Metabolic liver disease results from disruptions in metabolic processes leading to chronic hepatitis, liver cirrhosis, and liver cancer, which may necessitate liver transplantation. Three of the most common metabolic liver diseases include Wilson’s disease, Alpha-I antitrypsin deficiency (AATD), and Hereditary hemochromatosis, all of which involve an overproduction of a specific molecule that accumulates in hepatic cells and causes liver damage. All three diseases have a genetic basis, with a mutation in a particular gene responsible for their development.1 Further details on each disease's genetic etiology will be discussed.
Wilson disease is a rare genetic disorder of copper metabolism that affects about 1 in 30,000 individuals worldwide. The disease results from mutations in the ATP7B gene which plays a critical role in copper metabolism. The gene codes for a protein that transports copper from the liver into bile for excretion from the body. Mutations in this gene cause a decrease in the ability of this protein to transport copper, leading to the accumulation of copper in the liver and other organs like the brain, kidneys, and eyes.2
Symptoms of Wilson disease typically affect the liver and the brain. Hepatic symptoms include abdominal pain, vomiting, jaundice, itching, weakness, and oedema. Neurological symptoms include tremors, seizures, difficulty with speech and coordination, migraines, insomnia, anxiety, and hallucinations.2 The hallmark of Wilson’s Disease is the presence of dark rings encircling the iris due to copper deposition in the eyes, known as Kayser-Fleischer Rings.3
The diagnosis of Wilson disease typically involves the measurement of ceruloplasmin and copper levels in the urine. Ceruloplasmin is an enzyme that plays a key role in copper metabolism, carrying copper in the body and facilitating its excretion from the liver.2 Low ceruloplasmin levels (100 mcg/dL) are suggestive of Wilson disease.5 Liver biopsy can be used to confirm the diagnosis. Molecular genetic testing is also performed and involves sequencing the ATP7B gene to detect disease-causing mutations.2
Treatment of Wilson disease involves reducing copper levels in the body through chelation therapy with penicillamine or trientine, which bind copper and facilitate its excretion from the body. Zinc supplements can also be given to prevent the absorption of copper. In severe cases, liver transplantation may be the only curative option. Neurological symptoms can be managed with medications like baclofen and levodopa.2
The largest risk factor for Wilson disease is a family history of the disease, particularly if first-degree relatives show symptoms. Once a family member is diagnosed with Wilson disease, it's recommended that each first-degree relative undergo diagnostic testing even if they are asymptomatic.2
Wilson disease can lead to liver failure, encephalopathy, splenomegaly, ascites, variceal bleeding, hepatorenal syndrome, and death. However, with early diagnosis and appropriate treatment, many individuals can lead normal, healthy lives.2
Alpha I antitrypsin deficiency (AATD)
Alpha-1 antitrypsin deficiency is a genetic condition that results in a decreased production of functional alpha-1 antitrypsin protein which protects the body from infection-fighting enzymes; the condition is caused by mutations in the SERPINA1 gene, which leads to accumulation of abnormal AAT protein in the liver causing liver damage and lung damage due to the destruction of alveoli by neutrophil elastase.The occurrence of AATD differs among different ethnic groups, with individuals of European ancestry being affected at a rate of approximately 1 in 1500 to 3500, while it is not very common in people of Asian origin.5
AAT deficiency affects three organs: the lung, liver, and skin. Lung disease symptoms are similar to COPD, including dyspnea, cough, sputum production, and wheezing. Extrapulmonary symptoms can manifest as chronic hepatitis, cirrhosis, hepatocellular carcinoma, necrotizing panniculitis, and vasculitis.5
To diagnose AAT deficiency, a serum level below 11 micromoles/L is sufficient. Phenotype and genotype testing are also performed.5
The treatment of AATD is aimed at managing the symptoms and preventing complications. For lung disease, smoking cessation, oxygen therapy and in advanced cases, lung transplantation is an option. For liver disease, avoiding alcohol is necessary. Liver transplantation may be necessary in cases of advanced cirrhosis or liver failure. In some cases, intravenous infusions of purified AAT protein are used to increase serum levels of AAT.6
According to the American Thoracic Society, the major risk factor for AATD is having a family history of the condition, as it is an inherited disorder. Other risk factors may include smoking, exposure to air pollution or irritants, and respiratory infections.6
Alpha-1 antitrypsin deficiency can lead to asthma, emphysema, chronic bronchitis, and chronic liver disease.5
Hereditary hemochromatosis (HH) is an autosomal recessive genetic disorder that causes the body to absorb and store too much iron, leading to iron overload and damage to various organs, including the liver, heart, and pancreas.7 HH is one of the most common genetic disorders among people of Northern European descent, affecting approximately 1 in 200 to 250 individuals in this population.7
Hemochromatosis can lead to harmful levels of iron buildup resulting in symptoms such as tiredness, joint pain, loss of interest in sex, liver pain, and skin darkening.8
Hemochromatosis is diagnosed by measuring levels of iron and specific proteins, as well as genetic testing to identify gene mutations that often cause hemochromatosis. Occasionally, a liver biopsy may be required to confirm the presence of iron overload.8
Therapeutic phlebotomy is the first line of treatment, which involves removing a certain amount of blood regularly to reduce the iron overload. Iron chelation therapy may be used in rare cases where phlebotomy is not possible.9
The primary risk factor for hereditary hemochromatosis is having specific genetic mutations, such as the C282Y and H63D mutations. Other risk factors include a diet high in iron, liver disease and alcoholism.8
Complications of hereditary hemochromatosis may include liver damage, cirrhosis, liver cancer, heart problems, diabetes, and skin discoloration.8
How can I prevent metabolic liver disease?
