Liver diseases represent a major socioeconomic and health problem worldwide, causing more than 2 million deaths annually. There are various causes of these diseases (viral infections, obesity, genetic alterations, etc.) and their prevalence has varied over time depending on diagnosis, treatment, or society’s lifestyle changes.
Hepatitis C
Until recently, one of the most common liver diseases was caused by the C virus. This virus is parenteral transmitted (transfusions, sharing syringes, etc.) and can cause acute hepatitis (with spontaneous recovery in about 10- 30% of cases) or chronic hepatitis, which can progress to liver cirrhosis and liver cancer. Hepatitis C was the leading cause of liver transplantation until 10 years ago when very effective drugs were developed that inhibit various regions of the virus (NS3, NS4 or NS5), thus preventing its replication. With these new treatments, consisting of pills administered daily for 2 months with excellent tolerance, a cure is obtained in approximately 95% of patients. So much so that daily consultations for hepatitis C accounted for 30% of the total care activity in the specialty of Hepatology and now, they have practically disappeared.
The WHO has proposed as a goal for 2030 the worldwide eradication of hepatitis C and that becomes a rare disease. However, the impact of COVID-19 may change these forecasts. Thus, during the pandemic, the number of diagnostic tests performed against the hepatitis C virus decreased considerably and, furthermore, since hepatitis C is asymptomatic in 90% of cases, there may be a significant number of patients undiagnosed and therefore untreated and spreading the virus
In addition, the repercussion of what is known as occult hepatitis C virus infection remains to be determined. This is a different form of hepatitis C in which the virus markers are not detected (neither antibodies nor the viral RNA) but there is viral RNA in peripheral blood cells and in liver. It was first described in 2004 and since then more than 100 articles have been published confirming its presence on all continents. Patients with occult C virus infection have an immune system capable of controlling and maintaining virus replication at very low levels and therefore the virus is not detected in the blood. In general, they suffer from a milder disease than classic hepatitis C, although 3% of cases have cirrhosis and its presence has been shown to be associated with liver cancer. The impact that this occult infection may have on the maintenance of hepatitis C (as of 2030) is unknown. However, in our experience, over the years patients tend to spontaneously clear this occult virus.
Hepatitis B
Another virus that causes hepatitis is the B virus. B virus infection can lead to an asymptomatic carrier state (excellent prognosis), chronic hepatitis, cirrhosis, and liver cancer. An available and effective vaccine against B virus, that induces protection in 90% of people, exists for 40 years. The genetic material of the B virus is DNA and there are drugs (tenofovir, entecavir) that inhibit virus replication and improve liver disease, although the virus cannot be eradicated (hepatitis B surface antigen or HBsAg undetectable in serum).
The persistence of HBsAg can be due to two reasons. On the one hand, the DNA of the virus can integrate into the hepatocytes and although there is no replication (viral DNA is negative in serum), HBsAg continues to be produced. On the other hand, the virus genome can persist in the nucleus of hepatocytes as covalently closed circular DNA (cccDNA) with the capacity to produce HBsAg and even reinitiate virus B replication. It would be important to differentiate between these situations. For this, a liver biopsy would have to be performed to detect the cccDNA (complex technology). If not detected, treatment could be interrupted but not otherwise. Current treatments do not eliminate cccDNA and different strategies are being investigated to eliminate it (use of nucleases, epigenetic modifications, interfering RNAs, etc.)
Non-alcoholic fatty liver
Currently the most common liver disease in developed countries is fatty liver, which affects 20-30% of the population. There are various causes of non-alcoholic fatty liver disease: being overweight, increased levels of glucose, cholesterol, triglycerides or the intake of drugs (cortisone,…). The diagnosis of fatty liver is almost always made by imaging techniques or by performing a liver biopsy. Accumulation of fat in the liver may not cause damage or it can end in liver cirrhosis and liver cancer. To know the prognosis of the disease, the rs738409 polymorphism of the PNPLA3 gene (change of a cytosine for a guanine) is determined because it is associated with increased levels of fat in the liver and with the risk of progressing to severe forms of the disease.
The treatment of fatty liver consists in lifestyle changes (diet and exercise) and in the correction of the causes of the disease: statins, hypoglycemic agents, etc. Vitamin E and ursodeoxycholic acid may also be prescribed. Trials are currently underway with new drugs (semaglutide, cyclofexor, firsocostat) but there are no definitive results yet.
Alcoholic hepatitis
Another cause that induces liver disease is alcohol. An alcohol intake greater than 40 g/day in women and 60 g/day in men for more than 5 years can cause liver cirrhosis and require a liver transplant. Other than alcohol withdrawal there is no specific treatment.
Autoimmune hepatitis
Autoimmune chronic hepatitis is a disease caused by the immune system. The trigger can be viral (hepatitis A virus), drugs, environmental agents, genetic predisposition, etc. In recent years, autoimmune hepatitis cases are increasing globally but the reason is unknown. It has been suggested that both COVID-19 and the coronavirus vaccine could trigger autoimmune hepatitis but this has not been proven.
Without treatment, autoimmune hepatitis can lead to cirrhosis and liver cancer or liver transplantation. Treatment with immunosuppressive agents (prednisone, azathioprine) is very effective since in 90% of cases the disease is inactivated. Treatment is generally prolonged for 3-5 years and can then be discontinued, with a 75% chance of definitive cure. It is advisable to perform a liver biopsy prior to stopping treatment to check whether the inflammatory activity has been completely eliminated, otherwise the possibility of reactivation is high. There is no serological marker that could be useful to decide whether or not to interrupt treatment and it would be important to carry out studies on this.
Summary
In recent years there have been important advances in the diagnosis and treatment of liver diseases. In the near future, thanks to genomic medicine, individualized therapies (based on the genetic information of each patient) will be available, which will have a great impact on the treatment of liver diseases.
Vicente Carreño
President of the Fundación para el Estudio de las Hepatitis Virales
C/Guzmán el Bueno 72
28015 Madrid (Spain)
