Neurological manifestations of deficiencies and intoxications

1. Vitamin deficiencies

Thiamine deficiency is usually caused by poor nutrition in chronic excessive alcohol consumption, but can also occur in hyperemesis (gravidarum) or in inadequate parenteral nutrition. The neurological manifestations are polyneuropathy, Wernicke's encephalopathy and Korsakov's syndrome.

1.1 Thiamine (vitamin B1)

- Polyneuropathy

- Wernicke's encephalopathy

- Korsakoff's syndrome

1.2 Pyridoxine (vitamin B6)

1.3 Cyanocobalamin (vitamin B12)

2. Excessive alcohol consumption

2.1 Alcohol intoxication

2.2 Manifestations of chronic alcohol use

2.3 Withdrawal symptoms

3. Medicines

3.1 Disturbances of consciousness

3.2 Epileptic seizures

3.3 Extrapyramidal side effects

3.4 Neuroleptic malignant syndrome

3.5 Malignant hyperthermia

3.6 Serotonin syndrome

3.7 Polyneuropathy

3.8 Muscle cramps and myopathy

4 Drugs  

4.1 Sympathomimetic substances

4.2 Narcotics

4.3 Sedatives

Cirrhosis is a chronic disease with multiple etiologies, multiple manifestations, and multi-organ involvement. It affects about 200 million people worldwide and its main complication is portal hypertension (PHT). Cirrhotic cardiomyopathy is a consequence of PHT, with heart failure (HF) being the main manifestation. On the other hand, for people with cardiopathy due to reasons beyond cirrhosis, the presence of the last could act as a trigger to acute HF. Finally, when HF and cirrhosis coexist, the renal system suffers the most, originating from type 5 cardiorenal syndrome, a complex entity with many challenges in diagnosis and treatment.

The proper balance between acids and bases is maintained by the integrated function of kidneys, lungs and liver. The liver is the principal organ responsible for hydrogen ion (H + ) metabolism from the body's daily protein intake and a resulting acid loading on the body. 

The liver plays a role in pH homeostasis in addition to the well-established role of lungs and kidneys. Hepatic and renal nitrogen metabolism are linked by an interorgan glutamine flux, which couples both renal ammoniagenesis and hepatic ureogenesis to systemic acid-base regulation. Hepatic urea synthesis is a major pathway for the removal of metabolically generated bicarbonate. A structural-functional organization in the liver acinus uncouples urea cycle flux control from the vital need to maintain ammonium homeostasis. There is a sensitive and complex control of bicarbonate disposal via hepatic ureogenesis by the extracellular acid-base status, suggestive of a feedback control loop between acid-base status and the rate of bicarbonate elimination, i.e., a hepatic bicarbonate-homeostatic response. Pathophysiological implications arise from the pH-stat function of the liver. 

The prevalence of local complications, persistent organ failure, and mortality were also higher in patients with fatty liver. Even after adjusting for age, sex, body mass index, and cause of pancreatitis, fatty liver was significantly associated with moderately severe or severe acute pancreatitis. 

The prevalence of local complications, persistent organ failure, and mortality were also higher in patients with fatty liver. Even after adjusting for age, sex, body mass index, and cause of pancreatitis, fatty liver was significantly associated with moderately severe or severe acute pancreatitis. 

Daily rhythms in bile acid homeostasis are regulated by both the molecular clock and the daily rhythm in food intake. While food intake directs daily rhythms in plasma bile acids and hepatic gene expression of Shp, the hepatic clock directs daiuly rhythms in gene expression of the two bile acid pool-defining enzymes Cyp7a1 and Cyp8b1. Which pathway is leading in bile acid biosynthesis and subsequent bile acid signaling in the enterohepatic and systemic circulating? The question remains. Clear is however the indication that eating during the inactive period will effect the bile acid metabolism.

Bile acids may mediate the positive effects of time restricted on body weight during high fat diet (Chaix and Zarrinpar, 2015), the reverse could also be true, namely that bile acids may mediate the adverse effects of eating at the wrong time.