Unfortunately, due to the genetic nature of the disease, it cannot be prevented, but we can avoid its complications by early diagnosis and treatment and maintaining a healthy lifestyle.
How common is metabolic liver disease?
It is estimated that up to 30% of the adult population in developed countries may have non-alcoholic fatty liver disease (NAFLD), a common type of metabolic liver disease.
When should I see a doctor?
You should see a doctor if you experience fatigue, abdominal pain, jaundice, or unexplained weight loss. Additionally, if you have a family history of metabolic liver disease, it's recommended to get regular check-ups to assess liver function.
The three most common metabolic liver diseases are Wilson’s disease, Alpha-I antitrypsin deficiency (AATD), and Hereditary hemochromatosis. Wilson disease is a genetic disorder that causes the accumulation of copper in various organs, resulting in abdominal pain, vomiting, and tremors. Its diagnosis involves measuring ceruloplasmin and copper levels, liver biopsy, and molecular genetic testing. Treatment involves reducing copper levels through chelation therapy or liver transplantation. Alpha-1 antitrypsin deficiency is a genetic condition that causes liver and lung damage due to decreased production of functional alpha-1 antitrypsin protein, and symptoms include COPD, chronic hepatitis, and cirrhosis. Diagnosis involves a serum level below 11 micromoles/L, isoelectric focusing, and PCR testing. Treatment involves managing symptoms and preventing complications, such as smoking cessation for lung disease and avoiding alcohol and managing hepatitis for liver disease. Hereditary hemochromatosis is a genetic disorder that causes iron overload, leading to damage in the liver, heart, and pancreas. Symptoms include fatigue, joint pain, liver pain, and skin darkening. Treatment involves therapeutic phlebotomy or iron chelation therapy.
- Metabolic liver disease [Internet]. [cited 2023 Apr 25]. Available from: https://www.bidmc.org/conditions-and-treatments/kidney-liver-and-urinary/metabolic-liver-disease
- Chaudhry HS, Anilkumar AC. Wilson disease. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 [cited 2023 Apr 25]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK441990/
- Ferenci P. Pathophysiology and clinical features of Wilson disease. Metab Brain Dis [Internet]. 2004 Dec;19(3–4):229–39. Available from: https://pubmed.ncbi.nlm.nih.gov/15554419/
- Bennett J, Hahn SH. Clinical molecular diagnosis of wilson disease. Semin Liver Dis [Internet]. 2011 Aug [cited 2023 Apr 25];31(3):233–8. Available from: http://www.thieme-connect.de/DOI/DOI?10.1055/s-0031-1286054
- Meseeha M, Attia M. Alpha 1 antitrypsin deficiency. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 [cited 2023 Apr 28]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK442030/
- American Thoracic Society, European Respiratory Society. American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2003 Oct 1;168(7):818–900.
- McLaren CE, Emond MJ, Subramaniam VN, Phatak PD, Barton JC, Adams PC, et al. Exome sequencing in HFE C282Y homozygous men with extreme phenotypes identifies a GNPAT variant associated with severe iron overload. Hepatology [Internet]. 2015 Aug [cited 2023 Apr 29];62(2):429–39. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4508230/
- Hemochromatosis - niddk [Internet]. National Institute of Diabetes and Digestive and Kidney Diseases. [cited 2023 Apr 29]. Available from: https://www.niddk.nih.gov/health-information/liver-disease/hemochromatosis
- Treatment of hemochromatosis - niddk [Internet]. National Institute of Diabetes and Digestive and Kidney Diseases. [cited 2023 Apr 29]. Available from: https://www.niddk.nih.gov/health-information/liver-disease/hemochromatosis/treatment