Dengue is a mosquito-transmitted virus, and dengue fever is the leading cause of the arthropod-borne viral disease worldwide, posing a significant global health concern. This disease is also known by various monikers, such as breakbone or 7-day fever, and is characterized by intense muscle spasms, joint pain, and high fever, reflecting both the severity and the duration of symptoms. Most dengue virus cases are asymptomatic, yet severe illness and mortality can occur, especially in regions where female Aedes mosquitoes—Aedes aegypti and Aedes albopictus—primarily transmit the virus. Dengue fever, with over 100 million cases annually and 20 to 25,000 deaths, presents a substantial public health challenge, marked by epidemics across different regions globally. Diagnosis usually entails identifying virus antigens using diverse laboratory techniques.
Indonesia, a transcontinental unitary sovereign state located in Southeast Asia, is a tropical country where both main mosquito vector species of dengue virus, Aedes aegypti and Ae. albopictus, are endemic almost in all regions. Dengue prevention and control programs have been in place on a national scale by the Ministry of Health (MoH) of Indonesia through the Directorate General for Communicable Diseases Control since 1968.The programs include the implementation of peri-focal adult spraying, mass larviciding, and disease control education to the community. Despite the efforts of these control programs, dengue has expanded in both incidence and geographical range over the years and has become hyperendemic with multiple co-circulating nationwide. Several major dengue outbreaks have been reported in the country.
Severe dengue diseases develop in a small proportion of these patients, and the common organ involvement is the liver. The hepatocellular injury was found in 60%-90% of DHF patients manifested as hepatomegaly, jaundice, elevated aminotransferase enzymes, and critical condition as an acute liver failure (ALF). Even the incidence of ALF in DHF is very low (0.31%-1.1%), but it is associated with a relatively high mortality rate (20%-68.3%). The pathophysiology of liver injury in DHF included the direct cytopathic effect of the dengue virus causing hepatocytes apoptosis, immune mediated hepatocyte injury induced hepatitis, and cytokine storm.
Liver disease is a general term that refers to any condition affecting your liver. These conditions may develop for different reasons, but they can all damage your liver and affect its function. Your liver is a vital organ that performs hundreds of tasks related to metabolism, energy storage, and waste filtering. It helps you digest food, convert it to energy, and store the energy until you need it. It also helps filter toxic substances out of your bloodstream.
Liver disease symptoms vary, depending on the underlying cause. It’s also possible for someone to have liver disease and not have any symptoms at all. However, Hepatitis NSW says that a few general symptoms can indicate some kind of severe liver damage. These include:
The spectrum of symptoms in DHF patients is very diverse, ranging from mild to severe dengue disease (SDD). Dengue virus infection (DVI) has an incubation period of 3-14 d with the same symptom as a common cold and gastroenteritis. The patients usually have an abrupt fever, retro-orbital pain, headache, muscle ache, arthralgia, nausea, vomiting, diarrhea, and rashes.
Dengue viral infections are one of the most rapidly evolving vectors borne infections, which now affects 125 countries, causing approximately 100 million apparent infections each year. It is predicted that the transmission of dengue will be more intensified in dengue endemic countries, and due to climate change and other factors, the infection may spread to countries.
Infection with the dengue virus results in asymptomatic disease or an undifferentiated viral fever like illness in the majority of infected individuals. However, in others, it may result in dengue fever (DF), dengue haemorrhagic fever (DHF) leading to shock (DSS). Involvement of the liver leading to hepatic dysfunction is a well-recognized complication of dengue. Dengue associated acute liver failure has a high mortality due to complications such as encephalopathy, severe bleeding, renal failure and metabolic acidosis. Varying degrees of liver involvement are seen during acute dengue infection and are thought to result from hepatocyte apoptosis directly by the virus, hypoxic damage due to impaired liver perfusion resulting from fluid leakage, oxidative stress or immune mediated injury. Since the rise in liver transaminase and GGT levels peaked around day 6–7, assays of liver function tests done around day 4–5 (on admission).
Elevated transaminitis levels can be caused by many things. The liver breaks down nutrients and filters toxins out of your body, which it does with the help of enzymes. Transaminitis, sometimes called hypertransaminasemia, refers to having high levels of certain liver enzymes called transaminases. Transaminitis is a condition where serum aspartate transaminase (AST) and alanine transaminase (ALT) increase. The serum transminases increase when the hepatocytes are damaged during different diseases, and thus transaminases may act as a surrogate marker for assessing the hepatic involvement with the severity of different disease. Serum AST is usually elevated more than ALT in dengue during the early days of infection.
Transaminitis in dengue infection could be due to the direct dengue virus effect on the hepatocytes or the host’s immune response to the viral infection. The receptors present on hepatocytes and Kupffer cells are the primary targets of the dengue virus to which they attach and infect the cells. This causes cellular apoptosis due to viral cytopathy, mitochondrial dysfunction, immune response and accelerated endoplasmic reticular stress.
