Rare Liver Diseases

• Per the FDA, The Orphan Drug Act defines a rare disease as a disease or condition that affects less than 200,000 people in the United States.

• There are many different types of rare liver diseases: acute hepatic porphyria (AHP); acute liver failure; Alagille syndrome; alpha-1 antitrypsin deficiency (ie, AAT deficiency, AATD, Alpha-1, inherited emphysema, genetic emphysema); autoimmune hepatitis; biliary atresia (BA); Budd–Chiari syndrome; cancers of the liver: hepatoblastoma, cholangiocarcinoma;; congenital hepatic fibrosis; Crigler-Najjar syndrome; galactosemia; glycogen storage disease; hemochromatosis (i.e., hereditary hemochromatosis, iron overload disorder); hepatic porphyria (acute hepatic porphyrias); immune-mediated and inflammatory diseases: primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC); intrahepatic cholestasis of pregnancy (ICP, cholestasis of pregnancy); lysosomal acid lipase deficiency (LAL-D); polycystic liver disease; progressive familial intrahepatic cholestasis (PFIC); Wilson disease.

Acute Hepatic Porphyria (AHP)

• Acute hepatic porphyria (AHP) is a genetic disorder characterized by sudden “attacks” of symptoms in some people, which can be severe and life-threatening. AHP symptoms include nerve pain, abdominal pain, vomiting, neuropathy, and seizures.

• AHP begins in the liver and can eventually affect the nervous system: AHP occurs secondary to mutations that lead to abnormal pathways for production of proteins in the liver but can affect the nervous system.

• There are different types of AHP, representing different missing enzymes as a result of the disorder.  From most to least common: acute intermittent porphyria (AIP); variegate porphyria (VP); hereditary coproporphyria (HCP); ALAD-deficiency porphyria (ADP).

• The genetic mutations that cause AIP, VP, HCP are equal in males and females, but it is females who are predominantly symptomatic. In ADP, all symptomatic patients have been male.

• AIP attacks have been reported five times more frequently in non-Hispanic females as compared with males.

• 80% of those who develop AHP/AIP symptoms are female and of childbearing age.

• Any race or ethnicity may inherit the AHP genetic mutation, from one or both parents.

• AHP is often undiagnosed.

• AHP symptoms are triggered by hormonal changes, some drugs, alcohol use, smoking, and severe stress.

• Most people with the AHP gene mutation never develop symptoms, only 1 in 10. Worldwide, estimates for the prevalence of AHP range from 1 in 500 to 1 in 50,000 people.

• The US prevalence for AHP is 1 in 25,000 people.

• The mutation for AIP, the most common type of AHP, has an incidence of 1/1600 in Caucasians, but <10% of the at-risk population develops the disease.

• AHP is diagnosed with a genetic test.

• Treatment mostly focuses on symptom relief, including anti-seizure medication in about 20% of cases. Precipitating factors, such as smoking and alcohol, should be eliminated during attacks.

• People experiencing life-threatening AHP symptom attacks may be eligible for a liver transplant, which can cure them. However, this is rarely done because of the invasive nature of a liver transplant and the need for lifelong immunosuppressive treatment.

Alagille Syndrome (ALGS)

• Alagille Syndrome (ALGS) may also be referred to as syndromic bile duct paucity or syndromic bile duct paucity.

• Alagille Syndrome (ALGS), a progressive genetic disorder, affects the liver, heart, skeleton/spine, eyes/face, blood vessels, skin (itchy skin, hard skin bumps), and kidneys.

• Most patients with ALGS have liver disease.

• ALGS causes destruction of the bile ducts. Bile then builds up in the liver because there are too few ducts to drain bile, resulting in liver damage (cholestasis).

• Children with ALGS can have unique facial characteristics: a pointy chin, broad brow, and widely spaced eyes.

• Chronic itchy skin/hard skin bumps are often symptoms for people with ALGS.

• ALGS is caused by abnormal development of many organs.

• ALGS is usually diagnosed at infancy in about one of every 30,000 to 70,000 births but can also be diagnosed in early childhood. It affects both sexes and all races equally.

• More than 85% of patients with Alagille have liver disease.

• ALGS has a mortality rate of 10-17%. Most of the mortality in ALGS is secondary to cardiac or vascular involvement.

• About 75% of people diagnosed with ALGS in childhood live to at least age 20.

Alpha-1 Antitrypsin Deficiency (AATD)

• Alpha-1 antitrypsin deficiency (AATD) may also be referred to as AAT deficiency, Alpha-1, inherited emphysema or genetic emphysema.

• Alpha-1 antitrypsin deficiency (AATD) is a rare, inherited genetic disorder that damages the liver and/or lungs, depending on the type of AATD inherited.

• In a healthy person, A1AT protein is made by the liver, secreted into the blood stream, and travels to the lung where it helps to protect the lung. In people with AATD, however, the A1AT protein is underproduced or misfolded. This can result in buildup of the A1AT protein in the liver, leading to liver cell damage (cirrhosis; hepatoma) and/or decreased entry of A1AT in the lung, resulting in lung breakdown and chronic lung disease (chronic obstructive pulmonary disease (COPD), including bronchiectasis; emphysema). AATD can also, rarely, lead to a skin condition, panniculitis.

