Carbon Tetrachloride Toxicity

Etiology

CCl4 toxicity develops not due to the CCl4 itself but for the generation of free radical CCl3 and other metabolites produced by cytochrome P450. Ultimately they lead to cellular damage by alteration of cellular structure through lipid peroxidation and in some other pathways. Severe conditions may develop through multiple organ dysfunction by these free radicles.[5]

Epidemiology

Database of 1990–93 CAREX from 15 countries of the European Union and the 1981–83 U.S National Occupational Exposure Survey states that approximately 70,000 workers in Europe and 10,0000 workers in the U.S potentially suffered exposure to CCl4. Most of the exposure occurs in chemical industries, in laboratories, and during degreasing operations. 

Pathophysiology

Carbon tetrachloride(CCl4) induced cellular damage may result from either covalent bond formation between reactive intermediates and cellular components or from enhanced lipid peroxidation triggered by free radical intermediates. It causes intracellular and intramembranous lipid destruction.

The break-down products such as reactive aldehydes lead to further damage like increased membrane permeability, which is one indicator of impending cell death. Free radical formation of CCl4 induced hepatotoxicity depends on the partial pressure of oxygen. CCl3* and CCl2* radicals form in low partial pressure that leads to covalent metabolite binding, which mostly affects the metabolism of lipids(decreased transport out of the hepatocyte, increased synthesis) and ultimately causes steatosis or fatty liver. In contrast, CCl3- OO* radical forms in high oxygen partial pressure with consequent lipid peroxidation that push the cell from steatosis to apoptosis. Hepatocyte protein synthesis is also suppressed by CCl4, which leads to loss of structural and functional integrity of cells. Another product of CCl4 metabolism is phosgene that might be another cause of hepatotoxicity.[6][7]

In the liver, the metabolism of CCl4 to other toxic metabolites is catalyzed by cytochrome P450, especially by its isoenzyme CYP2E1. This enzyme is also a part of the hepatic microsomal ethanol-oxidizing system (MEOS), which is involved in the hepatic metabolism of ethanol. Both of these enzymes are inducible by prolonged alcohol use, and even a single dose of alcohol may induce MEOS activity. That's why an alcoholic person develops severe manifestation if associated with CCl4 toxicity.[1][8][9][10]

The liver, kidneys, and lungs suffer damage in the majority of cases of CCl4 poisoning. Experimental CCl4 poisoning shows that the glycogen loaded hepatocyte is much more resistant to injury than one in which fatty infiltration is present, and glycogen becomes depleted. That is why chronic misusers of alcohol are prone to develop more significant symptoms of CCl4 induced hepatotoxicity because their liver cells have glycogen depletion and are full of fat. Pulmonary damage is constant when CCl4 is inhaled but not significant with the oral ingestion of CCl4.[11]

At the molecular level, CCl4 activates multiple factors, including tumor necrosis factor (TNF)α, transforming growth factors (TGF)-α and -ß in the cell, and nitric oxide (NO). These factors appear to direct the cell toward self-destruction or fibrosis. TNFα directs the cells toward apoptosis, whereas the TGFs directs the cells toward fibrosis.[12][13][14]

Histopathology

Significant histopathologic changes in the liver and kidneys are observable in fatal cases of CCl4 toxicity.[4]

• Hepatic findings: Larger hepatic lobules; centrilobular hemorrhage; centrilobular necrosis
• Renal findings: Hydropic degeneration of the proximal convoluted tubules

History and Physical

The toxicity of CCl4 is dangerous because of hepatotoxicity or nephrotoxicity that may develop with even small amounts such as cleaning a carpet in an apartment. Clinical presentation of CCl4 toxicity classifies into three phases.[1]

• Phase 1: Presenting symptoms in this phase include headaches and gastrointestinal symptoms such as vomiting, diarrhea, and colicky abdominal pain.

• Phase 2: This phase is a free interval where the patient has increasing liver tests without causing symptoms and is the most common. 

• Phase 3: This phase is rare; the patient develops overt liver disease, liver failure, respiratory insufficiency, cardiac arrhythmias, and renal insufficiency.

In the respiratory system, pronounced pulmonary edema develops that causes lungs to be voluminous and very heavy. The bronchus may also become filled with edematous fluid.[4]

Evaluation

CCl4 toxicity may cause abnormal liver function tests (LFT) such as increased aspartate transaminase (AST), alanine transaminase (ALT), and glutamate dehydrogenase (GDH); these depend on the route and duration of toxin uptake. The toxin is absorbed rapidly in a great amount through inhalation than ingestion. So, AST, ALT, and GDH may increase within a very short period if inhalation is the route of toxin absorption.[1][15]

Serum electrolytes and arterial blood gases (ABGs) require monitoring if the patient develops acute renal failure. In the early phase of acute renal failure, the patient may have hyperkalemia and hyperphosphatemia, whereas hypokalemia develops in the late phase. An ABG test reveals metabolic acidosis, which is due to the retention of acid.[11]

Intraluminal CCl4 on the intestinal tract may present on the X-ray abdomen. 

Treatment / Management

Multiple strategies may be useful in the treatment of CCl4 toxicity.[1][6][16][17](B3)

• Endotracheal intubation should take place before the intended gastrointestinal lavage after evaluation for the risk of aspiration.
• Toxin should be eliminated by gastrointestinal lavage in the intubated patient.
• CO2-induced hyperventilation therapy may be useful to accelerate toxin removal by exhalation and maintained up to the normalization of hepatic and renal parameters. 
• Central venous access should be a consideration.
• Intravenous cimetidine may be an option. It acts by inhibiting cytochrome P450, and subsequently diminishing CCl4 metabolism to other toxic metabolites.
• Intravenous glucose to downregulate cytochrome P450 to reduce CCl4 degradation is also a potential intervention.
• Electrolytes require correction according to the blood level.
• Furosemide may be used for forced diuresis to prevent renal failure.
• Clinicians may consider heparin to minimize the risk of disseminated intravascular coagulation (DIC).
• S-adenosylmethionine administration leading to increased glutathione level, which reduces the CCl4-induced liver damage.
• After discharge, the patient should follow absolute alcohol abstinence for three months.

Differential Diagnosis

Differential diagnosis of CCl4 toxicity may include:

• Acetaminophen toxicity
• Diethylnitrosamine toxicity
• Amanita phalloides toxicity
• Halothane toxicity
• Alcoholic fatty liver disease
• Non-alcoholic fatty liver disease

Prognosis

Patients who survive an acute CCl4 intoxication generally have a good prognosis without permanent injury. Patients with CCl4 toxicity may have different outcomes, such as fatty degeneration on the short to the mid-term time scale, whereas fibrosis, cirrhosis, and cancer on the long-term scale. Prognosis depends on the early use of antioxidants or medications that counteract collagen deposition. Finally, it bears mentioning that prognosis also depends on the age of the patients as young individuals are less sensitive to CCl4 toxicity.[12][18]

Complications

Several complications may develop in patients with CCl4 toxicity:

• Fatty liver
• Acute liver failure
• Hepatic fibrosis
• Liver cirrhosis
• Liver tumor
• Acute renal failure
• Disseminated intravascular coagulation
• Respiratory insufficiency
• Cardiac arrhythmias