Progressive Familial Intrahepatic Cholestasis: Causes, Symptoms & Treatment

The term progressive familial intrahepatic cholestasis is used to describe three cholestases that are very similar in appearance and can be distinguished from each other by different genetic defects. The diseases are inherited in an autosomal recessive manner and lead to a stasis of bile fluids in the body due to defectively encoded membrane transport proteins in the bile capillary membranes. Cure of the disease requires liver transplantation; otherwise, the prognosis for all three forms of the disease is unfavorable.

What is progressive familial intrahepatic cholestasis?

Rare progressive intrahepatic cholestasis (PFIC) is an autosomal recessive inherited disease of the liver. Three different forms of the disease, PFIC type1 to type 3 (PFIC1, PFIC2, PFIC3), are known with little clinical difference. Their main distinguishing feature is different genetic defects, each of which defectively encodes a specific membrane transport protein in liver cells. This leads to impaired excretion of bile acids and causes a toxic build-up of bile acids in the liver cells (hepatocytes) and a build-up of bile in the body (cholestasis). PFIC type 1 is also known as Byler’s disease or Byler’s syndrome because the causative genetic defect was first identified in a Byler family. All three forms of the disease lead to the development of liver cirrhosis at an early age, which can only be delayed by medication and diet, but not prevented. The only cure is liver transplantation while the patient is still a child.

Causes

Progressive familial intrahepatic cholestasis is caused exclusively by certain genetic defects that are inherited in an autosomal recessive manner. This means that the disease is not sex-specific and only comes to fruition when both parents have the same genetic defect. PFIC1 is caused by the mutated ATP8B1 gene ATP on chromosome 18. The gene mutation causes disruption of the phosphoglyceride phosphatidylserine, which is important for the function of a specific aminophospholipid transporter. This results in intrahepatic cholestasis. Since the same cell type is also present in the pancreas, similar symptoms occur there as well. This explains the extrahepatic symptoms also observed with PFIC1. The disease variant PFICB2 can be traced back to a gene mutation of the ABCB11 gene on chromosome 2. The defective gene is involved in the functioning of a bile acid transporter and also leads to cholestasis. A gene mutation in the ABCB4 gene on chromosome 7 leads to decreased secretion of lecithin, resulting in decreased protection of hepatocytes. The effects of the gene defect that is causally responsible for the development of PFICB3 manifest as chronic cholangitis, which is the ultimate trigger for the development of liver cirrhosis.

Symptoms, complaints, and signs

The symptomatology in all three forms of PFIC varies little and in many cases occurs in the newborn. All three manifestations are accompanied by severe pruritus, which is only weaker in PFIC3. Byler syndrome is characterized soon after birth by chronic jaundice, diarrhea, pancreatitis, and growth retardation and hearing loss. The appearance of liver tumors and the formation of gallstones as early as the first or second year of life are typical signs of PFIC2. Although the course of the disease in PFIC3 appears to be slower and milder compared with the other two forms, cirrhosis of the liver develops later.

Diagnosis and disease progression

Neonates who present with symptoms of cholestasis without biliary obstruction are suggestive of the inherited disease PFIC. Laboratory chemistry testing provides information about liver enzyme levels and bile acid in the blood. Further diagnostic options include a liver biopsy followed by histological examination and testing for the presence of defective transport proteins. In principle, molecular genetic testing is helpful, especially in differentiating the three forms of PFIC from each other. However, the results of such an examination are not always reliable.The additional designation progressive already indicates that the disease takes a progressive course if left untreated. The survival prognosis is unfavorable for all three manifestations of the disease. The average life expectancy is less than ten years if untreated.

Complications

In this disease, death occurs in most cases if treatment does not occur. In this case, affected individuals are usually dependent on liver transplantation for survival. Self-healing does not occur. The symptoms occur in childhood and can lead to severe itching of the skin. Jaundice also occurs and reduces the patient’s quality of life enormously. The affected persons also suffer from hearing loss and disturbances in growth and development. Furthermore, the disease also leads to disturbing diarrhea or flatulence. The parents and relatives of the patients also very often suffer from depression or other psychological upsets due to the disease. If there is no treatment, this disease usually leads to cirrhosis of the liver, which eventually leads to the death of the affected person. Treatment of this disease is done with the help of medications. However, in most cases, patients rely on liver transplantation to increase life expectancy.