There is a mutual interaction between the function of the heart and the liver and a broad spectrum of acute and chronic entities that affect both the heart and the liver. These can be classified into heart diseases affecting the liver, liver diseases affecting the heart, and conditions affecting the heart and the liver at the same time. In chronic and acute cardiac hepatopathy, owing to cardiac failure, a combination of reduced arterial perfusion and passive congestion leads to cardiac cirrhosis and cardiogenic hypoxic hepatitis. These conditions may impair the liver function and treatment should be directed towards the primary heart disease and seek to secure perfusion of vital organs. In patients with advanced cirrhosis, physical and/or pharmacological stress may reveal a reduced cardiac performance with systolic and diastolic dysfunction and electrophysical abnormalities termed cirrhotic cardiomyopathy. Electrophysiological abnormalities include prolonged QT interval, chronotropic incompetance, and electromechanical uncoupling. No specific therapy can be recommended, but it should be supportive and directed against the heart failure. Numerous conditions affect both the heart and the liver such as infections, inflammatory and systemic diseases, and chronic alcoholism. The risk and prevalence of coronary artery disease are increasing in cirrhotic patients and since the perioperative mortality is high, a careful cardiac evaluation of such patients is required prior to orthotopic liver transplantation. 

Cirrhosis is a chronic disease with multiple etiologies, multiple manifestations, and multi-organ involvement. It affects about 200 million people worldwide and its main complication is portal hypertension (PHT). Cirrhotic cardiomyopathy is a consequence of PHT, with heart failure (HF) being the main manifestation. On the other hand, for people with cardiopathy due to reasons beyond cirrhosis, the presence of the last could act as a trigger to acute HF. Finally, when HF and cirrhosis coexist, the renal system suffers the most, originating from type 5 cardiorenal syndrome, a complex entity with many challenges in diagnosis and treatment.

ALCYDON-Innate-immunity-01

The innate immune signalling also maintains tissue and organ homeostasis, such as intestinal microflora, proliferation and apoptosis of intestinal epithelial cells, and liver regeneration after the loss of liver mass (Rakoff-Nahoum et al. 2004; Seki et al. 2005; Wen et al. 2008). Notably, aberrant activation of innate immune signalling may trigger ‘harmful inflammation’ that contributes to sepsis, chronic inflammation, autoimmune diseases, tissue and organ injuries, fibrosis and carcinogenesis (Seki & Brenner, 2008). 

The liver has a unique vascular system within the gastrointestinal tract, as the majority of the liver’s blood supply comes from the intestine through the portal vein.  The liver is the first extraintestinal organ that encounters venous blood from the small and large intestines via the portal vein. Due to this unique blood supply system, the liver is the first to detect bacterial products translocated from the gut lumen via the portal vein. 

Almost all blood that enters the liver via the portal tract originates from the gastrointestinal tract as well as from the spleen, pancreas and gallbladder. A second blood supply to the liver comes from the hepatic artery, branching directly from the celiac trunc and descending aorta. The portal vein supplies venous blood under low pressure conditions to the liver, while the hepatic artery supplies high-pressured arterial blood. Since the capillary bed of the gastrointestinal tract already extracts most O2, portal venous blood has a low O2 content. Blood from the hepatic artery on the other hand, originates directly from the aorta and is, therefore, saturated with O2. Blood from both vessels joins in the capillary bed of the liver and leaves via central veins to the inferior caval vein.

The liver holds a unique position with regard to the blood circulation. It receives venous blood draining from almost the entire gastrointestinal tract via the portal vein and from the systemic circulation via the hepatic artery. More than 2000 L of blood stream daily through the human liver, and peripheral blood leukocytes pass through the liver on average more than 300 times per day. These simple facts clearly demonstrate that the liver is a “meeting point” for antigens and leukocytes circulating in the blood. 

People with liver diseases, mainly hepatic cirrhosis and NAFLD, or those undergoing LT can develop heart systolic and diastolic dysfunctions in addition to electrophysiological cardiac abnormalities. 

Blood pressure in afferent vessels and pressure distribution inside the liver, is essentially similar for most species. Pressure in the hepatic artery, originating from the descending aorta and the celiac trunc, is considered to be the same as aortic pressure. This includes a high pulsatile pressure between 120 and 80 mmHg with a frequency equal to the heart rate. Vessel compliance causes a gradual decrease in pulsation as the hepatic artery branches and rebranches inside the liver. Once at the sinusoidal level, pulsation amplitude decreases to virtually zero and pressure drops to approximately 2-5 mmHg. On the other hand, pressure in the portal vein, originating from capillaries of the digestive tract, has no pulsation and a pressure of 10-12 mmHg. In the sinusoids, both portal venous and hepatic arterial pressure is 3-5 mmHg. Consequently, the pressure drop inside the liver is much less in the portal venous system than in the arterial system. The pressure drop from the col lecting central veins to the vena cava is then approximately 1-3 mmHg, fluctuating slightly with respiration.

more reading on flow distribution >

Role of the liver in acquired blood clotting disorders

Acquired coagulation deficiencies are much more common than hereditary defects. In contrast to hereditary deficiencies, there is usually a deficiency of more than one coagulation factor. The production disorders that occur with vitamin K deficiency or impaired liver function are clinically the most important.