• AATD lung symptoms usually develop in adulthood, but liver symptoms can present in infants (up to 73%).

• Patients with at-risk genes can present with a range of liver or lung diseases. Liver disease usually presents in infancy while lung disease usually becomes apparent in early adulthood.

• Approximately 15% of patients with A1AT require liver transplant.

• Notably, lung disease is more dominant in most patients.

• AATD is one of the most common genetic disorders among people with European ancestry. It is rare in non-European people, but all ethnicities can be affected.

• AATD has a global incidence of 1 in every 1500 to 3500 people with European ancestry.

• There is no known way to prevent AATD. There is a drug that replaces the antitrypsin that the body can't make, but it only helps in the lung aspects of the disease, not the liver. Patients with AATD may have reduced life expectancies.

• There is currently ongoing research on gene therapy for AATD that will treat all aspects of the disease if successful.

• AATD affects 1 in every 3000 to 5000 people in the U.S.

• AATD is often underdiagnosed or misdiagnosed.

• Severe cases of AATD are estimated at 70,000 to 100,000 people in the US. It is projected that less than 10% have obtained an accurate diagnosis.

• People with AATD are at increased risk for hepatocellular carcinoma (HCC), as with virtually any liver disease.

Gilbert's Syndrome

• Gilbert (zheel-BAYR) syndrome is a common, harmless genetic liver condition in which the liver doesn't properly process bilirubin, produced by the breakdown of red blood cells.

• Gilbert syndrome requires no treatment.

• Doctors may consider Gilbert syndrome if patients have unexplained jaundice (yellowish skin and eyes) or if their level of bilirubin is elevated.

• Gilbert syndrome can be discovered by accident because people may not know they have it. Approximately 1 in 3 people with Gilbert's syndrome don’t have symptoms.

• People with Gilbert's can lead long, healthy lives and don’t experience long-term health problems from the disease.

• Gilbert syndrome has a prevalence rate of 3%-16%.

• Gilbert's Syndrome is more common in males than females, and affects all ages, races, and ethnicities.

• According to one study, in children, Gilbert's syndrome manifests 2.22 times more often in boys than girls.

• Gilbert syndrome may become more noticeable during puberty.

• Gilbert syndrome can manifest during triggers such as fasting, hemolytic reactions, febrile illnesses, menstruation, and physical exertion.

Hereditary Hemochromatosis

• Hereditary Hemochromatosis is sometimes referred to as, bronze diabetes; bronzed cirrhosis; familial hemochromatosis; genetic hemochromatosis; haemochromatosis; HC; hemochromatosis; hereditary haemochromatosis; HH; HLAH; iron overload disorder; iron storage disorder; pigmentary cirrhosis; primary hemochromatosis; Troisier-Hanot-Chauffard syndrome; Von Recklenhausen-Applebaum disease) (See also “Liver Cancer”)

• Hereditary Hemochromatosis (HH) is a disorder causing excess dietary iron to build up in the body, damaging multiple organs including the liver, pancreas, heart, thyroid, joints, skin, gonads, and pituitary.

• Too much iron from hemochromatosis can lead to life-threatening conditions, such as liver disease, heart problems, and diabetes. As hereditary hemochromatosis worsens, patients may develop arthritis, liver cirrhosis/cancer, diabetes, heart abnormalities, or skin discoloration.

• In HH patients, there is an increased risk of hepatocellular carcinoma or liver cancer.

• The most common cause of hemochromatosis is genetics, but excessive iron absorption can also cause this condition.

• Hereditary hemochromatosis is the most common autosomal recessive disorder in White people.

• The prevalence of hereditary hemochromatosis is estimated to be between 1/220-1/250 people of northern European descent.

• Men and women are now being diagnosed equally with HCC.

• Symptoms of hereditary hemochromatosis include extreme fatigue, joint and abdominal pain, weight loss, and lowered sex drive. Severity of symptoms can be affected by the environment and lifestyle, such as diet (iron), alcohol use, and infections.

• There are a variety of genes mutations associated with HH, with C282Y being most common.

• Hemochromatosis can be difficult to diagnose because early symptoms (stiff joints, fatigue) can mirror other conditions.Many patients don't have any symptoms other than high iron levels. It can also be found when screening family members of people with the disease.

• There are three key blood tests for hemochromatosis: serum iron level; serum transferrin saturation; serum ferritin. Additional tests are made to confirm diagnosis: liver function tests; MRI; genetic tests; liver biopsy.

• Doctors can treat hereditary hemochromatosis by periodically removing blood from the body (phlebotomy) to reduce iron levels to normal.

• As with other liver diseases, hereditary hemochromatosis is a risk factor and cause of liver cancer (hepatocellular carcinoma (HCC), the most common form of liver cancer). (See also section on “Liver Cancer.”)