When should you see a doctor?

The first signs of irregularity appear shortly after the sufferer is born. Itching, changes and abnormalities in the appearance of the skin, as well as discoloration of the skin, should be examined and treated. In many cases, the abnormalities are noticed immediately after birth by members of the nursing and helping team. Midwives and physicians perform the initial examinations of newborns. If irregularities are present at this time, they are documented and followed up. In these cases, parents and relatives should maintain close contact with the attending physician. If growth disturbances become apparent during the further development process, clarification of the observations is advisable. If a direct comparison with peers shows a short stature, a doctor should be consulted. Disorders of hearing, decreased hearing power, and speech irregularities should also be investigated and treated. Pimples, ulcers and growths on the skin indicate liver dysfunction. A visit to the doctor is advised so that clarification of the symptoms can take place. Indigestion, diarrhea and pain in the abdomen should be presented to a doctor. An increased body temperature, inner restlessness as well as nausea and vomiting should be examined by a doctor. If there is a feeling of weakness and listlessness, a physician is needed to determine the cause.

Treatment and therapy

PFIC is not curable due to its genetic causation, so therapies focus on treating the symptoms to delay the progressive course of the disease. It is important to provide a high quality diet with high caloric elements to compensate for the reduced intestinal absorption capacity caused by diarrhea. Regarding nutrition, adequate intake of fat-soluble vitamins and fortification with medium-chain fats (MCT diet) should also be ensured. Itching is usually treated with antihistamines, but not all patients respond to these. Possible side effects of these mildly sedating medications must be considered. Some patients respond to ursodeoxycholic acid, which may stop or at least greatly slow fibrotic remodeling of the liver. Particularly in PFIC1 and 2, partial external biliary diversion may be able to halt disease progression. A stoma, an artificial outlet for the gallbladder, is created using a small bowel loop, creating a bypass to the outside for about 30 to 50 percent of the bile. Alternatively, a bypass can be used to bypass about 15 to 20 percent of the small intestine, reducing the reabsorption of bile salts. The advantage is that no artificial outlet needs to be created. As a last resort, the only remaining option to cure the disease is a liver transplant.

Prevention

Because of the genetic causation of PFIC, no preventive measures exist that would have an impact on preventing the disease.Research within one’s own family is recommended to determine if there are any known cases of diagnosed PFIC.

Follow-up

Follow-up for progressive familial intrahepatic cholestasis is only scheduled if the patient has had a new liver transplant. After surgery, regular follow-up visits are scheduled for the first few months. The physician checks whether the new organ has been well accepted by the body and whether the patient’s blood values have improved. Since the patients are mostly of young age, the surgery may cause complications. Due to the immunosuppressants administered, there is a risk of pathogens taking hold in the patient’s body. A simple cold can spread to a severe flu. That is why patients are also given broad-spectrum antibiotics. The risk of organ rejection is comparatively low. Nevertheless, the physician checks whether the new organ is efficient or whether rejection reactions are evident. In a large proportion of cases, it is sufficient to adjust the dosage of the drugs until the patient’s body gets used to the new liver. However, if the performance of the liver deteriorates too much, liver rejection can no longer be prevented. In such cases, care is taken to alleviate the patient’s suffering and keep him or her as pain-free as possible. There is no longer a cure for progressive familial intrahepatic cholestasis or a repeat transplant.

Here’s what you can do yourself

The disease is associated with many different severe lifestyle limitations. Therefore, in the context of self-help, attention should be paid to an optimal organization of everyday life. Well-being as well as enjoyment of life should be promoted so that the adversities and circumstances of the disease can be well managed. The patient should be comprehensively informed by doctors and relatives about the course of the disease as well as the further development steps. In addition, self-research can be helpful to get open questions answered. Information about the disease is exchanged in self-help groups. Communication with other affected persons can be perceived as emotionally supportive. According to current scientific knowledge, the only way to cure or improve the situation is to transplant the liver. In order to survive this procedure well, a healthy lifestyle should be followed. The immune system can be stabilized with a balanced diet rich in vitamins. In addition, the consumption of harmful substances such as nicotine and especially alcohol should be completely avoided. Mental techniques or relaxation procedures can be used to stabilize the psyche. These serve in the reduction of existing stressors and strengthen the inner balance. A healthy self-confidence is necessary to be able to overcome possible teasing of the growth disorders well in everyday life.