The gut-liver axis is a complex, bidirectional communication network that links the gastrointestinal tract and the liver via the portal vein, bile ducts, and systemic circulation. This physiological interaction plays a critical role in maintaining hepatic and systemic homeostasis. The liver, as a central metabolic organ, processes nutrients, hormones, and microbial-derived metabolites that are absorbed from the gut. In return, the liver regulates gut function through bile acids and immunological signals. This dynamic relationship ensures the maintenance of intestinal barrier integrity, bile acid metabolism, and immune surveillance. Gut-derived metabolites, microbial components, and immune signals significantly influence liver health. These include short-chain fatty acids (SCFAs), bile acids, and 

Bile acids are potent metabolic and immune signaling molecules synthesized from cholesterol in the liver and then transported to the intestine where they can undergo metabolism by gut bacteria. The combination of host- and microbiota-derived enzymatic activities contribute to the composition of the bile acid pool and thus there can be great diversity in bile acid composition that depends in part on the differences in the gut bacteria species. Bile acids can profoundly impact host metabolic and immunological functions by activating different bile acid receptors to regulate signaling pathways that control a broad range of complex symbiotic metabolic networks, including glucose, lipid, steroid and xenobiotic metabolism, and modulation of energy homeostasis. Disruption of bile acid signaling due to perturbation of the gut microbiota or dysregulation of the gut microbiota-host interaction is associated with the pathogenesis and progression of metabolic disorders. 

Gut microbiota facilitate nutrient harvesting and producing molecules that interact with host transporters, enzymes, and receptors. Bacterial enzymes directly metabolize non-digestible carbohydrates to salvage energy from food to fuel the host and produce short chain fatty acids (SCFAs) as end products that influence host cellular metabolism and signaling (Brown et al., 2003; Kasubuchi, Hasegawa, Hiramatsu, Ichimura, & Kimura, 2015; Sun, Wu, Liu, & Cong, 2017). Among other types of bacterial-derived metabolic and immunological signaling molecules are bile acids (Fiorucci & Distrutti, 2015). Bile acids are a group of steroid acids synthesized in the liver from cholesterol, transported to the intestine, and metabolized and transformed by the gut microbiota through deconjugation, dehydroxylation, oxidation and epimerization, re-conjugation, and other reactions (Gropper & Smith, 2012; Lucas et al., 2021; Macdonald, Bokkenheuser, Winter, McLernon, & Mosbach, 1983; Ridlon, Kang and Hylemon, 2006, Ridlon, Kang and Hylemon, 2010). 

Disruption of the intestinal epithelial barrier results in a leaky gut, which contributes to bacterial translocation (Seki & Brenner, 2008; Crispe, 2009; Pradere et al. 2010). Translocation of large amounts of gut-derived products is usually prevented by intact barrier systems provided by intestinal epithelial cells (Crispe, 2009). Thus, in a healthy organism only minor quantities of translocated bacterial products reach the liver. In general, the hepatic immune system tolerates these bacterial products in order to avoid harmful responses, which is also known as ‘liver tolerance’ (Crispe, 2009). The liver not only consists of parenchymal hepatocytes, but also contains non-parenchymal cells including immune and non-immune cells. Members of the hepatic immune system are resident liver tissue macrophages (Kupffer cells), natural killer (NK) cells, NKT cells, T cells and B cells; these cell types strictly regulate the liver immune system including liver tolerance (Seki & Brenner, 2008). 

Bile acids profoundly impact host metabolic and immunological function as they can activate different bile acid receptors including the farnesoid X receptor (FXR), G-protein-coupled receptor-1 (TGR5/GPBAR1), pregnane X receptor (PXR), and vitamin D receptor (VDR) (Fiorucci & Distrutti, 2015). These bile acid receptors regulate signaling pathways within a complex symbiotic metabolic network that controls lipid, glucose, steroid, xenobiotic, and energy metabolism (Claudel, Staels, & Kuipers, 2005; Jiang et al., 2013; Qi et al., 2015; Watanabe et al., 2006). 