Severe dengue may be due to exaggerated immune reactions to recurrent infections. Infection with dengue virus stimulates a cytokine storm often called a cytokine Tsunami causing the concentrations of different cytokines like interleukins, tumor necrosis factor-α, and interferon-? to reach peaks. The higher level of AST compared to ALT could be due to the release of the enzymes from the damaged myocytes, which helps to differentiate dengue infection from other acute hepatitis caused by Hepatitis A, B, and C because of their reverse AST/ALT pattern.
Transaminitis Symptoms
Transaminitis by itself doesn’t cause symptoms, but underlying liver disorders may cause symptoms including:
Strategies to Help Prevent Transaminitis
Transaminitis, also known as elevated liver enzymes, can be indicative of liver inflammation or damage. Preventing transaminitis involves managing risk factors and maintaining liver health through various lifestyle and dietary measures. Here are some strategies to help prevent transaminitis:
A. Lifestyle and Dietary Measures:
B. Supplementation with Liver Protector Agent
a. Silymarin
Herbal products are increasingly used, mainly in chronic liver disease like Silymarin. Silymarin is a complex of at least seven flavonolignans that are the most common class of compounds present in milk thistle extract, and one flavonoid, Taxifolin. Silybin represents about 50% to 70% of the silymarin extract. Experimental studies have clearly demonstrated the antifibrotic, antioxidant and metabolic effects of silybin. The antioxidant effects of Silybin have been demonstrated in all cells studied.
Silybin acts as an antioxidant because it inhibits radical formation, binds some radical species (scavenger), interferes with lipid peroxidation of membranes (and therefore modulates membrane permeability), and increases the intracellular content of scavengers. In fact, in the presence of oxidative and nitrosative stress, silybin inhibits the formation of superoxide anion radicals and nitric oxide (NO), increases ATP content through the phosphorylation of ADP, decreases the content of malondialdehyde (MDA) and totally abolishes the decrease of glutathione, of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase.
Flavonolignans like Silymarin or Silybin are known for their poor and erratic bioavailability, low solubility in water, and poor intestinal absorption. To counteract this aspect, different more soluble derivates of silybin have been synthesized, such as silybin-phosphatidylcholine. Bioavailability of Silybin-Phosphatidylcholine is higher than that of silymarin and is less influenced by liver damage.
b. Folate
Folate, also known as vitamin B9, plays a crucial role in various bodily functions, including DNA synthesis and repair, red blood cell formation, and homocysteine metabolism. In particular, in several animal studies, low folate levels have been linked to oxidative stress, liver damage, and hepatocarcinogenesis. Folate plays an important role in regulating hepatic metabolism.
Folate deficiency can result in elevated homocysteine levels, a risk factor for cardiovascular diseases, which are common comorbidities in patients with liver disease. Folate supplementation may be beneficial for patients with liver disease to prevent or correct deficiencies. This can help mitigate of the associated risks, such as elevated homocysteine levels.
PT. SIMEX PHARMACEUTICAL INDONESIA as one of the pharmaceutical companies in Indonesia presents HEPARLIC® products as a herbal medicine contain the newest combination of Silybin-Phosphatidylcholine Complex, the active form of Silymarin and 5-MTHF as a biologically active form of folic acid. HEPARLIC® can help to support liver health because of its effects as an antioxidant and antifibrotic.
Referensi
https://www.ncbi.nlm.nih.gov/books/NBK430732/
Harapan H., Michie A., Mudatsir M., et.al. 2019. Epidemiology of dengue hemorrhagic fever in Indonesia: analysis of five decades data from the National Disease Surveillance. Harapan et al. BMC Res Notes (2019) 12:350
https://www.healthline.com/health/liver-diseases#common-problems
Fernando S., Wijewickrama A., Gomes L., et.al. 2016. Patterns and causes of liver involvement in acute dengue infection. BMC Infectious Diseases (2016) 16:319.
Rayamajhi RJ., Thapa S., Rayamajhi P., Maharjan S., et.al. 2023. Transaminitis among Patients with Dengue Fever Visiting a Tertiary Care Centre. JNMA Vol. 61, Issue 265
https://www.webmd.com/a-to-z-guides/what-is-transaminitis
Loguercio C., Festi D. 2011. Silybin and the liver: From basic research to clinical practice. World J Gastroenterol 2011 May 14; 17(18): 2288-2301.
Welzel TM., Katki HA., Sakoda LC., et.al. 2007. Blood Folate Levels and Risk of Liver Damage and Hepatocellular Carcinoma in a Prospective High-Risk Cohort. Cancer Epidemiol Biomarkers Prev 2007;16(6):1279–82