Lysosomal Acid Lipase Deficiency (LALD)

• Lysosomal acid lipase deficiency (LALD) is a genetic condition in which the body does not properly break down fats and cholesterol (lipid metabolism), causing harmful amounts of fats (lipids) to accumulate in cells and tissues leading to liver disease.

• There are two forms of LALD:
  • Infantile-onset LALD – the most severe and rarest form. It begins in infancy.
    • LALD is often fatal within first 12 months of life.
    • Signs of the disease begin occurring shortly after birth as fat begins to accumulate in the body. Symptoms/signs of the disease can include severe malnutrition; abdominal distention; enlarged liver/spleen (hepatosplenomegaly); abnormalities in the adrenal glands; jaundice; delayed development; poor appetite; fatty stools (steatorrhea); vomiting; diarrhea; poor growth (weight/height) gain; anemia.
  • Late-onset LALD – This form is more common than early-onset. It is less severe, and first symptoms occur at various ages, from mid-childhood to adolescence to late adulthood.
    • Symptoms/complications can include enlarged liver and spleen (hepatosplenomegaly); fatty stools (steatorrhea); vomiting; diarrhea; high cholesterol (hypercholesteremia); liver disease; fatty deposits in arteries (atherosclerosis).

• The incidence of LALD is unknown. LALD prevalence is estimated to be between 1:40,000 to 1:300,000 people, depending on ethnicity and geographical location.

• There is no cure for LALD.

• Treatment options include enzyme replacement therapy (ERT) which replaces the enzyme lysosomal acid lipase (LAL) that is missing or not working in people with LALD.

• Other treatments include lipid lowering agents, though these have not had great success.

Wilson Disease (WD)

• Wilson disease may also be referred to as Wilson’s Disease, hepatolenticular degeneration syndrome, hepatolenticular degeneration syndrome or copper storage disease.

• Wilson disease is a rare, progressive, genetic disorder characterized by excessive copper accumulating in body tissues, particularly the liver, brain, kidneys, heart, skin, and corneas. If untreated, the excess copper poisons the liver or brain, causing liver, neurologic or psychiatric symptoms, and death. Wilson is a multisystem disorder.

• Wilson disease can be fatal unless detected and treated before serious illness from copper poisoning develops. The mortality rate for Wilson disease complicated by acute liver failure (ALF) without liver transplantation is 95 percent, with death occurring in days to weeks. However, liver transplantation cures Wilson disease with ALF, and prognosis following liver transplantation is excellent.

• Wilson disease carries a risk of liver cancer.

• Symptoms start to appear at all ages, as early as 3-11 to 65+ years. Symptoms usually appear in late adolescence to early adulthood, but can also occur in early childhood, middle or old age (some patients are detected by genetic studies in their 70s or 80s).

• Wilson disease symptoms: weakness, abdominal pain, jaundice, personality change/ Psychiatric symptoms, seizures, migraine headaches, insomnia, tremors, Parkinsonian movement disorder, etc.

• Early diagnosis is crucial to prevent serious disability and life- threatening complications.

• Treatment reduces the amount of copper in the body and focuses on maintaining normal levels.

• If both parents carry a defective Wilson disease gene, there is a 25% chance each child will have the disorder.

• Children with Wilson disease can have asymptomatic liver disease, cirrhosis, or ALF, with or without neurological and psychiatric symptoms.

• An estimated 8,300 to 11,000 people in the U.S. have Wilson disease.

• Wilson disease affects males and females equally and is found in all races and ethnicities.

• Wilson disease incidence is approximately 1 in 30,000 to 40,000 people worldwide, though estimates vary. Wilson disease is more common in certain geographic areas, such as Sardinia, Sicilians, southern Italians, and some Eastern European countries.

• About 1 in 90 people may be carriers of Wilson disease, though estimates vary. (One study puts the range at 1:90 to 1:150. Another study in the UK showed 1:7,000 have the Wilson disease gene mutation.)

• In younger children the liver is most often affected by Wilson disease.

• In adults, the brain may be more affected.

• 40-50% of WD patients experience liver disease as initial symptoms around the age of 15 years.

• Other people with Wilson disease may be misdiagnosed with other neurological, liver, or psychiatric disorders. Many doctors aren’t familiar with Wilson symptoms that can be wide-ranging.

• WD patients can present with ALF; most other untreated patients have chronic progressive hepatitis or cirrhosis.

• 50-60% of Wilson patients present with liver symptoms. About 5% of patients with Wilson disease have ALF with severe liver damage.

• Of all causes of ALF in adults, 5% is due to Wilson disease.

• Of all causes of ALF in the pediatric population, 3.2% is due to Wilson.

• One summary of studies of organ-specific Wilson disease manifestations at presentation:
  • Liver disease: 18% - 84% of patients
  • Neurologic symptoms: 18%-73%
  • Psychiatric symptoms: 10% - 100 %.
  • Most symptomatic pediatric patients (<18 years) present with liver disease alone.

• It is estimated that 35%-45% percent of patients have cirrhosis at diagnosis of Wilson disease.

Last updated on December 10th, 2025 at 04:45 pm