The diversity and composition of the gut microbiota can be perturbed by environmental factors including diet composition, xenobiotic exposure (e.g., drugs, environmental toxicants, antibiotics) and lifestyle (e.g., smoking, exercise, stress, social interactions) (Claus, Guillou, & Ellero-Simatos, 2016; Clemente, Ursell, Parfrey, & Knight, 2012; Conlon & Bird, 2015). Disrupted bile acid signaling due to perturbation of the gut microbiota by environmental chemicals or through disruption of the gut microbiota-host interaction has been associated with various inflammatory metabolic disorders including obesity, type 2 diabetes (T2D), nonalcoholic liver disease (NAFLD), cholestasis and gallstone disease, and inflammatory bowel disease (IBD) (Arab, Cabrera and Arrese, 2017, Arab, Karpen, Dawson, Arrese and Trauner, 2017; Grice & Segre, 2012; Li & Apte, 2015; Prawitt, Caron, & Staels, 2011; Quinn et al., 2020; Wang, Yao, Lv, Ling, & Li, 2017). 

Understanding the link between the microbiota and the pathophysiology of liver diseases will help in the design of innovative therapies. 

The proper balance between acids and bases is maintained by the integrated function of kidneys, lungs and liver. The liver is the principal organ responsible for hydrogen ion (H + ) metabolism from the body's daily protein intake and a resulting acid loading on the body. 

LXR alpha

Macrophages use LXRs to regulate thymic lipid homeostasis, TECs use LXRs for self-renewal and thymic regeneration, and thymocytes rely on LXRs. 

LXRα expression is restricted to liver, kidney, intestine, fat tissue, macrophages, lung, and spleen and is highest in liver, hence the name liver X receptor α (LXRα). LXRβ is expressed in almost all tissues and organs hence the early name UR (ubiquitous receptor). The nuclear receptors liver-X-receptors (LXRs) are important regulators of intracellular cholesterol and lipids homeostasis. They have also key regulatory roles in immune response, as they can regulate inflammation, innate and adaptive immunity. 

The liver X receptors (LXRs) are nuclear receptors that play central roles in the transcriptional control of lipid metabolism. LXRs function as nuclear cholesterol sensors that are activated in response to elevated intracellular cholesterol levels in multiple cell types. Once activated, LXRs induce the expression of an array of genes involved in cholesterol absorption, efflux, transport, and excretion. In addition to their function in lipid metabolism, LXRs have also been found to modulate immune and inflammatory responses in macrophages. The ability of LXRs to integrate metabolic and inflammatory signaling makes them particularly attractive targets for intervention in human metabolic disease. 

FGF21

Fibroblast growth factor 21 (FGF21) is expressed in the thymus as well as in the liver. In line with this expression profile, FGF21 was recently reported to protect against ageing related thymic senescence by improving the function of thymic epithelial cells (TECs). 

Retinol-binding protein 4 (RBP4) is crucial for vision as it is the primary carrier of retinol (vitamin A) in the bloodstream, delivering it to the retinal pigment epithelium (RPE). This delivery is essential for the visual cycle, where retinol is converted into 11-cis-retinal, the chromophore of visual pigments in photoreceptor cells. RBP4 deficiency can lead to impaired visual function, including night blindness and photoreceptor cell loss. Retinol-binding protein 4 (RBP4, Q5VY30) is a major blood transporter of retinol from hepatocyte to target organs. Pathogenic variants in RBP4 are associated with both ocular developmental abnormalities and retinal degeneration. Retinol binding protein 4 (RBP4) is a member of the lipocalin family and the major transport protein of the hydrophobic molecule retinol, also known as vitamin A, in the circulation. Expression of RBP4 is highest in the liver, where most of the body’s vitamin A reserves are stored as retinyl esters. For the mobilization of vitamin A from the liver, retinyl esters are hydrolyzed to retinol, which then binds to RBP4 in the hepatocyte. After associating with transthyretin (TTR), the retinol/RBP4/TTR complex is released into the bloodstream and delivers retinol to tissues via binding to specific membrane receptors. So far, two distinct RBP4 receptors have been identified that mediate the uptake of retinol across the cell membrane and, under specific conditions, bi-directional retinol transport. Although most of RBP4’s actions depend on its role in retinoid homeostasis, functions independent of retinol transport have been described.

Severe liver diseases, including NAFLD, ALD, liver fibrosis and cirrhosis and recently diagnosed viral hepatitis, were associated with cataract. The revelation of liver-eye connection suggests the importance of ophthalmic care in the management of liver disease, and the intervention precedence of patients with liver disease in the early screening and diagnosis of cataract. Even mild forms of liver disease have been linked to decreased vision, primarily night vision, as well as the reduced ability to distinguish shapes and colors. 

