence or absence of the ABCB4 mutation.

How can it be treated?

The treatment of LPAC syndrome is based on the daily intake of Ursodeoxycholic acid (UDCA) at a dose of 10mg/kg. This molecule helps the excretion of phospholipid in the bile, restores the balance in the biliary composition and thus facilitates the solubilization of cholesterol.

The UDCA therefore has a preventive role, by preventing the synthesis of new stones, and a curative role, by promoting the solubilization of stones already present.

This treatment is well tolerated and also very effective and avoids cholecystectomy, which is unfortunately still proposed in excess. The treatment is rapidly effective on pain (in a few weeks), more slowly on the disappearance of intrahepatic stones (in a few months or even years). However, the objective of the treatment is to improve symptoms.

The duration of treatment remains poorly codified, but should be considered for life.

No specific diet is recommended. While a low-fat diet is usually prescribed for lithiasis pancreatitis, there is no medical evidence to suggest it for LPAC. However, patients report improved comfort by adapting their diet empirically, according to their own reactions.

How will my follow-up take place?

Joint follow-up by the treating physician and the gastroenterologist is essential. To date, there is no recommendation for the rhythm and modalities of the follow-up of this disease.

Nevertheless, LPAC syndrome warrants medical and particularly gastroenterological follow-up at least once a year after diagnosis to evaluate the efficacy and tolerance of the treatment.

Regular monitoring of the blood balance, and particularly the liver, can detect the presence of stones in the main bile duct in the case of chronic cholestasis (elevated GGT and PAL).

Finally, young women with LPAC syndrome who are planning a pregnancy must have a gastroenterological follow-up, because 50% of them will present a picture of gravidic cholestasis, which exposes them to a risk of premature delivery in 2/3 of cases.

Another essential aspect is family screening.

What is the risk of transmission to my family?

This disease is not contagious. But the genetic origin of this disease induces a risk of transmission to the descendants, and this even in the absence of identified ABCB4 mutation.

At present, we do not know the mode of transmission (autosomal dominant or recessive).

It is also important to specify that it is a disease with « incomplete penetrance », i.e. 2 patients with the same genetic mutation will not necessarily have the same clinical picture. It is therefore possible to transmit the mutated gene without the child developing the disease.

LPAC syndrome does not warrant prenatal screening.

Can I be cured of LPAC syndrome?

LPAC syndrome is linked to a genetic mutation. By definition, these mutations are present for life. Therefore, LPAC will accompany you for life.

LPAC syndrome is a disease with an excellent prognosis. Treatment is effective and well tolerated.

What medical research is being done on this disease?

• search for other genes involved in the physiopathology of this disease.
• development of techniques for the extraction of intrahepatic lithiasis (ERCP)
• epidemiological studies to better characterize the patients affected, and to make practitioners aware of this diagnosis.