There is a significant, rather than just anecdotal, connection between the liver and the eyes. This connection is evident in noticeable cases such as jaundice, where the sclera has a yellow tint. But this can be seen through even more subtle indicators, such as molecules known as hepatokines. This relationship is not merely anecdotal; in some studies, it is referred to as the “liver–eye axis”. Ubiquitous environmental contaminants, such as microplastics (MPs), can enter the bloodstream and human body through the conjunctival sac, nasolacrimal duct, and upper respiratory tract mucosa. Once absorbed, these substances can accumulate in various organs and cause harm. Toxic substances from the surface of the eye can lead to local oxidative damage by inducing apoptosis in corneal and conjunctival cells, and irregularly shaped microparticles can exacerbate this effect. Even other toxicants from the ocular surface may be absorbed into the bloodstream and distributed throughout the body. Environmental toxicology presents a challenge because many pollutants can enter the body through the same ocular route as that used by certain medications. Previous research has indicated that the accumulation of MPs may play a major role in the development of chronic liver disease in humans. It is crucial to investigate whether the buildup of MPs in the liver is a potential cause of fibrosis, or simply a consequence of conditions such as cirrhosis and portal hypertension. 

Eye conditions often associated with liver imbalances include: myopia, astigmatism, AMD, retinitis pigmentosa, Presbyopia, dry eyes, floaters, glaucoma, Stargardt's, cataracts, red and dry eyes. Other eye issues include: photophobia, bloodshot eyes, poor night vision, blurry vision, headaches.     

In chronic liver diseases, splenomegaly and hypersplenism can manifest following the development of portal hypertension. These splenic abnormalities correlate with and have been postulated to facilitate the progression of liver fibrosis to cirrhosis, although precise mechanisms remain poorly understood. 

Clinically, liver cirrhosis is frequently accompanied by multiple complications including splenomegaly and hypersplenism. Studies have suggested that these splenic abnormalities may promote the progression of liver fibrosis to cirrhosis and exacerbate disease prognosis through multiple possible pathways. 

The liver is a central immunological organ with a high exposure to circulating antigens and endotoxins from the gut microbiota, particularly enriched for innate immune cells (macrophages, innate lymphoid cells, mucosal-associated invariant T (MAIT) cells). In homeostasis, many mechanisms ensure suppression of immune responses, resulting in tolerance. Tolerance is also relevant for chronic persistence of hepatotropic viruses or allograft acceptance after liver transplantation. The liver can rapidly activate immunity in response to infections or tissue damage. Depending on the underlying liver disease, such as viral hepatitis, cholestasis or NASH, different triggers mediate immune-cell activation. Conserved mechanisms such as molecular danger patterns (alarmins), Toll-like receptor signalling or inflammasome activation initiate inflammatory responses in the liver. The inflammatory activation of hepatic stellate and Kupffer cells results in the chemokine-mediated infiltration of neutrophils, monocytes, natural killer (NK) and natural killer T (NKT) cells. The ultimate outcome of the intrahepatic immune response (for example, fibrosis or resolution) depends on the functional diversity of macrophages and dendritic cells, but also on the balance between pro-inflammatory and anti-inflammatory T-cell populations. As reviewed here, tremendous progress has helped to understand the fine-tuning of immune responses in the liver from homeostasis to disease, indicating promising targets for future therapies in acute and chronic liver diseases. 

The Potential Role of Cellular Senescence in Non-Alcoholic Fatty Liver Disease

Cellular senescence is an irreversible cell cycle arrest implemented by the cell as a result of stressful insults. Characterized by phenotypic alterations, including secretome changes and genomic instability, senescence is capable of exerting both detrimental and beneficial processes. Accumulating evidence has shown that cellular senescence plays a relevant role in the occurrence and development of liver disease, as a mechanism to contain damage and promote regeneration, but also characterizing the onset and correlating with the extent of damage. 

Cellular senescence is also one of the main hallmarks of aging.37 Senescent cells appear to increase in number in a variety of aged mammalian tissues,38–42 either due to the accumulation of potentially deleterious mutations or due to the decline in senescence-clearing mechanisms with age.30,43 This persistence leads to local and systemic inflammation, procarcinogenic effects, and the emergence of a pernicious microenvironment that promotes further injury.15,43

A transient response (in which the senescent cells are rapidly cleared) promotes tissue regeneration, whereas persistent senescence can have devastating effects for the organism.

Deciphering the detailed interaction between NAFLD and cellular senescence will be essential to discover novel therapeutic targets preventing disease progression.